CISPLATIN A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES
J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS
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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright 2004 by ICON Group International, Inc. Copyright 2004 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1
Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Cisplatin: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-497-00262-0 1. Cisplatin-Popular works. I. Title.
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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.
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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on cisplatin. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.
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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.
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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes&Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health
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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON CISPLATIN ................................................................................................. 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Cisplatin........................................................................................ 6 E-Journals: PubMed Central ....................................................................................................... 63 The National Library of Medicine: PubMed ................................................................................ 66 CHAPTER 2. NUTRITION AND CISPLATIN ..................................................................................... 107 Overview.................................................................................................................................... 107 Finding Nutrition Studies on Cisplatin .................................................................................... 107 Federal Resources on Nutrition ................................................................................................. 110 Additional Web Resources ......................................................................................................... 110 CHAPTER 3. ALTERNATIVE MEDICINE AND CISPLATIN ............................................................... 113 Overview.................................................................................................................................... 113 National Center for Complementary and Alternative Medicine................................................ 113 Additional Web Resources ......................................................................................................... 138 General References ..................................................................................................................... 140 CHAPTER 4. DISSERTATIONS ON CISPLATIN ................................................................................. 143 Overview.................................................................................................................................... 143 Dissertations on Cisplatin ......................................................................................................... 143 Keeping Current ........................................................................................................................ 144 CHAPTER 5. PATENTS ON CISPLATIN............................................................................................ 145 Overview.................................................................................................................................... 145 Patents on Cisplatin................................................................................................................... 145 Patent Applications on Cisplatin............................................................................................... 164 Keeping Current ........................................................................................................................ 175 CHAPTER 6. BOOKS ON CISPLATIN ............................................................................................... 177 Overview.................................................................................................................................... 177 Book Summaries: Federal Agencies............................................................................................ 177 Book Summaries: Online Booksellers......................................................................................... 178 Chapters on Cisplatin ................................................................................................................ 178 CHAPTER 7. PERIODICALS AND NEWS ON CISPLATIN.................................................................. 181 Overview.................................................................................................................................... 181 News Services and Press Releases.............................................................................................. 181 Academic Periodicals covering Cisplatin ................................................................................... 183 CHAPTER 8. RESEARCHING MEDICATIONS .................................................................................. 185 Overview.................................................................................................................................... 185 U.S. Pharmacopeia..................................................................................................................... 185 Commercial Databases ............................................................................................................... 186 Researching Orphan Drugs ....................................................................................................... 186 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 191 Overview.................................................................................................................................... 191 NIH Guidelines.......................................................................................................................... 191 NIH Databases........................................................................................................................... 193 Other Commercial Databases..................................................................................................... 195 APPENDIX B. PATIENT RESOURCES ............................................................................................... 197 Overview.................................................................................................................................... 197 Patient Guideline Sources.......................................................................................................... 197 Finding Associations.................................................................................................................. 199 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 201 Overview.................................................................................................................................... 201
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Preparation................................................................................................................................. 201 Finding a Local Medical Library................................................................................................ 201 Medical Libraries in the U.S. and Canada ................................................................................. 201 ONLINE GLOSSARIES................................................................................................................ 207 Online Dictionary Directories ................................................................................................... 207 CISPLATIN DICTIONARY ......................................................................................................... 209 INDEX .............................................................................................................................................. 287
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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with cisplatin is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about cisplatin, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to cisplatin, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on cisplatin. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to cisplatin, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on cisplatin. The Editors
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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.
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CHAPTER 1. STUDIES ON CISPLATIN Overview In this chapter, we will show you how to locate peer-reviewed references and studies on cisplatin.
The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and cisplatin, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “cisplatin” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •
Metoclopramide: A Dopamine Receptor Antagonist Source: American Family Physician. 41(3): 919-924. March 1990. Summary: This article discusses metoclopramide, a dopamine receptor antagonist with unique properties of increasing lower esophageal sphincter pressure and increasing the rate of gastric emptying. These gastrointestinal motility actions are useful in the treatment of diabetic gastroparesis and severe gastroesophageal reflux and in postoperative situations involving visceral atony. The author covers the chemistry, pharmacology, clinical uses, adverse reactions, and drug interactions of metoclopramide. Metoclopramide is a useful adjunctive drug for intestinal intubation and radiologic examination. It has also been used intravenously to control the nausea and vomiting of intensive cancer chemotherapy, such as with cisplatin. Intravenous metoclopramide is generally not intended for long-term use. The most common adverse
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reactions are restlessness, drowsiness, fatigue, and lassitude. 3 tables. 35 references. (AA-M). •
Ototoxicity and Irradiation: Additional Etiologies of Hearing Loss in Adults Source: Journal of the American Academy of Audiology. 6(5): 351-357. September 1995. Summary: This article offers a brief review of the effects of the seven groups of substances and chemicals known to affect hearing and the vestibular system, followed by a more detailed discussion of cisplatin (cisplatinum). The authors provide an illustrative case study that exemplifies a recent finding of some recovery of hearing, following withdrawal of cisplatin chemotherapy. Some suggestions for reducing the potential for ototoxicity are also presented. The authors continue with a discussion of the effects of irradiation on hearing and the ear and they provide an illustrative case study. Included are some reported results from patients in the Ukraine who were exposed to excessive radiation as a result of the Chernobyl nuclear disaster. The authors also discuss the effects on the ear and vestibular system caused by the interaction between chemotherapy and irradiation treatment. The authors caution that due to recent successes of these treatments in fighting cancer, more patients with hearing loss triggered by these techniques will be seen in audiology clinics. 5 tables. 22 references. (AA-M).
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Prognostic Factors in Major Salivary Gland Cancer Source: Laryngoscope. 111(8): 1434-1439. August 2001. Contact: Available from Lippincott, Williams, and Wilkins. 530 Walnut Street, Philadelphia, PA 19106-3621. (215) 521-8300. Fax (215) 521-8902. Website: www.lww.com. Summary: This article reports on a study undertaken to identify features of major salivary gland cancers that are prognostic for disease free survival. The retrospective study included 78 patients with major salivary gland cancer (64 parotid and 14 submandibular, under the lower jaw, gland) who underwent surgery for definitive treatment from 1976 to 1996. A select group of patients also received adjuvant radiation (56 percent) and or chemotherapy (13 percent). Clinical and pathological risk factors were obtained from patients' charts and pathology reports. In this series, the 5 year disease free survival was 65 percent. Examining clinical and histologic features one at a time, the authors found poorer prognosis was associated with submandibular tumors compared with parotid, higher T stage, positive cervical (neck) nodes, perineural invasion, and high grade or adenoid cystic tumors. A multivariable analysis indicated that positive lymph nodes and perineural invasion were important histologic predictors of shorter disease free survival. Receipt of both adjuvant radiation and cisplatin based chemotherapy was an independent predictor of longer disease free survival. The authors conclude that the presence of positive lymph nodes and perineural invasion are important independent predictors of disease free survival. Adjuvant chemotherapy and radiation therapy may improve disease free survival. 2 figures. 5 tables. 23 references.
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Drug-Induced Hearing Loss: How It Can Be Prevented Source: Hearing Loss. 20(3): 14-18. May-June 1998. Contact: Available from Self Help for Hard of Hearing People, Inc. (SHHH). 7910 Woodmont Avenue, Suite 1200, Bethesda, MD 20814. Voice (301) 657-2248; TTY (301) 657-2249; Fax (301) 913-9413; E-mail:
[email protected]; http://www.shhh.org.
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Summary: This article reviews drug-induced hearing loss and how it can be prevented. After an introductory section that outlines ototoxicity and other threats to hearing (from noise and heavy metals), the bulk of the article focuses on aminoglycoside antibiotics and their effect on hearing. Hearing loss is generally observed only when these drugs are administered over a long period of time. However, risk factors that can activate the ototoxic potential of these drugs include genetic predisposition, advanced age, impaired kidney function, poor nutrition, noise exposure, pre-existing disorders of hearing or balance, and administration of diuretics together with aminoglycosides. In addition, aminoglycoside-induced loss of balance may occur with or without accompanying hearing loss. Iron chelators (medications used to soak up excess iron in the bloodstream) have now been shown to prevent these toxic side effects of aminoglycosides. If clinical trials show that iron chelators work as well in humans as they do in animals, this research will lead to a safe and inexpensive way to eliminate the threat of hearing loss to future patients treated with antibiotics. The article concludes with a brief discussion of other ototoxic drugs, notably cisplatin, a drug used for cancer chemotherapy. 1 figure. 1 table. •
Ototoxicity: Mechanisms, Protective Agents, and Monitoring Source: Current Opinion in Otolaryngology and Head and Neck Surgery. 8(5): 436-440. October 2000. Contact: Available from Lippincott Williams and Wilkins. 12107 Insurance Way, Hagerstown, MD 21740. (800) 637-3030. Fax (301) 824-7390. Website: www.lww.com. Summary: This article reviews recent progress in determining the mechanisms of ototoxicity (toxic effects of drugs on the ear) but also in finding otoprotective agents. For aminoglycosides, new dosing protocols and protective agents, including growth factors and salicylates, show promise for eventually reducing ototoxicity. Further evidence of genetic susceptibility has been published. For chemotherapeutic (cancer drugs, in the majority) agents, further evidence of oxidative damage and ion channel blockade mechanisms reinforces earlier work. Protective agents for cisplatin induced ototoxity have been further investigated and include antioxidants and metal binders. Protection has been demonstrated not only for the organ of Corti but also for the stria vascularis. For audiologic monitoring of ototoxicity, new methods of collecting and interpreting high frequency audiometry, auditory brainstem responses (ABR), and otoacoustic emissions (OAEs) have been proposed to enhance early detection. High frequency audiometry has also been proposed to monitor industrial solvent exposure. 24 references (6 annotated).
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Ototoxicity and Antineoplastic Drugs Source: Current Opinion in Otolaryngology and Head and Neck Surgery. 7(5): 239-243. October 1999. Summary: This article reviews recent research dealing with the ototoxicity (ear or hearing damage) of chemotherapeutic agents. Recent experimental studies suggest that platinum based chemotherapy may damage the cochlea through the generation of reactive oxygen species. These reactive compounds could then cause extensive damage to the hair cells of the cochlea. New risk factors have been identified in patients receiving chemotherapy with cisplatin and or carboplatin. The author notes that previous noise exposure may also result in an increased risk for cisplatin ototoxicity. The author also reviews future strategies to reduce of prevent hearing loss from these chemotherapeutic agents. 15 references (6 annotated).
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Federally Funded Research on Cisplatin The U.S. Government supports a variety of research studies relating to cisplatin. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to cisplatin. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore cisplatin. The following is typical of the type of information found when searching the CRISP database for cisplatin: •
Project Title: ADENOVIRUS BASED P53 GENE THERAPY FOR OVARIAN CANCER Principal Investigator & Institution: Mathis, J Michael.; Cell Biology and Anatomy; Louisiana State Univ Hsc Shreveport P. O. Box 33932 Shreveport, La 71103 Timing: Fiscal Year 2002; Project Start 08-DEC-1998; Project End 30-NOV-2003 Summary: (Applicant's Abstract) The goal of this application is to develop a preclinical therapeutic model of ovarian cancer involving an adenovirus-based vector encoding the human p53 tumor suppressor gene. This application involves the introduction of a gene that has direct tumor cytotoxicity or indirect tumor growth inhibitory function (through a phenomenon termed the "bystander effect"), or potentially both. The applicant has demonstrated the efficacy of gene therapy in vivo using an adenovirus vector for the transfer of biologically active p53 into ovarian cancer cells. The goal of this project is to further define the following five aspects of adenovirus-based p53 gene therapy in the treatment of ovarian cancer. First, while p53 gene therapy has shown efficacy in a microscopic disease model, the applicant plans to determine whether this treatment will be effective in the presence of larger tumor volumes that more closely model human ovarian cancer. Second, because mutant p53 protein can inhibit wild type p53 function, he plans to investigate the role of specific endogenous p53 mutations on the response to adenovirus-based p53 gene therapy. These results may allow him to predict patient response to p53 gene therapy. Third, he will determine the mechanisms by which p53 acts to inhibit tumor growth in G2. It is well documented that introduction of cancer cell lines with wild-type p53 results in a G1 arrest. However, he has recently observed that certain cells arrest at the G2/M checkpoint. The arrest of cells during DNA synthesis and replication after DNA damage is thought to provide the cell with sufficient time to repair the damage before progression through the cell cycle. Fourth, because p53 has been shown to re-sensitize chemo- resistant cells to alkylating agents, he plans to determine the effectiveness of adenovirus-based p53 gene therapy alone or in combination with cisplatin therapy. Finally, some data suggest that wild-type p53 regulates a balance of potent angiogenic and anti- angiogenic factors. Thus, he plans to
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Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).
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investigate the bystander effect of adenovirus-based p53 gene therapy on tumor angiogenesis. In this application, he intends to take the first steps toward the translation of promising preliminary data on an adenovirus-based cancer gene therapeutic model system into practical and scientifically based human trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ANTICANCER DICTYOSTELIUM
DRUG
RESISTANCE
STUDIES
USING
Principal Investigator & Institution: Alexander, Stephen; Associate Professor; Biological Sciences; University of Missouri Columbia 310 Jesse Hall Columbia, Mo 65211 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2004 Summary: Human tumors frequently develop resistance to many of the widely used chemotherapeutic agents. Many different mechanisms have been proposed for the molecular basis of this resistance. Studies on drug resistance in tumor cells have often focused on the mechanism of action of the drug, and looked for resistance due to altered drug concentration in the cell, different models of drug inactivation or altered damage repair. As such, other pathways that may be involved with the cellular cytotoxic response to individual drugs have been overlooked. We propose to use the cellular slime mold Dictyostelium discoideum in an unbiased approach to identify novel molecular targets that can be modulated to increase sensitivity of tumor cells to chemotherapeutic drugs. The genes and pathways of Dictyostelium are highly conserved with those of humans, and molecular genetic methods are well developed for this organism. Our preliminary system on cisplatin resistance resulted in the identification of 6 genes. Significantly, none of these had been previously associated with cisplatin, and each represents a potential new target for therapy. The goal of the present study is to demonstrate the general utility of this system and to show that it can be applied to the understanding of resistance to other drugs. We have focused on four classes of DNA damaging drugs that damage DNA by different mechanisms. These include: both intra- and inter-strand crosslinkers, monoalkylators, and oxygen radicals. We will 1) create a comprehensive Dictyostelium insertional mutant library, 2) isolate mutants resistant to drugs of each of the four classes and identify the cognate genes, and 3) test the mutants for cross-resistance to the other drugs. These studies will identify new mechanisms for drug resistance and new targets for chemotherapeutic intervention which can subsequently be validated in human cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ANTIOXIDANT INVOLVEMENT IN NOISE INDUCED HEARING LOSS Principal Investigator & Institution: Henderson, Donald; Professor and Chairman; State University of New York at Buffalo Suite 211 Ub Commons Buffalo, Ny 14228 Timing: Fiscal Year 2002; Project Start 01-JAN-2002; Project End 31-DEC-2002 Summary: This research focuses on the relation between the cochlea's antioxidant system and resistance to noise or carboplatin. The project is a logical extension of previous research in our lab that showed (1) the ear could acquire resistance to noise by prior exposure to benign moderate level noise; (2) the antioxidant enzymes catalase, glutathione reductase and gamma-glutamyl cysteine synthtase (GCS) are increased in concentration in both stria and organ of Corti after prophylactic noise exposures; (3) the degree of temporary and permanent hearing loss as well as hair loss from exposures to a traumatic noise could be reduced by prior treatment of R- phenylisopropyladenoisine
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(R-PIA). Collectively, these results suggest that high level noise exposures produce hearing loss by the mechanism of reactive oxygen intermediates (ROI) cytotoxicity and that prophylactic noise exposures, as well as intervention by R-PIA, can reduce both the effects of noise and cisplatin (Ryback et al., 1995). The proposed set of experiments has four specific aims: (1) What is the relation between glutathione related enzymes (specifically GCS), and susceptibility to noise? (2) Can the susceptibility to noiseinduced hearing loss be decreased with drugs that up-regulate GCS or increased with drugs that suppress GCS? (3) What is the normal anatomical distribution of glutathione (GSH) and does it change with exposure to noise? (4) Is the otoxicity of carboplatin influenced by drugs that up-regulate or down- regulate the antioxidant system? These experiments will be conducted on chinchillas. Hearing functions will be measured by evoked potentials and otoacoustic emissions. GCS levels will be assessed by our collaborator Dr. Howard Steinman at Albert Einstein College of Medicine. Cochlear analysis will include cell counts from surface preparations and confocal studies of GSH distribution. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: APOPTOTIC PATHWAY DEFECTS IN NEUROBLASTOMA Principal Investigator & Institution: Kidd, Vincent J.; Professor; St. Jude Children's Research Hospital Memphis, Tn 381052794 Timing: Fiscal Year 2003; Project Start 15-JUL-1995; Project End 31-DEC-2007 Summary: (provided by applicant): Late stage neuroblastoma tumors, particularly those with amplified MYCN genes, have a poor prognosis, primarily due to their ability to survive treatment with multiple chemotherapeutic agents/irradiation. The continuing goal of this research program is to understand how genetic alterations, such as MYCN gene amplification and chromosome lp36 loss-of-heterozygosity (LOH), contribute to this tumor phenotype. During the last funding period we found that a critical apoptotic signaling molecule, caspase-8, is preferentially silenced by methylation in >60% of the stage 4 neuroblastoma patient tumors with simplified MYCN, whereas <4% of those stage 1-4 tumors without amplified MYCN silence expression of the CASP8 gene. A similar observation has now been made in N-Myc-induced neuroblastoma tumors from mice. We also found that reprogramed expression of caspase-8 in human NB cells that are normally caspase-8 null resensitized them to apoptosis induced by the chemotherapeutic drugs doxorubicin and cisplatin. This was observed in both cell culture and in vivo xenograft mouse models. Finally, we have reported, as have others, that caspase-8 is capable of functioning as both an initiator and executioner caspase, allowing it to amplify certain mitochondrial-mediated cell death signals. This function is somewhat unique among the caspases identified thus far, and could be one reason it is selectively silenced in certain tumors. Based upon this data we hypothesize that the silencing of CASP8 by methylation may provide a more permissive cellular environment that can tolerate the overexpression of N-Myc without undergoing cell death, and perhaps contribute to the ability of these tumor cells to survive treatment with certain chemotherapeutic drugs. To test this hypothesis we propose to develop mouse models by gene knockout or transgenic expression of an inactive, dominant negative form of caspase-8 that either totally eliminate, or down-regulate enzyme activity, and determine whether it contributes to accelerated tumor cell growth in the presence of N-Myc overexpression or the response of these tumors to chemotherapeutic drugs. These experiments will include the use of complementary approaches; namely the induction of oncogenes such as MYCN in cultured neural crest cells isolated from these mice, as well as the response of the various cells, xenografts, and in vivo tumors to
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therapy. Finally, we will examine these different mouse NB tumors and normal adrenal gland tissue, as well as human patient samples of various stages and matchedtreated/untreated samples by microarray analysis to identify possible genes, other than CASP8, whose expression is significantly altered by N-Myc overexpression and/or drug treatment. Such studies will provide significant insight into how these tumor cells circumvent apoptosis and prolong their life. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ATM, P53, GADD45 AND P21 EFFECTS ON RECOMBINATION Principal Investigator & Institution: Schiestl, Robert H.; Professor of Pathologyi; Pathology; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 01-JUN-1999; Project End 31-MAY-2004 Summary: DNA lesions such as double-stranded breaks (DSBs), DNA adducts and DNA strand cross links cause cancer. Such lesions may result in cell cycle arrest and if repairable, initiate repair reactions including recombination which may lead to genomic rearrangements. The following genes may be involved in DNA damage detection or processing and executing cellular responses. ATM may signal the presence of DNA damage, p53 activates transcription of p21 and Gadd45, which are involved in cell cycle arrest, stopping DNA synthesis in response to the damage and in coordinating repair reactions. Mouse models lacking these genes have been developed. Genome rearrangements such as deletions are associated with carcinogenesis. We have previously shown that X-rays, benzo(a)pyrene (B(a)P) and cisplatin cause DNA DSBs, DNA adducts and DNA cross links respectively increase the frequency of deletions between repeated DNA sequences in the mouse genome. Disruption of the p gene by a DNA duplication, the p/un mutation, results in a diluted coat color and pink eyes. The reversion of this duplication to wildtype in the embryo results in black spots on the fur and the retinal pigment epithelium in the eyes. We have previously shown p53 is involved in X-ray but not in B(a)P induced p/un reversions. Furthermore, X-rays but not B(a)P acts in a p53 independent manner. X-rays induce p53 in an ATM dependent way and in contrast, cisplatin induces p53 in an ATM independent way. These carcinogens will be used to dissect the ATM/p53/p21/Gadd45 DNA damage recognition and repair in mouse embryos. These data will be correlated with induction profiles of these gene products induced by the carcinogenesis in embryos. It has also been proposed that oxidative stress plays a role in the pathogenesis of AT. We propose to determine whether oxidative stress is involved in any different responses of ATM mice to ionizing radiation and we will determine whether nutritional factors such as pro-oxidants and anti-oxidants have any effect on such oxidative stress parameters. If the frequency of deletions in ATM deficient mice can be reduced by exposure to antioxidants this may indicate that oxidative stress may at least partially be responsible for the high incidence of carcinogenesis which in turn may raise the possibility of intervention with nutritional antioxidants. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: BALANCING SURVIVAL AND OTOTOXICITY IN CISPLATIN THERAPY Principal Investigator & Institution: Li, Yuelin; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 191044399 Timing: Fiscal Year 2002; Project Start 15-FEB-2001; Project End 31-JAN-2004
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Summary: (from applicant's abstract): Evaluating the tradeoffs between patient survival and treatment toxicity has been, and always will be, a major challenge to clinicians. Treatment options that improve the Disease Free Survival (DFS) rate are often accompanied by increased side effects whereas options with lower DFS rates are usually less toxic. The administration of Cisplatin to pediatric germ cell tumor patients entails a tradeoff between mortality and ototoxicity. Increasing the dose of Cisplatin from 100mg to 200mg raises the DFS rate from 82% to 92%, yet also results in an increased incidence of permanent hearing loss, from 20% to 76%. The primary goal of this project is to evaluate whether the increase in cancer survival is worth the increased risk of suffering the functional impacts of Cisplatin ototoxicity. The project will proceed in four sequential aims: (1) To understand the hearing impairments due to alternative Cisplatin dosages. Data available from a recent (unpublished) CCG protocol will be used for finding a probability distribution of hearing deficits as a function of dosage. (2) To study the Quality of Life (QOL) consequences and construct health vignettes for decision analysis. Specific hearing deficits will be mapped onto their corresponding patient functional states. This summarizes the real-life difficulties as a result of hearing loss from Cisplatin treatment. Functional status of the child will be assessed by validated inventories from parental ratings and child self-assessments (N = 60). (3) To elicit parental utilities on hearing vignettes constructed from functional results. Using the Standard Gamble and an analog rating scale, five groups of parents will be asked to assign utilities to various hearing vignettes constructed from aim 2 (N = 20 per group). Group differences will be compared. (4) Finally, to perform decision and sensitivity analyses to determine the normative Cisplatin dosage. Preliminary recommendations will be made involving the use of high dose Cisplatin in pediatric germ cell patients. A Markov model is proposed, which extends the time horizon of the analysis and considers hearing deterioration, cancer relapse, second cancer, pediatric cancer, late effects in other organ systems, and additional functional deficits due to salvage regimes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BIOCHEMICAL EFFECTS OF DISRUPTING HSP90 Principal Investigator & Institution: Erlichman, Charles; Consultant/Associate Director Trnslation; Mayo Clinic Coll of Medicine, Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2005 Summary: (provided by applicant): Heat shock protein 90 (HSP90) is a chaperone protein critical in the function of transcription factors, serine/threonine, and tyrosine kinases involved in tumor cell signaling. Geldanamycin (GA), an ansamycin benziquinone, binds HSP90 and disrupts its function. HSP90 is being targeted clinically with the analog of GA, 1 7-aHyl-aminogedanamycin (17AAG). Efforts from the applicant's laboratory are directed towards understanding the mechanisms of resistance to GA and 17AAG, biochemically characterizing the role HSP90 co-chaperone and HSP9O client proteins in GA cell killing, and identifying chemotherapeutic agents that can be combined with GA or 17AAG to yield additive or synergistic toxicity in tumor cells without increasing toxicity to normal tissue. Preliminary results demonstrate a 100fold variation in tumor cell sensitivity to GA in a colony-forming assay that is correlated with inhibition of binding of the co-chaperone p23 to HSP90, decreased intracellular concentrations of GA, and increased levels of the co-chaperone HDJ2. Further studies have shown that there is a synergistic cytotoxicity when GA has been combined with cisplatin or with gemcitabine (gem) in a sequence dependent manner. Based on these preliminary results we propose to: 1) Investigate the mechanism of tumor cell resistance to GA. HSP90 complex formation, co-chaperone and client protein levels will be
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measured to identify which elements of the complex are critical for GA resistance. In addition, the role of cytochrome P450 isozymes NQO1 expression in GA resistance will be determined. 2) Determine the mechanism of synergy between GA and cisplatin. The effect of cisplatin on HSP90 function and the impact of GA on platinum-DNA adducts formation and removal will be determined. Further studies to establish the effect of GA and cisplatin on client proteins that control cell proliferation will be performed. 3) Determine the mechanism of synergy between GA and gem. The effect of gem on HSP90 function and the impact of GA on gem metabolism will be assessed. Additional experiments to explore the effect of GA and gem on client proteins that control cell proliferation will be performed. Together, results from these studies will provide a better understanding of GA mechanism of action alone and in combination with chemotherapeutic agents, identify the factors that affect sensitivity to this class of agents and will provide a rational basis for further clinical trials incorporating these agents into combination chemotherapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BIOLOGY OF CHK2 KINASE IN LUNG CANCER Principal Investigator & Institution: Zhang, Peilin; Assistant Professor; Pathology; West Virginia University P. O. Box 6845 Morgantown, Wv 265066845 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2006 Summary: (provided by applicant): Maintenance of genetic integrity is essential for normal cells to ensure the error-free DNA replication and cell proliferation. In response to DNA damage agents, such as ionizing radiation, ultraviolet radiation and chemical compounds, a cellular mechanism is developed to protect the genetic integrity. This DNA damage signaling pathway is initiated by ATM kinase, a gene mutated in a rare genetic disease ataxia telangiectasia (AT). Activated ATM kinase leads to three major cellular events, cell cycle arrest, DNA damage repair and apoptosis. An immediate ATM downstream target, CHK2, plays a critical role in cell cycle checkpoint regulation and DNA damage induced apoptosis. CHK2 is a tumor suppressor and the germline mutation of CHK2 was found in a subset of familial genetic cancer syndrome, LiFraumeni Syndrome, in which p53 tumor suppressor is mutated in majority of the patients. We have detected the absence of CHK2 protein expression within the nonsmall cell lung cancer cell lines, and the absence of CHK2 protein expression is due to the absent expression of CHK2 mRNA. We have also demonstrated that under normal conditions, CHK2 is diminished in response to DNA damage agent cisplatin. We propose to determine the CHK2 expression levels in the tumor specimens from the lung cancer patients. We will study the molecular mechanism underlying the absence of CHK2 protein within the non-small cell lung cancer cell lines with particular emphasis of CHK2 promoter methylation and regulation of transcription. We will study the functional significance of re-introduction of CHK2 kinase into the lung cancer cells in relation to its sensitivity to DNA damage agents such as cisplatin and ionizing radiation. CHK2 null cells and the mice show remarkable resistance to DNA damage induced apoptosis, which bears significant similarity to clinical behavior of non-small cell lung cancer to DNA damage based therapy. The study of the molecular mechanism of the absent expression of CHK2 kinase in non-small cell lung cancer will not only greatly enhance the understanding of CHK2 function and cell cycle regulation, but also provide insight that potentially represent a new target for drug development for nonsmall cell lung cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: BRYOSTATIN IN COMBINATION W/ CISPLATIN IN CANCER PATIENTS Principal Investigator & Institution: Lenz, Heinz Josef.; Associate Professor; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2002; Project Start 01-DEC-2001; Project End 30-NOV-2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CANCER AND LEUKEMIA GROUP B--PET COMMITTEE Principal Investigator & Institution: Ratain, Mark J.; Professor of Medicine and Chairman; Medicine; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2002; Project Start 01-APR-1986; Project End 31-MAR-2003 Summary: (Adapted from the applicant's abstract): The overall objectives for the Pharmacology and Experimental Therapeutics (PET) Committee of the CALGB are to study population pharmacokinetics and pharmacodynamics of new and established anticancer agents in a multi-institutional setting; to introduce new drugs and combinations, including immunomodulatory and cytostatic agents into the CALGB for eventual phase II and III testing; to initiate and conduct a program of mucositis prevention in the CALGB; and to organize educational symposia for the Group on topics in cancer pharmacology and experimental therapeutics. The committee meets twice annually in addition to sponsoring an educational session at each of the full Group meetings. Population pharmacology are ongoing of suramin, carboplatin, paclitaxel, 9aminocamptothecin, 5-fluorouracil and etoposide. Studies are planned of irinotecan and docetaxel, in addition to two additional studies of paclitaxel with regard to the effects of age and body surface on toxicity and pharmacokinetics, Other special populations to be studied include race (docetaxel and irinotecan) and end-organ dysfunction (gemcitabine, irinotecan). Two novel therapeutic studies involving biologics are planned, including IL-2 in combination with an anti-HER-2 monoclonal antibody and interferon alpha in combination with tamoxifen. Another new initiative is a program to prevent mucositis. The initial study will evaluate the effect of IL-11 on mucositis secondary to cisplatin, 5-FU and leucovorin. Since many of the studies include analysis of pharmacological specimens, the Committee utilizes three core laboratories--at the University of Chicago, the University of Maryland and the University of Tennessee. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CARDIOVASCULAR RISK IN TESTICULAR CANCER SURVIVORS Principal Investigator & Institution: Vaughn, David J.; Member; Cancer Center; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2003; Project Start 29-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant): Testicular cancer (TC) is the most common solid tumor diagnosed among men aged 20 - 35 years, and TC survivors treated with cisplatin-based chemotherapy may be at increased risk for the premature development of cardiovascular risk factors and early cardiovascular events. Although cardiovascular risk may be indexed through objective measures of subclinical atherosclerosis, behavioral risk factors may moderate the overall risk of cardiovascular events and serve as the targets for future interventions aimed at reducing risk. However, definitive data regarding the cardiovascular risk proffered by cisplatin-based chemotherapy are not available and neither the degree to which TC survivors exhibit behavioral risk factors
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nor whether these behavioral factors moderate cardiovascular risk among individuals treated with cisplatin-based chemotherapy is known. The specific aims of this exploratory project are two-fold: 1) To establish the relationship between receipt of cisplatin-based chemotherapy and subclinical atherosclerosis among TC survivors using non-invasive studies; and 2) To describe the health and risk behaviors of TC survivors and determine the relationship between these behaviors, receipt of cisplatin-based chemotherapy and subclinical atherosclerosis among TC survivors. To address these aims, TC survivors will be surveyed regarding health and risk behaviors in Stage I to generate 30 TC survivors who received cisplatin-based chemotherapy and 30 chemotherapy-naive controls for study in Phase I1.Subjects in Stage II will undergo clinical evaluation that includes a TC patient questionnaire, physical examination, and standard laboratory measures (e.g., lipid analysis) and will complete valid, reliable selfreport assessments concerning cardiovascular risk-related lifestyle characteristics and health behaviors. Objective measure of subclinical atherosclerosis will be associated with lifestyle characteristics. This study will provide the framework for future studies examining cardiovascular risk reduction through physiological and behavioral interventions in TC survivors that received cisplatin-based chemotherapy. This study will also provide valuable data in a program of research with TC patients and survivors. The ultimate goal of this exploratory grant is to develop an intervention project aimed at reducing cardiovascular risk among TC survivors. However, prior to initiating an intervention study, these parameters need to be explicated. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CHEMISTRY AND BIOLOGY OF PLATINUM ANTICANCER DRUGS Principal Investigator & Institution: Lippard, Stephen J.; Professor of Chemistry; Chemistry; Massachusetts Institute of Technology Room E19-750 Cambridge, Ma 02139 Timing: Fiscal Year 2002; Project Start 01-JAN-1983; Project End 31-DEC-2004 Summary: The long-term goal of this research is to elucidate the mechanism of action of cis-diammineddichloroplatinum (II), cis-DDP or cisplatin, a leading anti-cancer drug used to treat testicular tumors and a paradigm for successful chemotherapy. The major underlying hypothesis is that the biological activity derives from the formation and persistence of cisplatin- DNA adducts, mainly 1,2-intrastrand d(GpG) and d(ApG) cross-links. Geometric information about these adducts in several of 16 possible N1GGN2 and N11AGN2 sequence contexts and their binding to cellular proteins will be provided. Novel synthetic routes to site-specifically platinated duplex DNAs are presented as well as thermodynamic, kinetic, and NMR and X-ray structural methods for characterizing their complexes with proteins. Among proteins that bind specifically major cisplatin-DNA adducts and affect cellular processing are those containing highmobility group (HMG) domains. HMG domain proteins shield platinum adducts from nucleotide excision repair (NER) and help elongate transcripts from chromatin. The ability of cisplatin-DNA intrastrand cross-links to be excised by NER and to block transcription will be investigated with reconstituted in vitro assays. Probes containing specific adducts and strategically placed photocross-linking agents will be introduced to identify factors contacting platinated DNA. Extracts from tumor and normal testis tissue from a new breed of mice that develops testicular cancer will be prepared for NER studies to test the hypothesis that poor repair of cisplatin adducts underlies its selective toxicity. Parallel work will be performed with cultured human testis cell. The (TTAGGG)n repeating sequence in human telomeres is a likely target for cisplatin. We shall investigate telomere length maintenance as a contributing factor to the cisplatin molecular mechanism by studying the platination of this sequence in duplex DNAs. The
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effect of cisplatin on telomere binding proteins (TBPs) such as TRF1 and TRF2 will be studied in cells or in situ immunofluorescence techniques. In vitro binding of TBPs to probes with embedded site-specifically platinated telomere sequences will also be examined. An additional aim, to improve the selective binding of HMG-domain proteins to cisplatin 1,2-cross-links, will be met by site-directed mutagenesis based on a recent structure of a complex between HMG1 domain A and a platinated 16-mer duplex. Phage display will provide additional peptides selected for their strong binding to cis0platin-cross-links. These protein constructs will be over- expressed in mammalian cells to evaluate whether they affect cisplatin sensitivity, ultimately for combined chemotherapy/gene therapy applications in human cancer. With a newly devised transcription inhibition assay have a fast fluorescent readout, combinatorial libraries of platinum compounds will be screened for anti-cancer drug candidates. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CHEMOTHERAPY AND ANTI-EGFR ANTIBODY C225 IN LUNG CANCER Principal Investigator & Institution: Perez-Soler, Roman; Chairman, Department of Oncology; Molecular Pharmacology; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2002; Project Start 28-SEP-2001; Project End 31-AUG-2005 Summary: There is strong experimental evidence that the epidermal growth factor receptor (EGFR) signal transduction pathway plays an important role as a cell survival mechanism and to sustain the growth of certain epithelial malignancies. EGFR is overexpressed in about 60 percent of non-small cell lung cancer (NSCLC) tumors. C225 is a humanized monoclonal antibody that specifically inhibits EGFR function by competing with EGF for binding to EGFR, thus resulting in cell growth inhibition. C225 has been shown to specifically sensitize tumors expressing EGFR to the effects of a variety of cytotoxic agents in in vivo experimental systems. There is also now emerging clinical evidence that C225 can sensitize cisplatin-resistant head and neck tumors to cisplatin. Neoadjuvant chemotherapy followed by surgical resection has been shown to improve the survival of patients with stage IIIA NSCLC in three separate randomized trials. However, the pathological complete remission rate with the regimens used ranges between 5 and 11 percent. It is reasonable to assume that a neoadjuvant regimen that would result in a higher rate of pathological complete response would further improve the survival of these patients. In this proposal, we will test the hypothesis that C225 synergizes with taxanes and platinum drugs in NSCLC tumors that have an activated EGFR signal transduction pathway. For that purpose: 1) we will study the antitumor activity of taxane/platinum +/- C225 in a series of human NSCLC heterotransplants in nude mice and will identify the molecular, determinants of synergism; and 2) we will conduct a Phase II clinical study of neoadjuvant taxane/platinum + C225 in patients with stage IIIA NSCLC tumors using a 20 percent pathological complete response as primary endpoint. Entry criteria for the clinical study will include tumors expressing the molecular determinants of synergism identified under number 1. In the context of the clinical study, we will correlate the degree of pathological response with the pre- and post-therapy EGFR activation status of the tumors. The results of the studies proposed will indicate the potential of this combination in the treatment of NSCLC, identify the specific subsets of tumors that are more likely to respond to this combination, and eventually justify the definitive testing of the hypothesis in a randomized clinical trial. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CIRCUMVENTION OF CISPLATIN RESISTANCE Principal Investigator & Institution: Siddik, Zahid H.; Professor; Clinical Investigation; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 01-AUG-1999; Project End 31-MAY-2004 Summary: Although platinum-based antitumor agents (i.e., cisplatin and carboplatin) play critical roles in the treatment of several cancers, a major impediment relapse in a majority of patients, who fail subsequent challenge with the platinum agent due to the onset of drug resistance in their tumor cells. This limitation has resulted in a concerted chemical effort to identify platinum analogs that are effective against resistant tumors. Indeed several such analogs (e.g., oxaliplatin and JM216) have entered clinical trials. However, we have little or no knowledge of the effective mode of action of these analogs. Such information is vital for their success and their rational clinical application in the resistant disease setting. Although reduced drug accumulation, increased intracellular glutathione, and increased DNA adduct repair are usually identified as key mechanisms of resistance of cisplatin, they have not provided satisfactory explanations for reversal of resistance by the analogs. Recently we have demonstrated that a loss in p53 activation in response to DNA damage by cisplatin is a fundamental mechanism of resistance to this platinum complex. It is possible for p53 to be activated through an alternative pathway. Thus, the proposed specific aims are designed to investigate the potential of the analogs to induce latent p53. We will examine the consequence of p53 function on the biochemical pharmacology of analogs at the DNA level, investigate recognition of DNA damage by the structurally- diverse analogs, and delineate p53 regulation. To address the specific aims, we will use standard transfection approaches to modulate p53 induction and/or function, and utilize biochemical, pharmacologic, and other molecular techniques to investigate the effect of this modulation on reversal of resistance. The specific techniques will include adduct quantitation, DNA strand breaks, RNA/protein isolation, protein immunoprecipitation, gel electrophoresis, detection by monoclonal/polyclonal antibodies, and flow cytometry. It is likely that our investigations will establish how the analogs reverse cisplatin resistance, and this may provide a basis for designing clinical protocols to treat resistant clinical cancers on a more rational basis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CISPLATIN AND LASER THERMAL THERAPY FOR CANCER Principal Investigator & Institution: Paiva, Marcos; Surgery; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2006 Summary: However, tumor margin recurrences are seen during follow-up in many Cases. Preclinical model tumor studies performed by this P.I. Confirm that combined injections of cisplatinum in a gel vehicle (CDDP/gel) followed by LITT led to significant improvement in both survival and cure rate. Intratumor drug therapy with a slow release cisplatinum gel (CDDP/gel) is effective for tumor palliation with most cancer patients experiencing only minor side effects and no drug-related toxicity. A promising next step is to combine intralesional anti-cancer drugs with laser photothermal activation via LITT for control of marginal recurrences and significantly improve survival in these patients. We hypothesize that laser thermal therapy after CDDP/gel will be: 1 - )safe and tolerable; 2-) effective, and 3-) will positively impact overall quality of life in head and neck cancer patients. The objectives is to: Initiate a Phase I study determining the maximum toxicity dose (MTD) of intratumor CDDP/gel for combined
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laser thermal therapy (Specific Aim1); define feasibility and effectiveness in a Phase II study (Specific Aim 2); assess patient's perceptions of treatment, toxicity, residual impairment, and their impact on patient related quality of life (Specific Aim 3). The Career Development Award will provide protected time for further training of the Minority Investigator in the responsible conduct of clinical trials, biostatistics, and outcomes in patient-oriented research, as well as to advance this novel technique combining CDDP/gel for improved LITT cancer treatment. He is in an excellent environment with a well-defined institutional plan, which should ensure optimal development for the candidate to become a successful Latino surgical oncologist experienced in Clinical Investigations. The candidate envisions CDDP/gel and LITT treatments under MR guidance as an ultimate merger of bioeletronics to improve tumor palliation outcome. After the Phase I-II trial, and with independent funds, the investigator plans to improve effectiveness of laser and drug therapy by performing combined treatment under magnetic resonance guidance. The UCLA investigators are one of the first groups to develop combined drug and laser therapy as well as imaging guided laser ablation procedures for cancer treatment. The minimally invasive procedures proposed have strong translational potential not only for less traumatic palliation of head and neck cancer, but may prove useful for other types of inoperable primary and metastatic tumors in advanced cancer patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CLINICAL TRIALS WITH ACTIVE IMMUNOTHERAPY AGAINST OVARIAN CANCER
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Principal Investigator & Institution: Livingston, Philip O.; Professor; Sloan-Kettering Institute for Cancer Res New York, Ny 100216007 Timing: Fiscal Year 2002; Project Start 23-AUG-2002; Project End 31-JUL-2003 Summary: In this project, two antibody-based approaches to the therapy of ovarian cancer are planned. One is based on active immunotherapy with conjugate vaccines and the other utilizes passive therapy with a radiolabeled antibody. Most ovarian cancers express at the cell surface GM2 ganglioside, the Thomsen-Friedenreich (TF), sialyl TN in cluster conformation (STN(C)), Lewis (Le/y) and Globo H carbohydrate antigens, the protein antigens MUC-1 and KSA, and the MX35 antigen. For well-defined carbohydrate and peptide antigens, conjugate vaccines have proven the most effective approach to augmenting the antibody response. Keyhole limpet hemocyanin (KLH) has been the most carrier molecule and the saponin fraction QS-21 the most immunological adjuvant. We now have KLH conjugate plus QS-21 vaccines capable of consistently inducing antibody responses in patients against GM2, sTn(C), Globo H, and MUC-1. A trial with Le/y is currently ongoing in ovarian cancer patients and trials with KSA and TF(C) conjugate vaccines are planned for the first half of 1998. The initial goals of Project III are to construct a consistently immunogenic polyvalent vaccine against ovarian cancer, to test this for immunogenicity and toxicity, and to compare systemic and intraperitoneal antibody titers after vaccination by the subcutaneous or intraperitoneal routes. A Phase II clinical trials with this polyvalent vaccine will be initiated late in the second year in patients with metastatic ovarian cancer who are free of grossly detectable disease after adjuvant chemotherapy, second-look surgery, and administration of intraperitoneal cisplatin and etoposide. The radio-labeled antibody 131/I MX35 F(ab')2 has been shown to localize to ovarian cancer peritoneal metastases when administered IP.A Phase I therapeutic trial is in progress; initial dosimetry results suggest significant therapeutic potential. Patients with visible disease (<1cm at second/look surgery) will be treated with 131/I-MX35 F(AB')2 in a second Phase II trial.
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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: COMBINED TREATMENT OF HEAD/NECK CANCER-EGFR/TK INHIBITOR Principal Investigator & Institution: Forastiere, Arlene; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 12-SEP-2002; Project End 31-MAY-2007 Summary: (provided by applicant): The epidermal growth factor receptor (EGFR) is overexpressed in the majority (approximately 90%) of head and neck squamous cell cancers (HNSC). EGFR inhibitors are attractive novel therapeutics to incorporate into current therapies as a strategy to achieve substantial improvement in the survival rates of patients with locally advanced HNSC. Binding the ligands to the EGFR activates a series of downstream signaling pathways, including the Ras/Erk/MAPK pathway and the P13K/Akt pathway. We have shown that the tyrosine kinase inhibitor 0SI-774 blocks EGFR signaling through the Ras/ErK/MAPK pathway but fails to inhibit the P13/Akt signaling pathway in selected patients with HNSC. We have shown that rapamycin and analog compunds, inhibitors in the P13/Akt downstream signaling pathway, reverse resistance to chemotherapy conferred by Akt hyperactivation in breast cancer cell lines. Clinical studies with 0SI-774 and other EGFR inhibitors show that not all patients respond to treatment. Thus, our central hypothesis is that EGFR blockade with 0SI-774 will inhibit the Ras/Erk/MAPK signaling pathway in the majority of HNSCs but that inhibition of the P13K/Akt pathway will require additional therapeutics. We will test this hypothesis by determining the molecular response of 0SI-774 in newly diagnosed patients with locally advanced HNSC enrolled in Phase I dose-finding trial of 0SI-774 combined with radiation therapy and cisplatin. Along with the tumor specimens, HNSC cell lines will be used in preclinical in vivo and in vitro experiments. The molecular findings from the patient tumor specimens will be used to validate our model system. Confirmation of the in vitro/in vivo model will allow us to explore the effects of adding other inhibitors of the P13K/Akt pathway in the model system. The Specific Aims are: (1) To determine the molecular response of 0SI-774 in newly diagnosed patients with locally advanced HNSC enrolled in a phase I trial. (2). To determine the biological effects of 0SI-774 on the EGFR signaling pathways in vitro and in vivo HNSC models. (3). To determine the molecular effects of combining 0SI-774 with inhibitors of the P13K/Akt signaling pathway in preclinical HNSC models. (4) To conduct a phase I clinical trial that incorporates inhibitors of P13k/Akt downstream targets to our backbone regimen of OSI-774/cisplatin/radiation treatment of patients with locally advanced head and neck cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DEVELOPMENT OF INHIBITORS OF THE DNA METHYLATION PROCESS Principal Investigator & Institution: Mikovits, Judy A.; Ceo/ Scientist; Epigenx Pharmaceuticals Pacific Training Center Santa Barbara, Ca 93111 Timing: Fiscal Year 2003; Project Start 20-AUG-2003; Project End 31-JUL-2005 Summary: (provided by applicant): There is now considerable evidence that DNA methylation, by silencing tumor suppressor and mis-match repair genes, has a major role in the causation and progression of cancer and is also involved in abnormal DNA methylation events following HIV (Human Immunodeficiency Virus) infection. In the past year, two primary mechanisms in epigenetic gene silencing, DNA methylation and
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chromatin remodeling have merged as an important new approach to cancer therapy and diagnostics. Unlike mutated genes, epigenetically silenced genes are intact and can be reactivated by drugs that target the methylation process. There is a great need for reversible, less toxic methylation inhibitors. The primary objective of this proposal is to develop lead compounds identified in a unique cell-based screen designed to identify inhibitors of the methylation process. The screening of two chemical diversity libraries totaling more than 50,000 compounds, conducted during the Phase I program, identified more than eight chemically distinct classes of methylation inhibitors. For the proposed Phase II work, we will undertake a comprehensive development program and preclinical evaluation of the most promising compound class(es). Lead candidates from this evaluation will be tested in animal tumor models and a cellular model of HIV infection. We will also evaluate the ability of our lead drug candidate(s) to reverse drug resistant properties of several important anticancer drugs in clinical use, including cisplatin in non-small cell lung cancer and colorectal cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DEVELOPMENT OF MEMBRANE RECEPTOR TARGETED AND TUMORICIDAL BREAST CANCER THERAPY Principal Investigator & Institution: Benz, Christopher; Professor of Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 30-NOV-2002 Summary: Project-1 will further develop and help evaluate clinically new immunoliposomal agents that target HER2-positive breast tumor cells in order to improve the survival of women with advanced breast cancer. The growth factor receptor tyrosine kinase encoded by the protooncogene HER2 (c-erbB-2/neu) represents an attractive target for therapy because its amplification and overexpression occur early in the development of breast cancer, resulting in aggressive disease resistant to systemic therapy. Several anti-HER2 antibodies, including a humanized monoclonal (rhuMAbHER2; Genentech, Inc.) showing clinical promise in patients with metastatic and chemotherapy-resistant HER2-positive breast cancer, are known to produce in vivo tumoristatic effects that become tumoricidal when administered in synergistic combination with either doxorubicin, cisplatin, or taxol. This project will proceed with the development of a first-generation tumoricidal immunoliposomal agent (l-L-dox) composed of humanized anti- HER2 monoclonal fragments, rhuMAbHER-Fab', expressed on the surface of liposomes (conventional or sterically stabilized) encapsulated with doxorubicin. Progress to date indicates that some but not all I-L-dox formulations exhibit in vitro membrane binding, intracellular uptake, and toxicity that is specific to HER2-positive breast cancer cells. Furthermore, preliminary in vivo studies suggest that when these I-L-dox formulations are administered i.v. or i.p. into SCID mice bearing HER2- positive BT-474 breast tumor xenografts, the immunoliposomes and their contents accumulate within the tumors and produce enhanced antitumor effects relative to treatment with free doxorubicin. Over the next project interval, emphasis will be given to the completion of in vivo preclinical studies and the initiation of a Phase-I clinical trial (conducted by the SPORE's Clinical Core) using the most effective preclinical formulation of I-L-dox. Collaborations have been established to facilitate the translational development toward ND approval of I-L-dox and to complete the pharmacokinetic, toxicologic, and efficacy testing necessary to demonstrate that tumortargeting by anti-HER2 immunoliposomes enhances the therapeutic index of an established breast cancer agent like doxorubicin. With confirmatory in vivo evidence for the targeting advantages of I-L- dox, increased attention will be given to the
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encapsulation of a Pt(II) or taxane derivative to initiate preclinical development of an additional tumoricidal anti-HER2 immunoliposomal agent. Furthermore, feasibility testing will begin on a second-generation of targeted therapeutics designed to exploit the novel property that anti-HER2 immunoliposomes (unlike untargeted conventional or sterically stabilized Iiposomes) deliver their contents beyond the coated pit-lysosome pathway and into the cytoplasm of HER2-positive breast cancer cells. This unique intracellular delivery potential of anti-HER2 immunoliposomes makes possible future development of alternative (non-chemotherapy-based) treatment approaches such as HER2-targeted breast cancer gene therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DEVELOPMENT OF MULTI-DEPOT POLYMER DRUG DELIVERY SYSTEM Principal Investigator & Institution: Brekke, John H.; Kensey Nash Corporation 55 E Uwchlan Ave, Ste 204 Exton, Pa 19341 Timing: Fiscal Year 2002; Project Start 11-SEP-2002; Project End 31-AUG-2003 Summary: (provided by applicant): Local disease control is a problem in the management of patients with cancer. Most chemotherapeutic drugs are given to patients systemically as an adjunct to the removal of malignant tumors. Even with radiation therapy, local recurrences too often develop. Sustained or controlled release of drugs directly into wounds after the removal of malignancies may provide control of microscopic residual cancer cells, avoid system toxicity and ameliorate wound healing problems. Development of a programmable, multi-depot chemotherapeutic polymer delivery system is proposed for the treatment of breast cancer. The hypothesis for the investigation is that a bioresorbable delivery device can provide a sustained therapeutic dose of chemotherapy while decreasing system toxicity and delaying or preventing distant metastasis. Furthermore, the device can be engineered to degrade very slowly after it has delivered its payload and act as an in vivo cell culture substratum to direct the pattern of tissue development within the wound. Preliminary results using a prototype have demonstrated the potential of the proposed system. Specific aims for the Phase I program are to: Design, engineer and fabricate the construct; develop and validate the analytical system needed to obtain a basic drug release profile of the device; and conduct normal in vivo studies to assess device pharmacokinetics, local and systemic effects. PROPOSED COMMERCIAL APPLICATION: Drug delivery is rapidly becoming an integral part of drug development strategies within the pharmaceutical and biotechnology industries. By the year 2002, revenues of pharmaceutical products which utilize drug delivery systems will reach $35 Billion in the U.S. and $50 Billion worldwide, or 20% of total pharmaceutical sales. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DEVELOPMENT OF POLY-L-GLUTAMIC ACID PACLITAXEL CONJUGATE Principal Investigator & Institution: Wallace, Sidney; Fem Cadet 3324 Pittsburgh St Houston, Tx 77005 Timing: Fiscal Year 2002; Project Start 15-APR-1999; Project End 31-MAY-2006 Summary: Chemoradiation improves survival for patients with locally advanced nonsmall cell lung cancer (NSCLC) over radiotherapy (R) alone. Les than 20% of patients have complete pathologic response to combination therapy. Paclitaxel (TXL) is effective as an anti-tumor agent and a radiosensitizer. Peripheral neurotoxicity and
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granulocytopenia limit its dosage; acute effects from TXL's infusion include nausea, hypotension, and cardiac arrhythmias related to Cremophor and ethanol. Conjugating TXL with poly-L-glutamate (PG-TXL/CT-2103) makes it water-soluble, allowing infusion of twice the amount of free TXL and higher intratumoral drug concentrations, which was confirmed by preclinical testing. Combining PG-TXL with radiation demonstrated synergistic radiation enhancement higher than that seen with other taxane or nucleoside analog. A phase I clinical trial of CT-2103 as single agent salvage therapy for patients with advanced solid tumors demonstrated safety and tolerability in dose up to 266 mg equivalent paclitaxel/m2 without significant alopecia. This Phase II STTR proposes a Phase I/II clinical trial of CT-213 given concurrently with chest RT in patients with unresectable Stage III or medically inoperable Stage II NSCLC. This study will determine MTD, DLT, pharmacokinetics, assess toxicity, and document patient costs. We expect this combination RT and CT-2103 to improve patient survival and response to treatment. PROPOSED COMMERCIAL APPLICATIONS: At M.D. Anderson Cancer Center, the combination of Taxol and cisplatin given concurrently with radiation therapy is the treatment of choice for lung cancer patients. In animal studies, CT-2103 is water soluble, infectable intravenously in 10 minutes without premedication, more effective (2-3X) and less toxic than Taxol. CT-2103 could possibly replace Taxol. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: RESISTANCE
DIHYDRODIOL
DEHYDROGENASE
MEDIATES
CISPLATIN
Principal Investigator & Institution: Simpkins, Henry; Pathology and Lab Medicine; Temple University 406 Usb, 083-45 Philadelphia, Pa 19122 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2008 Summary: (provided by applicant): Cisplatin is one of the most effective forms of chemotherapy for advanced stage ovarian cancer although it is generally used as a carboplatin taxol combination. However some patients relapse due to the development of a resistant cell population. In order to identify clinically relevant markers for cisplatin/carboplatin responsiveness, a stable cisplatin-resistant human ovarian carcinoma cell line (2008/C13*) derived from the parental human ovarian carcinoma cell line (2008) was analyzed by microarray analysis followed by semiquantitative RT-PCR. Four genes were found to be upregulated in the cisplatin-resistant ceils: tropomyosin, apolipoprotein J (clusterin), glucose dehydrogenase and dihydro dehydrogenase. All four were upregulated by cisplatin treatment of the 2008 cells. Transfection experiments showed that forced overexpression of only DDH1 induced cisplatin/carboplatin resistance in the parental cell lines. DDH mRNA expression posttransfection was monitored by RT-PCR, and protein expression by enzyme activity assays and immunohistochemistry. Transfection of DDH1 into two other human ovarian carcinoma cell lines, 2780 and SKOV3 resulted in cisplatin carboplatin resistance, but not to other anticancer drugs. Analysis of a human lung squamous cell carcinoma cell line (A549) which has a very high levels of endogenous DDH2 mRNA exhibited a degree of cisplatin resistance greater than that of the 2008/C13* cell line. We propose to continue this work by (a) transfection of non-ovarian cell lines, including Tera-2 (germ cell tumors), A431(cervical carcinoma cells), HTB56 (lung adenocarcinoma ceils) and H69 (small cell lung carcinoma cell), to show that DDH1/2 expression produces cisplatin carboplatin resistance in a variety of cell lines derived from cancers from different organs. (b) We will also attempt to determine the transcriptional control mechanisms responsible for DDH1 upregulation as well as the (c) mechanisms by which DDH1/2
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produces resistance to cisplatin (e.g. possible involvement of reactive oxygen species and apoptotic pathways involved). (d) Finally, we will study human ovarian and lung carcinoma tissues prior to and post-chemotherapy (with platinum containing drugs) utilizing monoclonal antibodies to DDH1/2 to determine if DDH expression can be used as a surrogate marker to identify whether, or not a tumor will respond to platinum-based chemotherapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DNA MISMATCH REPAIR AND CANCER IN MURINE MODELS Principal Investigator & Institution: Edelmann, Winfried; Associate Professor; Cell Biology; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2003; Project Start 01-DEC-1997; Project End 30-NOV-2007 Summary: (provided by applicant): The DNA mismatch repair (MMR) system is essential for maintaining the integrity of the mammalian genome and mutations in the mammalian MMR genes result in increased cancer susceptibility and meiotic failure. Eukaryotic MMR is a complex system that requires the interaction of several MutS and MutL proteins for the initiation of the repair reaction. Recent results suggest that the mammalian MMR proteins function in a number of processes which not only include the repair of base mismatches, but also the signaling of apoptosis in response to DNA damage as well as the suppression of recombination between non-identical sequences. Because it is likely that each of these activities contributes differentially to the prevention of genomic instability and cancer, it is necessary to study the impact of their individual loss. To accomplish this, we propose to create mouse lines that carry pathogenic missense mutations, which will disrupt the function of a particular motif but not completely inactivate the protein. We hypothesize that each of the distinct functions of the mitotic MutS homologs in mismatch repair, apoptosis and anti-recombination cooperate to suppress tumorigenesis. The specific aims of this proposal are: 1. To generate mouse lines that carry knock-in mutations in the ATPase domains of Msh2, Msh3 and Msh6 and analyze the resulting cancer susceptibility phenotype. This analysis will elucidate the significance of this motif in tumor suppression and also serve as a model for the generation of other Msh2, Msh3 and Msh6 knock-in alleles. 2. To analyze the effect of the Msh knock-in mutations on DNA repair functions in vitro and determine the resulting in vivo mutator phenotype in mouse tissues. 3. To study the DNA damage response in the Msh2-, Msh6- and Msh3- knock-in mouse lines. We propose to study the apoptotic response after exposure to DNA damaging agents in mouse embryonic fibroblast lines and in the in the gastrointestinal tract of the Msh knock-in mouse lines. In addition, we propose to analyze the sensitivity of embryonic stem cells and tumor cell lines derived from the knock-in mice to cisplatin and other chemotherapeutic drugs in a xenograft model in athymic nude mice. 4. To investigate the impact of the Msh2, Msh3 and Msh6 point mutations on the anti-recombination function of the MutS complexes. We will investigate DNA double strand break induced recombination in the chromosomes of embryonic stem cells to test whether the knock-in mutations result in a separation of DNA repair and anti-recombination functions in mice and assess the consequence of loss of this function on tumorigenesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DNA MISMATCH REPAIR--LESION REPAIR AND STRAND TARGETING Principal Investigator & Institution: Drummond, James T.; Assistant Professor; Biology; Indiana University Bloomington P.O. Box 1847 Bloomington, in 47402
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Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2005 Summary: Our broad, long-term goal is to define the molecular mechanisms by which the human DNA mismatch repair (MR) pathway processes DNA adducts and directs repair to one strand. When certain damaged DNA bases, such as those that result from chemotherapy with cisplatin or alkylating agents, are processed as mismatches, they can induce apoptosis. Clinically significant drug resistance is conferred when MR is silenced. We will define the molecular mechanism by which two of the most effective anticancer drugs, cisplatin and adriamycin, interact with the mismatch repair pathway. In addition, we have developed a new, straightforward method for constructing plasmids that contain a mismatch and a single nick in either DNA strand. This method will be extended to replace mismatches with one of several DNA modifications. Using this approach, we will characterize the mechanism by which covalent DNA damage is recognized and processed by MR. DNA modifications will include cisplatin, transplatin, O6- methylguanine, and 8-oxoguanine. An essential aspect of defining how DNA damage is processed is understanding how strands are distinguished. We will test several possible models by which MR can be targeted to one DNA strand. First, hemimethylation will be tested by constructing mismatch-containing molecules where one strand is selectively methylated at CpG-containing sequences by annealing fullymethylated homoduplex molecules with unmethylated, single-stranded partners. Assays will be performed in vitro, using nuclear extracts from MR-competent HeLa cells. Both covalently closed relaxed and supercoiled molecules will be tested. If hemimethylation is competent to direct MR, we will define the minimal sequence requirements for strand discrimination. We will also ask whether strand gaps or DNA ends can target MR. Free DNA ends, in particular the DNA end in the active site of replicative polymerases, have been proposed to target MR. We will test this model by asking whether free DNA ends, or defined gaps within circular DNAs, are capable of directing MR to the discontinuous strand. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DNA REPAIR AND DRUG RESISTANCE IN OVARIAN CANCER Principal Investigator & Institution: Hamilton, Thomas C.; Professor; Fox Chase Cancer Center Philadelphia, Pa 191112434 Timing: Fiscal Year 2002; Project Start 20-JUN-1990; Project End 31-MAY-2004 Summary: It has been our goal to determine how ovarian cancer cells become resistant to cisplatin therapy. To ascertain the reasons, we have studied in vitro models of cisplatin resistance and cell lines from ovarian cancer patients refractory to high dose platinum therapy. Although an understanding of this process is not complete, we can say that resistance can occur by several pathways and often involves the changes in expression of many genes. Furthermore, our data damage tolerance is repair of cisplatin DNA damage. Hence, DNA repair not only defines the innate sensitivity of a cell to cisplatin but also if the function of this pathway is enhanced produces resistance to cisplatin. These data suggest that perturbation of the DNA repair process may be one way to increase the cytotoxicity of cisplatin and in part reverse resistance to the drug. Therefore, we propose to test the hypothesis that genetic inactivation of ERCC1, an indispensable DNA repair [protein, will disruption the repair of cisplatin DNA damage, and make cisplatin more cytotoxic and that we can add specificity to this effect using an ovarian specific promote and cisplatin damage inducible promoter. We propose to use optimal circumstances to test our ideas and improve upon them by work on the following Specific Aims. SPECIFIC AIM #1: Determine the impact of down-regulation of ERCC1 n cisplatin sensitivity. We will eliminate functional ERCC1 from ovarian
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cancer cells with plasmids which produce antisense ERCC1, dominant negative ERCC1, or intrabodies against ERCC1. In this optimal test, transcription will be driven by the CMV promoter. These gene inactivation strategies will be tested for effects on ERCC1 amounts, function, and cisplatin cytotoxicity. SPECIFIC AIM #2: Modify an Ovarian Specific Transcript promoter to enhance its ability to drive gene expression in ovarian cancer cells but maintain and/or improve specificity. The promoter we have identified and will improve is a approximately 500bp portion of an endogenous rat retroviral- like element that encompasses the U3 region of the LTR of one of these genomic units. These units are specifically transcriptionally active in the rat ovary and the U3 region will regulate reporter gene expression in human ovarian cancer cells but not diverse other cell types. SPECIFIC AIM #3: Test the ability of an optimized tissue specific promoter and cisplatin damage inducible promoter to confer specificity tot the best method for ERCCl inactivation. The best method for ERCCl inactivation, as determined in Specific Aim #1, will be utilized in the construction of plasmids where the inactivation product will be expressed under the control of an optimized ovarian tissue specific promoter and by the promoter for P21 which showed marked inducibility when ovarian cancer cells are exposed to platinum. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ENDOGENOUS MODULATION OF COCHLEAR INJURY Principal Investigator & Institution: Rybak, Leonard P.; Professor of Surgery; Surgery; Southern Illinois University Sch of Med Box 19616, 801 Rutledge St Springfield, Il 62794 Timing: Fiscal Year 2002; Project Start 01-JUL-1994; Project End 31-MAR-2004 Summary: The optimal use of cisplatin for the best treatment of solid tumors has been prevented because of dose limiting nephro-and ototoxicity. Higher doses of cisplatin may be used with chemoprotectants such as diethyldithiocarbamate (DDTC), which prevents cisplatin toxicity for the kidney and bone marrow. Our preliminary data suggest that DDTC can also prevent cisplatin ototoxicity in an animal model. The proposed research seeks to address the basic question, "Can the ototoxicity of cisplatin be altered by manipulating the glutathione (GSH) content of the cochlea?" A corollary is that the GSH content of the cochlea is related to enzymes of the antioxidant system [superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px)] and the enzymes glutathione reductase (GR) and glutathione-S-transferase (GST) and that these enzymes are affected by cisplatin. The specific aims are: 1) to investigate the hypothesis that cisplatin ototoxicity is related to the diminution of the antioxidant system in the cochlea, and that such changes are specific for this target tissue. Physiological changes measured with auditory brainstem evoked response (ABER) testing and endocochlear potential (EP) measurements will be correlated with a) ultrastructural alterations using scanning electron microscopy (SEM) of the organ of Corti and transmission electron microscopy (TEM) of the stria vascularis; and b) biochemical changes in the antioxidant system of the cochlea in comparison to nontarget tissues, the liver and heart, 2) to test the hypothesis that some or all of the ototoxic injury caused by cisplatin is mediated by ototoxic metabolites such as GSH adducts, 3) to examine the hypothesis that the prevention of cisplatin ototoxicity by DDTC is mediated by preservatives of the antioxidant system in the cochlea, 4) to study the pharmacokinetics of cisplatin in plasma and cochlear tissues in ototoxic rats and in animals receiving cisplatin plus the rescue agent, DDTC. The techniques used for this investigation will involve the expertise of three investigators namely physiological measurements (ABER and EP), morphological studies (SEM and TEM) biochemical and metabolic studies: (HPLC) with ultraviolet and electrochemical detection (GSH and
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Cisplatin
GSSG), antioxidant enzymes and other enzymes of the glutathione pathway using spectrophotometry and pharmacokinetic studies by atomic absorption spectrophotometry of platinum levels. These studies should provide new insights into the mechanisms of cisplatin ototoxicity and mechanisms for protection from this doselimiting side effect arising from use of this life-saving chemotherapeutic agent. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ENZYMOLOGY OF EUKARYOTIC DNA MISMATCH REPAIR Principal Investigator & Institution: Modrich, Paul L.; James B. Duke Professor; Biochemistry; Duke University Durham, Nc 27710 Timing: Fiscal Year 2002; Project Start 01-JAN-1991; Project End 31-DEC-2002 Summary: Human cells possess a strand-specific mismatch repair system that is a homolog of the bacterial and yeast pathways as judged by similarities in specificity, mechanism, and involvement of MutS and MutL-like activities. As in microbial systems, human mismatch repair mutations confer hypermutability. Genetic defects in the human repair system are the cause of hereditary nonpolyposis colon cancer, have been implicated in a subset of sporadic tumors that arise in a variety of tissues, and also confer resistance to certain chemotherapeutic agents, including DNA methylators and cisplatin. Clarification of the molecular nature of the human mismatch repair reaction is therefore relevant to both the origin and treatment of human malignancies. We and others have identified six activities that are involved in the human repair reaction: the mismatch recognition activities MutS-alpha (MSH2.MSH6 heterodimer) and MutS-beta (MSH2.MSH3 heterodimer), MutL-alpha (MLH1.PMS2 heterodimer), PCNA, RPA, and DNA polymerase delta. One of our major goals for the requested extension of this work will be the identification and isolation of other components of the repair system, with emphasis on helicase and/or exonuclease activities involved in the excision step of the reaction. This fractionation work will also include the isolation and characterization of several novel MutL-like activities that have been identified in extracts derived from HeLa cells and certain MLH1- deficient tumor and drug-resistant cell lines. The second aim of the work will be to further clarify the molecular roles of the required activities in the mismatch repair reaction. Initial studies will emphasize the assembly of the initiation complex, including protein- protein interactions, and the role of ATP in initiation complex formation and evolution. Should excision activities become available during the course of the project, the molecular studies will be extended to include these activities. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: EPO REGULATED ERYTHROPOIESIS Principal Investigator & Institution: Wojchowski, Don M.; Professor; Maine Medical Center 22 Bramhall St Portland, Me 04102 Timing: Fiscal Year 2004; Project Start 05-JAN-1991; Project End 31-DEC-2007 Summary: (provided by applicant): Epo and its receptor (EpoR) are prime regulators of red cell production. EpoR function depends upon an upstream Jak2 kinase, which acts in part by phosphorylating conserved EpoR cytoplasmic sites for transduction factor binding. Unexpectedly, PY-null EpoR forms in transgenic and knock-in mice retain significant activity, with only apparently mild defects observed in vivo. In new work, we have adopted an EpoR knock-in system, and in PY-null "EpoR-HM" mice have discovered: i) clear Epo dose-dependent defects in erythroid progenitor cell growth and development; ii) compensatory increases in serum growth factors; and iii) ineffective
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stress erythropoiesis. By comparison, the adding-back of a PY343 Stat5 binding site confers hyper-activity (EpoR-H form). Aim 1 will employ (anti)apoptotic factor analyses, RTqPCR, and global profiling to define core response pathways for EpoR-HM, EpoR-H and wt-EpoR receptors in purified primary cells. Roles for EpoR PY-dependent pathways in bcl-x gene induction will be investigated. For select factors, RNAi approaches will be used to assess functional significance. Aim 2 will examine stress erythropoiesis in EpoR-HM mice (including cisplatin and Cs137-induced anemia). EpoR-H mice also will be analyzed, as will underlying EpoR, Kit and/or glucocorticoid receptor linked mechanisms. Aim 3 will assess compensatory mechanisms invoked in EpoR-HM mice, including Epo production. The hypothesis that EpoR-H (and possibly EpoR-HM) function is assisted by a collateral (hematopoietic) growth factor-receptor system also will be investigated. Lyn kinase also appears to play important roles in EpoR action: Aim #4 will test the extent to which activity of the minimal EpoR form EpoR-HM depends upon Lyn by studying compound lyn -/-, EpoR-HM mice and assessing (advanced) erythropoietic defects. Such defects in lyn -/- mice per se also will be investigated. Aim #5 will use primary ceils from EpoR-H and EpoR-HM mice to extend new findings from cell line models that EpoR-PY343 and Kit PY567 support EpoR and Kit cofunction. This work in primary models should advance a basic understanding of core EpoR action mechanisms (including those essential for stress erythropoiesis). Insight also will be gained into the erythropoietic actions of Lyn and Kit PTK proto-oncogenes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ERROR PRONE REPLICATIVE BYPASS OF PLATINUM ADDUCTS Principal Investigator & Institution: Chaney, Stephen G.; Professor; Biochemistry and Biophysics; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2002; Project Start 01-JUL-2000; Project End 31-MAR-2004 Summary: Cisplatin is a probable human carcinogen. Platinum compounds such as oxaliplatin have shown promise for the treatment of cisplatin resistant tumors, but their potential mutagenicity is unknown. The mutagenicity of these compounds is likely to be determined in part by the DNA polymerase(s) which catalyze error-prone translesion synthesis past Pt-DNA adducts. The identity if these polymersases is not currently known, but pol beta, pol zetu, and pol eta have all been shown to perform translesion synthesis past Pt-DNA adducts in vitro. Cell lines exist which under- or over-express each of these polymersases. Thus, we plan to determine the effects of pol beta, pol zetu, and pol eta expression on the mutagenicity and cytotoxicity of cisplatin and oxaliplatin adducts (Aim 1). An analysis of the conformational differences of the adducts formed by these compounds is likely to be essential for understanding the mechanisms which determine their mutagenicity and efficacy. Thus, we plan to use a combination of NMR and molecular modeling to characterize the adducts formed by these compounds (Aim 2). Detailed information on the efficiency and fidelity of translesion synthesis by purified DNA polymerases is important for confirming the contribution of those polymersases to error-prone translesion synthesis in vivo (Aim 1) and for modeling their interaction with the adducts (Aim 4). Thus, the efficiency and fidelity of translesion synthesis past cisplatin and oxaliplatin adducts by pol beta, pol zetu, and/or pol eta will be determined in vitro (Aim 3). It is likely that the conformation and mutagenicity of Pt-DNA are affected by their binding to the active site of the polymerases involved in error-prone translesion synthesis. Based on the conformational data on the adducts (Aim 2) and the known crystal structures of pol beta, molecular dynamics simulations
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will be used to model the interactions of pol beta with each of the adducts (Aim 4). This project will define the role of pol beta, pol zetu, and pol eta in error-prone replicative bypass of Pt-DNA adducts. It will also result in models of Pt-DNA adduct conformation and polymerase-adduct interaction that will be useful in understanding the mechanism(s) of mutagenesis by these and other Pt complexes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: EVALUATION OF A NOVEL AKT INHIBITOR IN OVARIAN CANCER Principal Investigator & Institution: Lin, Jiayuh; Obstetrics and Gynecology; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2006 Summary: (provided by applicant): This research project will focus on the evaluation of a novel AKT-selective small molecule inhibitor in ovarian cancer cells and the effect of this inhibitor on AKT downstream targets. AKT or Protein Kinase B (PKB) is a serine/threonine kinase that is activated in response to growth factor or cytokine. The AKT protein has three isoforms AKT1 (PKBalpha), AKT2 (PKBbeta) and AKT3 (PKBgamma) that have greater than 85% sequence identity and have the same structural organization. The AKT2 proto-oncogene is amplified in ovarian carcinoma. The elevated AKT1 phosphorylation and AKT1 kinase activity have also been detected frequently in ovarian cancer cells and tumors. Ovarian cancer patients with AKT alterations appear to have a poor prognosis. Since AKT may provide a survival signal that protects cells from apoptosis induced by anti-cancer drugs or stresses, development of potent and selective inhibitors targeting AKT is an attractive therapeutic strategy for treating ovarian carcinoma. Through structure-based design and screening, we have identified a potent and selective small molecule inhibitor of AKT (termed API-59). In this proposal, we propose to evaluate the potency, selectivity and molecular mechanism of API-59 in ovarian cancer cells that express elevated AKT activity. The following specific aims will be studied to address this concept: 1. Evaluation of the effect of API-59 on AKT pathway in ovarian cancer cells. 1.1. Synthesis of API-59. 1.2. Evaluate induction of apoptosis by API-59 in ovarian cancer cell lines that express constitutively active AKT. 1.3. Determine the effect of API-59 on AKT kinase activity and AKT downstream targets. 1.4. Evaluate the effect of API-59 on normal cells lacking constitutively active AKT. 2. Examination of the effect of API-59 in combination with cytotoxic agents in ovarian cancer cells. 2.1. Test the effect of API-59 in combination with cisplatin on inducing apoptosis and inhibiting the AKT pathway in ovarian cancer cell lines that express constitutively active AKT. 2.2. Examine the inhibitory effect of API-59 in combination with taxol on inducing apoptosis and inhibiting the AKT pathway in ovarian cancer cells that express constitutively active AKT. 3. Evaluation of the efficacy of API-59 in a nude mouse tumor model in vivo. Determine the efficacy of API-59 treatment to inhibit elevated AKT activity in established mice tumors and retard the growth of established tumors in nude mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: EVALUATION OF HYPOXIA BY EF5 BINDING IN CERVIX CANCER Principal Investigator & Institution: Evans, Sydney M.; Associate Professor; Radiation Oncology; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 20-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant): It has been known for many years that anemic cervix cancer patients have a poorer prognosis and response to radiation therapy than
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similar patients with normal blood hemoglobin levels. The Gynecologic Oncology Group (GOG) is performing the first Phase III trial (GOG191) to determine whether modifying patient hemoglobin levels with recombinant human erythropoietin will improve outcome following radiation therapy and cisplatin. One possible mechanism underlying the poor prognosis of anemic cervix patients is that their tumors are hypoxic. This would make the tumors radiation resistant and/or more biologically aggressive due to hypoxia-mediated molecular/cytokine changes. The methodology to evaluate the importance of pretreatment tumor hypoxia was not incorporated into the GOG191 trial for logistical reasons but the GOG has identified this to be a critical biologic question. The GOG is supporting this analysis by providing us with access to patient tissues; the trial is referred to as GOG8002. We have proposed to assess tumor hypoxia in patients entered onto GOG191 and to determine the clinical significance of this finding. Our overall hypothesis is that hypoxia, as determined by EF5 binding, is a critical determinant of cervix cancer biology and treatment response. EF5 has been studied in detail using quantitative fluorescence immunohistochemistry and can be used to measure both hypoxic area and absolute tissue pO2. This technique is compatible with large multi-institutional trials because the drug is safely and easily administered and tissue can be sent to a central facility for processing. Our specific aims are to: 1: Determine the relationship between the level of EF5 binding and pre-treatment hemoglobin level, tumor size, and stage; 2: Explore whether pre-treatment tumor hypoxia (as measured by EF5 binding) is associated with overall survival, progressionfree interval and local control and 3: Explore the relationships between EF5 binding and CD-31 labeling (tumor vasculature), and EF5 binding and Ki-67 labeling (cellular proliferation). EF5 binding will be quantified in several ways. The maximum binding rate will be determined in vitro and the in situ binding will be assessed as a percent of maximum. This will allow conversion of binding to tumor pO2. Further analyses will incorporate the area of tissue involved at various binding levels. Patient follow-up and statistical evaluations will be provided by the GOG. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENETIC ALTERATIONS IN BREAST CELLS FROM BRCA1 CARRIERS Principal Investigator & Institution: Hartman, Anne-Renee; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2003; Project Start 08-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): The purpose of this proposal is to identify a temporal pattern of specific genetic alterations in the nucleotide excision repair (NER) pathway that are associated with a multistep carcinogenic progression of normal to premalignant to invasive breast cancer in BRCAl-mutated breast epithelial cells. The long-term objective is to identify specific molecular markers that are predictive of breast cancer risk, and that may serve as targets for prevention or early detection of breast cancer in this population. Key components of this project are to utilize MRI screendetected breast tissue and premalignant cells identified in ductal lavage specimens in BRCA1 carriers to address the hypothesis. The aim are as follows: Aim 1: To evaluate nucleotide excision repair activity and sensitivity to DNA damaging agents in a BRCAInull human cell line. I have previously shown that overexpression of BRCA1 enhances NER of ultraviolet (UV)-induced photoproducts and that a potential mechanism is through transcriptional regulation of NER genes. These experiments were done in cell lines that contain endogenous BRCA1. I will confirm these results in a BRCAI-null human cell line and extend the analysis to determine cellular susceptibility to different
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DNA damaging agents that are targeted by NER for repair and are more relevant for breast cancer treatment. Aim 2: To determine if MRI screen-detected breast lesions in BRCA1 carriers contain additional genetic mutations or alterations in the expression of nucleotide excision repair DNA-damage recognition genes compared to normal tissues from these individuals. I will analyze this tissue for LOH of the normal allele of BRCA1, mutations in the p53 gene, and alterations in the NER genes that are regulated by BRCA1 and p53. Aim 3: To determine the expression levels of nucleotide excision repair DNA-damage-recognition genes and evaluate nucleotide excision repair activity in benign (histologically normal or hyperplastic), atypical, and malignant ductal cells from women with BRCA1 mutations. LOH of BRCA1, mutations in p53, and loss of expression of NER genes will be correlated with histopathology. In order to validate the functional consequences of these alterations, assays for repair activity will be performed on these ductal cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENOTOXICITY OF CISPLATIN, A PLEIOTROPIC TOXIN Principal Investigator & Institution: Essigmann, John M.; Professor of Chemistry & Toxicology; Center for Cancer Research; Massachusetts Institute of Technology Room E19-750 Cambridge, Ma 02139 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2005 Summary: Cisplatin (cis-diamminedichloroplatinum (II)) is a metal coordination complex that kills cells by mechanisms initiated by its interaction with DNA. Using biochemical and genetic approaches, the goal of this project is to continue our work probing the how this compound kills cells. The practical value of the work stems from the use of this compound as an anticancer drug with organotropic specificity for the testis, and to a lesser extent, ovary. While study of the anticancer activity of cisplatin is not our goal, any basic mechanisms we uncover could be of value in the design of new selective toxins. In previous work we discovered that the architecture of cisplatin-DNA adducts is unusual in that it attracts certain cellular proteins. We have postulated and in some cases demonstrated that there are deleterious effects of these interactions. First, the binding of cellular proteins to adducts shields the adducts from DNA repair enzymes; the adducts persist and have an enhanced likelihood of killing the cells. Second, some adduct binding proteins are transcription factors. If the transcription factor becomes associated with an adduct, and not its promoter, gene expression is adversely affected. Third, adducts attract mismatch repair proteins and possibly disrupt their role in genetic recombination. The proposed work is divided into three areas. Having established that adducts act as molecular decoys for transcription factors in vitro, we plan experiments to test whether a transcription factor, specifically hUBF (which regulates rRNA synthesis), is hijacked in vivo. Our second aim is to continue recent work that has shown that mutations in specific recombination genes can result in enhanced sensitivity to cisplatin by as much as 10^4 fold over an isogenic wild type cell. Our proposal is to continue to uncover the mechanism by which recombination affects cellular responses to cisplatin and, in addition, determine by using genetic techniques if the mismatch repair pathway interacts with recombination pathways in affecting cellular survival. Finally, we plan biochemical experiments to complement the aforementioned genetic studies on recombination and mismatch repair. It is hypothesized that cisplatin adducts will be substrates for purified recombination enzymes and that mismatch repair proteins, which control many aspects of recombination, may interfere with the orderly progress of events that would otherwise allow tolerance of the adducts. Taken together these
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studies will provide mechanistic detail on the toxic effects of an important DNA damaging agent. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GRP78 AND HYPERSENSITIVITY TO DNA CROSS LINKING AGENTS Principal Investigator & Institution: Belfi, Charles A.; Medicine; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2005 Summary: We have associated over-expression of the glucose-regulated stress protein, GRP78, with increased sensitivity to DNA cross-linking agents and with the impairment of DNA cross-link repair. This sensitization, first shown in V79 hamster cells, was extended to three human tumor cell lines each bearing a different genetic alteration. Under these conditions, tumor cells deficient in p53, alkylguanine transferase or the mismatch repair protein, hMLH1, were sensitized to BCNU, cisplatin or melphalan. This is important, first, since it is known that in many cases, tumors bearing genetic mutations are resistant to chemotherapy, a means of sensitizing these resistant cells would be of great interest. Second, in direct contrast to the conventional approach of targeting therapy to a single genetic deficiency this approach may lead to an alternative direction in therapy. The thrust of this application is to determine the mechanisms underlying the association of GRP78 up-regulation with hypersensitivity to crosslinking agents. We propose to examine the following plausible mechanism of sensitization: It has been reported that when GRP78 is over-expressed, it moves from the endoplasmic reticulum to the cell nucleus. In character with its nature as a binding protein, GRP78 binds to one or more DNA repair enzymes involved in cross-link repair and thus explain the increased sensitivity to cross-linking agents. We propose to confirm the nuclear localization of GRP78 in human cancer cell lines by immunofluorescence techniques and to link the nuclear localization of GRP78 in human cancer cell lines by immunofluorescence techniques and to link the nuclear localization of GRPF78 to increased sensitivity to cross-linking agents as well as to reduced levels and activity of DNA repair enzymes. We will use several complementary systems to induce or suppress the expression of GRP78 in order to link the protein directly with alterations of elements of DNA repair. We will measure the cellular responses to cross-linking agents under stress conditions via several indices of nucleotide excision repair efficacy. Finally, we will examine whether GRP78 binds directly to selected DNA repair enzymes by coimmunoprecipitation. A basic understanding of the mechanisms behind the sensitization of cells during GRP78 up-regulation may provide a new direction in improving the efficacy of cancer chemotherapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: GYNECOLOGIC ONCOLOGY GROUP Principal Investigator & Institution: Disaia, Philip J.; Professor and Chairman; American College of Ob and Gyn 409 12Th Street Sw Washington, Dc 20024 Timing: Fiscal Year 2002; Project Start 01-MAY-1980; Project End 31-MAR-2003 Summary: The Gynecologic Oncology Group (GOG) is the foremost multi-disciplinary cooperative clinical trial research group devoted to the study of gynecologic malignancies. Since its inception in 1970, the GOG has been a recognized leader in the development of new forms of treatment and has relied on the phase III trial as the design to identify new information. Supporting that major activity are the concerted
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efforts of modality committees providing recent approaches and procedures in each of the relevant diagnostic and therapeutic disciplines. The GOG has an active, effective program in the study of new chemotherapeutic agents in gynecologic cancers and this program has introduced important findings for study in the Phase III setting. In patients with advanced cervical, endometrial and ovarian cancers, the GOG has defined significant improvement associated with the use of cisplatin. The GOG has performed a series of trials to examine the role of paclitaxel either as a single agent or in combination with other agents. Isofamide was found to be one of the most active single agents in squamous carcinoma of the cervix. The results of Phase III studies by the GOG have provided a new standard of treatment in suboptimal ovarian cancer using platin and taxol. Two recently completed trials of post-operative patients with intermediate risk endometrial and cervical cancer showed a significant improvement with adjuvant radiotherapy. The benefit of post-operative adjuvant chemotherapy has been confirmed for patients with totally resected, early stage ovarian cancer. In addition, the GOG has been active in developing new mechanisms to enhance translational research, cancer prevention and control and medical informatics. The Group has collaborative actively with the NCI in evaluating new data management collection and reporting systems. After more than 25 years, the GOG continues to be foremost in developing new strategies in the management of these cancers. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HYPOXIC CHEMOTHERAPY
STRESS
MECHANISMS
IN
RADIATION
AND
Principal Investigator & Institution: Murphy, Brian J.; Sri International 333 Ravenswood Ave Menlo Park, Ca 940253493 Timing: Fiscal Year 2002; Project Start 12-AUG-1992; Project End 30-NOV-2005 Summary: A growing body of evidence suggests that many human solid tumors contain a significant fraction of hypoxic cells which can directly affect a number of malignant phenotypes, including therapeutic resistance, sustained angiogenesis, evasion of programmed cell death, tissue invasion and metastasis, and self-sufficiency in growth signals. This scenario is supported by clinical studies that correlate hypoxia with poor prognosis in a number of solid tumor types. These hypoxia-dependent phenotypic alterations are believed to involve, in part, a set of diverse hypoxic stress genes whose expression is controlled by specific hypoxia-sensitive transcription factors. The proposed research is based on the findings that the metal transcription factor-1 (MTF-1) is activated by hypoxia and that tumor expansion in hypoxic mouse fibrosarcomas requires MTF-1 expression. Furthermore, hypoxia-activated MTF-1 contributes to the development of cisplatin resistance in vitro. This ubiquitous transcription factor controls a number of hypoxic stress genes that, if overexpressed, could contribute to the development of clinically important malignant phenotypes in tumors containing transiently hypoxic microregions. The first set of studies (Aim 1) proposed in this competitive renewal is designed to clearly define the mechanisms associated with MTF1 activation by hypoxia, including analysis of potential signaling pathways, phosphorylation events, regulation of the redox state of the MTF- 1 DNA binding domain, and nuclear translocation. Aim 2 uses microarray technology to identify other hypoxic stress genes that are controlled by MTF-1 and involves transcriptional analysis of a selected number of these MTF-dependent genes. The studies in Aim 3, utilizing both tumor xenograft and in vitro models will address the functional significance of hypoxiamediated activation of MTF-1 in malignant progression. An understanding of these mechanisms will aid in the development of novel prognostic and therapeutic modalities,
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including gene therapy approaches, for solid tumors containing significant regions of recurring or transient hypoxia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: IDENTIFICATION OF NOVEL CISPLATIN RESISTANCE GENES Principal Investigator & Institution: Huang, Ruea-Yea; Roswell Park Cancer Institute Corp Buffalo, Ny 14263 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2006 Summary: (provided by applicant): Cisplatin is highly effective in the treatment of various cancers. Resistance to this drug, however, poses a major problem to the success of chemotherapy. Several possible mechanisms that can contribute to platinum resistance have been identified; however, a clear correlation between the known in vitro mechanisms of cisplatin resistance and clinical outcome is lacking. This is likely a result of alterations in multiple genes within tumors. To improve the efficacy of cisplatin treatment, it may be necessary to use multiple tractable molecular markers for prediction of tumor response to chemotherapy. The long-term goal of this project is to identify novel genes and/or molecular pathways, which mediate cisplatin resistance. The approach has been first to identify yeast genes, which when deleted, confer resistance to cisplatin and then to evaluate the human homologues for their role in cisplatin toxicity. By screening the collection of S. cerevisiae deletion mutants created by the Yeast Genome Deletion Project, several novel yeast genes, which when deleted confer resistance to cisplatin, have been identified. Genes involved in two cellular pathways were chosen for further study because they were identified multiple times and/or when deleted conferred higher resistance, and they have human homologues. First are the FCY2 and HPT1 genes involved in the AMP biogenesis pathway; second are 2 genes in the NMD (nonsense-mediated mRNA decay) family, which are involved in mRNA surveillance and regulation of translation. The specific aims of this application are: 1) to characterize selected biochemical mechanisms by which the identified genes may mediate cisplatin resistance in yeast, and 2) to evaluate the human homologues for their roles in cisplatin resistance using a genetic complementation assay and the RNAi interference strategy. Identification of new mechanisms accounting for cisplatin resistance is of fundamental importance. Evaluation of these targets may identify new biomarkers for pre-treatment screening of tumor samples for mutations that could allow for the identification of patients who are unlikely to benefit from cisplatin treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: IN VIVO EPR IMAGING OF REDOX STATUS AND THIOLS IN TUMOR Principal Investigator & Institution: Kuppusamy, Periannan; Associate Professor of Internal Medicine; Internal Medicine; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2008 Summary: (provided by applicant): Ovarian Cancer is the fifth leading cause of death among women in the United States. Early stages of this disease are usually asymptomatic with high malignant potential. Due to lack of adequate diagnostic techniques, the disease is usually detected at late stages. Surgery is used for debulking followed by chemotherapy as a supplemental treatment modality. Platinum-based complexes (for example, cisplatin, carboplatin) in combination with natural products (e.g. paclitaxel, docetaxel) are the primary chemotherapeutic agents used in the
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treatment of ovarian cancer. However, a major limitation to the success of the platinumbased chemotherapeutic regimen is the frequent development of drug resistance in the recurrent tumor. Evidences suggest that increased cellular thiol levels are associated with the reduced sensitivity of tumor cells to cisplatin. Therefore, a reliable and noninvasive method to determine the thiol level in the tumor should be a useful adjunct for the clinical oncology, pharmacology and chronotherapy of ovarian cancer. The objective of this proposal is to develop and apply electron paramagnetic resonance (EPR) spectroscopy and imaging techniques to measure tumor redox status, including thiol levels, in vivo. The EPR technique has the unique advantage of direct and noninvasive detection of overall redox as well as thiol redox in tissues. In addition, reliable and accurate in vitro measurements can be performed in cell suspension and biopsy tissues with ease of preparation and minimum processing. Preliminary data on in vitro cellular systems and in vivo murine tumor models show that the thiol levels can be measured and imaged utilizing EPR spectroscopy. The specific aims are: 1. Development of an in vitro EPR technique to perform measurement of intracellular thiols in human ovarian cancer cells; 2. Development of in vivo EPR techniques to perform non-invasive imaging of redox status and thiols of normal tissue and tumor in mice; 3. Monitoring thiol levels in ovarian cancer cells before, during and after treatment with platinum antitumor drugs and taxanes; 4. In vivo measurement and imaging of thiols in human ovarian cancer cells grown as solid tumor xenografts in athymic nude mice. The results will enable a better understanding of the development of drug resistance in ovarian cancer and offer efficient diagnosis for effective treatment of ovarian cancer patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INNOVATIVE TOXICOLOGY MODELS FOR DRUG EVALUATION Principal Investigator & Institution: Yee, Jiing-Kuan; Associate Professor; City of Hope/Beckman Research Institute Helford Building Duarte, Ca 910103000 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2005 Summary: (provided by applicant): A. Specific Aims: The overall goal of this proposal is to use reversible immortalization approach to establish cell lines derived from primary human renal proximal tubule epithelial cells (RPTECs) and hepatocytes. Liver and kidney are two critical organs for drug metabolism and excretion, and are frequently affected by drug-induced toxicity. Currently, no suitable human kidney cell line is available for drug screening in the early stages of drug discovery and development. While primary human hepatocytes are available, the high cost to culture such cells precludes their use in the drug screening process. If immortalized cell lines that are phenotypically stable and retain all or most of the primary cell functions can be established, they can be used for high-throughput screening of potential drugs. There are three specific aims in this proposal. I. Characterization of TH1 and TH7 cells for kidney functions: In our preliminary study, we used human immunodeficiency virus (HIV)-based vectors containing the cDNAs encoding the SV40 T antigen (Tag) and the catalytic subunit of human telomerase (hTERT) to establish several immortalized cell lines derived from primary human RPTECs. We propose to characterize the biochemical and functional activities in two of these cell lines, TH1 and TH7. We will determine the basal expression and the activity of xenobiotic metabolizing enzymes in these two cell lines. We will evaluate the activity of drug transport proteins, drug uptake and efflux. We also propose to use Cre-LoxP mediated recombination system to remove the introduced Tag and the hTERT cDNAs from these two cell lines and examine its effect on cell proliferation, differentiation and biochemical functions. II. Establishment and
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characterization of immortalized human hepatocytes: We propose to use the same strategy as described in specific aim I to establish and characterize immortalized human hepatocytes. Ill. Evaluation of drug toxicity in the immortalized cell lines: We will determine the drug sensitivity of the established cell lines, including methotrexate (MTX), cisplatin, cyclophosphamide and paclitaxel. The toxicity induced by these drugs in primary human cells and in cell lines derived from hepatocytes and RPTECs will also be examined and the results will be compared with those from the immortalized cell lines established in this current study. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: LABELED THYMIDINE -- DEVELOPMENT AS A PET IMAGING AGENT Principal Investigator & Institution: Shields, Anthony F.; Professor; Internal Medicine; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2004; Project Start 01-JAN-1988; Project End 31-MAR-2009 Summary: (provided by applicant): We have worked to develop thymidine and its analogs for use in positron emission tomography (PET) and the evaluation of cancer. Of the different analogs that we have developed FLT (3'-deoxy-3'-fluorothymidine) has been found to be one of the most promising. FLT provides high contrast tumor images and has a low background particularly within the thorax. We have produced kinetic models of its retention and validated them on biopsy specimens. FLT is retained in cells primarily in its phosphorylated form by the action of thymidine kinase (TK1). While little FLT is incorporated into DNA, its uptake has been shown by others to correlate with proliferation in patients with non-small cell lung cancer (NSCLC) and lymphoma as measured by ki67. Further work is needed to develop FLT for use in the assessment of cancer and compare it to FDG. To develop and test these uses we will study the uptake of FLT in the evaluation of NSCLC treatment as follows: 1) Patients with resectable, locally advanced disease (stage IlIA) will be treated with radiation and cisplatin/etoposide. Such patients will be imaged with FLT prior to therapy and at least at the completion of 4500 CGy of radiation treatment, when they are being considered for surgery. Specimens removed at surgery will be analyzed to validate the imaging. [F18] fluorodeoxyglucose (FDG) imaging will also be done at concurrently for comparision. Imaging results will be compared to the ultimate clinical results including time to progression and survival. 2). Patients with metastatic disease (stage IV) will be studied before and after one and two cycles of therapy with carboplatin/paclitaxel using both FLT and FDG. Changes in FLT retention will also be examined in culture, to correlate changes seen in vivo with changes in proliferation and thymidine kinase expression. 3) Finally we will examine the retention of FLT in patients undergoing therapy that combines targeted agents; inhibitors of epidermal growth factor receptor gefitinib (Iressa, ZD1839) and cyclooxygenase 2 (celecoxib). We seek to determine if PET can provide an early measure of efficacy before conducting large phase III trials. In summary, our proposal seeks to develop FLT imaging for use in the evaluation of lung cancer treatment. Our ultimate goal is to demonstrate that this approach is useful in evaluating both experimental and routine clinical treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Cisplatin
Project Title: MCAV IN ORGAN-CONFINED BLADDER CA BASED ON P53 STATUS Principal Investigator & Institution: Cote, Richard J.; Associate Professor of Urology and Patho; Pathology; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2003; Project Start 01-MAY-1997; Project End 31-MAR-2007 Summary: (provided by applicant): This is a renewal application to our on-going "p53/MVAC" study. Tumor progression in transitional cell carcinoma (TCC) of the urinary bladder is believed to occur through a multistep accumulation of genetic alterations. p53 alterations are involved in the transformation of normal urothelium to carcinoma-in-situ of the bladder and in the progression to invasive disease. We have shown that (1) adjuvant chemotherapy prolongs the recurrence free interval in a group of patients with invasive TCC at high risk for recurrence and that (2) detection of p53 alterations in a bladder tumor is significantly associated with an increased chance of progression in patients with organ-confined TCC managed by radical cystectomy. Our hypothesis is that p53 alterations organ-confined TCC of the bladder significantly increase the risk of recurrence and death, and that adjuvant chemotherapy will improve survival in these high risk patients. To test this we have designed a study that will enroll patients who have already undergone a radical cystectomy with a pathologic stage of P1, P2a/b N0 M0. Patients with TCC demonstrating p53 alterations (p53+) who are willing to be randomized will be assigned either to no further treatment, i.e. observation which is the standard of care for patients with organ-confined disease, or to 3 cycles of MVAC chemotherapy. Those who are p53+ and decline randomization, and those who are p53- (no alteration in p53), will be observed. The specific aims of this prospective study are to (I) compare the recurrence free interval and overall survival of p53+ patients who are treated with MVAC to p53+ patients who are observed, (II) compare the recurrence free and overall survival of p53+ patients who are observed to p53patients who are also observed, (III) study the expression of other genes involved in cell cycle regulation that may be involved in the response to chemotherapy, (IV) examine the association of p53 mutational gene status with p53 protein expression, outcome, and response to chemotherapy. This is a new aim to this renewal application. To date over 30 academic institutions in the United States, Canada and Europe participate in this prospective study. The study was activated at the Southwest Oncology Group (SWOG) in 2001 and we are making a substantial effort to attract other Canadian and European institutions to this study. As of May 2002, 281 patients have been registered to the study and 58 p53+ patients have been randomized to MVAC or observation, making this one of the largest adjuvant trials in bladder cancer. The infrastructure to support this study is firmly established including 1) Full compatibility of data management with SWOG. (2) Completion of the interim audit by July 2002. (3) Fourth Annual meeting of the Data Safety Monitoring Committee planned for August 2002. (4) Institution of the patient advocacy program, the first for bladder cancer. (5) The 5th annual investigator's meeting took place May 2002. With the participation of new institutions and with patient accrual and randomization increasing, we expect to complete accrual by 2006 (approximately 33-35 patients randomized per year). This is the first study in bladder cancer in which therapeutic decisions are made based on the status of a molecular alteration. The results of this studio could fundamentally change the management of bladder cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MECHANISM OF DNA DAMAGE RECOGNITION IN HIGHER EUKARYOTES Principal Investigator & Institution: Lee, Suk-Hee; Assistant Professor; Biochem and Molecular Biology; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2002; Project Start 01-JUN-2001; Project End 31-MAY-2006 Summary: Cisplatin is widely used anti-cancer chemotherapeutic drug that induces DNA damage by forming Cisplatin-DNA abducts in cells. In vivo and in citron studies strongly suggest that most of the Cisplatin-DNA abducts are repaired through nucleotide excision repair (NER) pathway. Due to extensive efforts, we now have significant knowledge about the mechanism of NER and the proteins involved. Recognition of DNA damage is a critical step in the early stage of repair. Xeroderma pigmentosum group A complementing protein (XPA), replication protein A (RPA), XPC-hHR23B, and XPE can independently bind damaged DNA. However, it is still in debate how the damaged recognition proteins function at the damaged DNA site. In this proposal, we will use biochemical and molecular approaches to address the following specific questions: 1) how multiple damage recognition factors function at the damaged DNA site? 2) do zinc-finger proteins (RPA and XPA) cause structural distortion at the damaged site? If so, is it necessary for dual incisions? 3) how do the damaged recognition factors affect the efficiency and accuracy of 3' and 5'- incisions? In the first aim, binding kinetics of individual damage recognition proteins to damaged DNA, interactions between damaged recognition factors, and assembly of a preincision complex will be analyzed using purified repair proteins (RPA,XPA,XPC-hHR23B, and TFIIH) and Cisplatin-induced intra strand crossed-linked DNA. In the second aim, we will analyze the molecular basis for structural dissertation of Cisplatin-damaged DNA. Conformational charges of damage recognition proteins following their interment with amazed DNA and the role of the zinc-finger motif of RPA and XPA in this event will be analyzed. We will use a foot printing assay to analyze the structural distortion of damaged DNA induced by damage recognition factors. In addition, fluorescence resonance energy transfer (FRET) method will be utilized to simultaneously monitor both the conformational change of damage recognition proteins and distortion of the damaged DNA. In the third aim, we will attempt to functionally define the role of damage recognition factors in 3' and 5' incision activity by XPG and ERCCI-XPF will be examined. Both the accuracy and efficiency of the 3' and 5' incisions will be analyzed in advance with the kinetics of incision activity. Various mutants of damage recognition factors (RPA and XPC) will be used to examine any unique role these proteins possess in 3' and 5' incising. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MECHANISMS OF NEURONAL DEATH AND NEUROPROTECTION Principal Investigator & Institution: Windebank, Anthony J.; Mayo Clinic Coll of Medicine, Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2002; Project Start 01-JUN-2000; Project End 31-MAY-2005 Summary: Adapted from the Investigator's Abstract): "Mechanisms of Neuronal Death and Neuroprotection" Chemotherapeutic neurotoxins provide model systems in which basic cellular mechanisms relevant to human disease can be studied. Findings can lead directly to design of treatment trials. Neurotoxicity is dose limiting for cisdiamminedichloroplatinum (cisplatin; CDDP), a first line agent for treating ovarian, testicular, and other neoplasms. The primary target is the dorsal root ganglion (DRG)
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Cisplatin
neuron or its axon. We have demonstrated in a rat model that CDDP induces apoptosis in DRG and have replicated this process in vitro. Nerve growth factor (NGF) prevents this cell death. In cancer cells CDDP binds to DNA. Dividing cells respond to DNA damage by slowing or arresting growth allowing the cell to repair damage before proceeding to DNA replication. If DNA damage is extensive, the cell undergoes apoptosis. The investigators have previously demonstrated that CDDP induces apoptosis in neurons. This is preceded by up regulation of nuclear cyclin D1 expression and increased phosphorylation of the retinoblastoma gene product. These biochemical changes and ceil death are prevented by nerve growth factor (NGF). They propose that DNA damage in neurons induces repair processes that up regulate genes associated with transition from G0 to G1. Since it is highly disadvantageous for post-mitotic neurons to divide, they undergo apoptosis. We will test this hypothesis by (1) determining whether CDDP induces DNA damage by forming Pt-DNA adducts in DRG neurons and whether Pt-DNA complexes are sufficient to induce apoptosis; (2) determining which steps in DNA damage recognition or repair are necessary to initiate cisplatin induced neuronal death using mouse knockouts. If they are necessary, do they occur upstream of the cell cycle changes? (3) Determine where NGF interrupts the death pathway and which NGF signal transduction pathway is responsible for rescue. NGF can be used therapeutically as a specific neuroprotectant. It is one of the primary survival factors for DRG neurons, it has been safely administered to humans, systemic NGF has access to DRG neurons in vivo, and most cancer cells do not have NGF receptors. In the future we will determine whether NGF can be used therapeutically in animal and human models of GDDP neurotoxicity. We will also determine whether the effects of NGF are shared by the other DRG growth factors, brain derived neurotrophic factor (BDNF), and neurotrophin-3 (NT3). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANISTIC STUDIES ON NEW PLATINUM CLINICAL AGENTS Principal Investigator & Institution: Farrell, Nicholas P.; Professor; Chemistry; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2002; Project Start 30-SEP-1998; Project End 31-JUL-2007 Summary: (provided by applicant): This application proposes to study the unique aspects of the DNA adducts formed by the polynuclear platinum compounds that have emerged from our laboratory and the biological consequences of formation of these novel structures. These compounds, where two or three platinum coordination units are linked in a linear fashion, comprise an important new class of anticancer drugs. The first clinical compound, currently denominated BBR3464, is a trinuclear, bifunctional DNA binding agent with an overall 4+ charge. BBR3464 is now in Phase II clinical trials in cancer patients. The Phase I trials demonstrated a clear pattern of responses in cancers not normally treatable with cisplatin, (cis-DDP cis-[PtCl(2)(NH(3))(2)]) including responses in melanoma, pancreatic and lung cancer. Objective responses in Phase II have been verified in relapsed ovarian cancer and non-small cell lung cancer. Preclinical studies indicated activity in p53-mutant tumors and a minimal induction of p53 following BBR3464 treatment. A second drug, a polyamine-bridged dinuclear compound, will enter Phase I clinical trials in early 2002, and thus allows comparison between di- and trinuclear compounds within the general class. The high positive charge, the presence of at least two Pt coordination units binding to DNA and the consequences of such DNA binding are remarkable structural and mechanistic departures from the cisplatin paradigm, and indeed all other DNA-modifying anticancer agents. It is the long-term goal of this project to understand how a unique
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pattern of DNA adduct formation may result in different cellular signaling or "downstream" effects such as protein recognition and whether such events may be dictated to lead to a genuinely new pattern of antitumor activity. It is a further longterm goal of this project to place the cytotoxic effects of these compounds into the context of molecular pathways leading to cell death. Elucidating the mechanism of action of this new class of anticancer agents will lead to design of better, more specific drugs for treatment of cancer. The proposed research explores a variety of structurefunction relationships within the diverse polynuclear platinum class. The specific aims build on the understanding gained to date. The hypothesis that formation of long-range interstrand crosslinks, and their conformational flexibility, may lead to delocalization of the lesion and represent formidable challenges to repair will be examined. The importance of pre-association of the charged drug on the DNA backbone in determining the nature and direction of long-range intra and interstrand crosslinks will be elucidated. New, high-affinity DNA-binding agents will be studied to determine the effect of electrostatic and hydrogen-bonding interactions on DNA structure and function, in the absence of covalent binding. Finally, the unique structure of polynuclear platinum compounds will be exploited to study consequences of binding to singlestranded DNA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MICROARRAY ANALYSIS OF HNSCC AS A PREDICTOR OF TREATMENT Principal Investigator & Institution: Shores, Carol S.; Otolaryngology/Head & Neck Surgery; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2006 Summary: (provided by applicant): Candidate: The proposed research will develop a microarray based assay to predict the prognosis and response to treatment of primary head and neck squamous cell carcinomas (HNSCC). Dr Shores will utilize the training time provided by this grant to develop the necessary skills to translate her background in protein biochemistry to a strong base in molecular genetics. Dr Shores' career goal is to provide excellent patient care in an academic setting while developing clinical/translational cancer research. Her primary research interest is to develop novel diagnostic and treatment modalities for head and neck squamous cell carcinoma. The long term goal is to biopsy the primary tumor at first patient presentation and based on molecular analysis of the tumor, predict how aggressive the tumor will be and which treatment modality it will best respond to. Funding of this proposal will ensure that 75% of Dr Shores' time will be devoted to the proposed research project. Environment: Support for this proposal comes from the UNC Lineberger Comprehensive Cancer Center (LCCC), the Division of Otolaryngology/Head and Neck Surgery, the UNC Genomics Core Facility and the UNC Center for BioInformatics. Dr Shores is provided space in the lab of her collaborator, Dr Wendell Yarbrough, in the LCCC. All of the core facilities of the LCCC will be available for this research project. Support will include equipment, reagents and consumables for the project. Research: A microarray of genes will be assembled for this proposal. They will include genes shown to predict aggressiveness of HNSCC and all of the known genes in the DNA damage response, p53, Rb and apoptosis pathways. Sensitivity of HNSCC cell lines to cisplatin and gamma radiation will be correlated with the changes in array pattern before and after these treatments. The cell will be grown in raft cultures, a three dimensional model system of mucosal tumors. Primary HNSCC tumors will then be collected and RNA
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isolated for gene expression determined by the microarray. The same cells will be place in raft culture, and treated with and without cisplatin or gamma radiation. RNA will be isolated from the cultured cells, and analyzed using the microarray. Patients will be followed for initial and long term response to therapy. Gene expression patterns will be analyzed, with the goal of predicting response to therapy. In addition, microarray analysis will shed light on the molecular basis of cisplatin and radiation resistance in HNSCC. The arrays will also shed light on the molecular mechanism of resistance to therapy and control of apoptosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ESOPHAGEAL CA
MOLECULAR
CORRELATES--OXALIPLATIN/5FU/XRT,
Principal Investigator & Institution: Pendyala, Lakshmi; Roswell Park Cancer Institute Corp Buffalo, Ny 14263 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2004 Summary: (Provided by applicant): There is a pressing need for new agents in the treatment of esophageal cancer and to identify intratumoral molecular markers predictive for tumor response to chemotherapy. Although cisplatin/5-fluorouracil (5FU) plus radiation (XRT) is considered standard therapy for patients with locally advanced esophageal cancer, distant tumor recurrence, representing chemotherapy failure, is the rule. Moreover, the toxicity profile for cisplatin may be disabling. Oxaliplatin (OXP) a diaminocyclohexane platinum complex has a more manageable toxicity profile. Clinical/pre-clinical data suggest OXP-5FU synergy; mechanisms behind the synergy are not understood. Prior studies have shown that response and survival after therapy with 5FU (colon cancer) or 5FU/cisplatin (gastric cancer) are inversely associated with thymidylate synthase (TS), dihydropyrmidine dehydrogenase (DPD) and the excision repair cross-complementing-1 (ERCC-1) gene expressions. Studies of OXP resistant cell lines indicate that resistance is multifactorial, as evidenced by lowered drug accumulation, increased glutathione and decreased DNA-Pt adducts. Resistant cells also had elevated expression of gamma-glutamyltranspeptidase (gamma-GT) and ERCC- 1 genes. Thus, the underlying hypotheses in this application are: A) molecular markers within a primary esophageal tumor will predict sensitivity or resistance to chemotherapy, B) oxaliplatin affects 5FU by lowering TS gene expression and C) pharmacokinetics (PK) of OXP will influence the changes in gene expression. The specific aims of this study are to determine: 1) the intra-tumoral mRNA expression of TS, DPD, gamma-glutamylcysteine synthetase (gamma-GCS), gamma-GT, multidrug resistance associated protein-2 (MRP-2), ERCC-1 and xeroderma pigmentosum A (XPA) at pretreatment, 1 week after OXP alone, and after 1 cycle (with 5FU/radiation), exploring the relationship between these expression levels and response/resistance to treatment; 2) the PK of ultrafilterable platinum on day 1 when OXP is given alone and again on day 15 a week after combination with 5FU + XRT and 3) the relation between PK and changes in intratumoral gene expression and 4) maximum tolerated dose (MTD), dose limiting toxicity (DLT), and the potential therapeutic responses to OXP when given with continuous infusion 5FU + XRT. The gene expression studies will be carried out using real time quantitative RT-PCR (Taqman( r )) assays in endoscopic biopsies. Preliminary results indicate that the regimen is tolerable, the proposed gene expression measurements can be carried out using endoscopic biopsies and changes in gene expression are being detected for some genes during therapy. The long term objectives are to identify a drug combination for better clinical outcome and to identify molecular parameters predictive for response or resistance.
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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOUSE MUTAGENESIS
MODEL
FOR
CHEMICAL
AND
RADIATION
Principal Investigator & Institution: Tischfield, Jay A.; Professor and Chair of Genetics; Genetics; Rutgers the St Univ of Nj New Brunswick Asb Iii New Brunswick, Nj 08901 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 31-JUL-2007 Summary: (provided by applicant): There are distinct kinds of DNA damage caused by environmental chemicals and ionizing radiation (IR). However, double strand breaks (DSBs) in DNA are among the most serious. Failure to repair or gross misrepair of DSBs results in cell death or sometimes, in the case of humans, somatic cell diseases such as cancer. Knockout mice and work with cultured cells has demonstrated that DSB repair in vertebrates is much more complex than previously imagined. It was thought that most DSB repair in mammals was by non-homologous end-joining (NHEJ), but it is now clear that homologous recombination (HR) and other homology-directed processes play key roles in maintaining genome integrity. Further, these mechanistically distinct processes interact in novel ways with each other as well as those for mismatch repair (MMR) and apoptosis. We developed a mouse model that detects somatic genetic endpoints of DSB and other kinds of repair. These include mitotic recombination (MR), interstitial deletion and chromosomal deletion and translocation, all of which may result in loss of heterozygosity (LOH). This model also allows for the quantitation and characterization of point mutation, chromosome loss and epigenetic gene inactivation leading to LOH - key biological events to the etiology of cancer and diseases such as polycystic kidney disease. By introducing knockout defects of DNA repair or apoptosis into our model and by exposing these mice to IR or DNA cross-linking agents such as mitomycin C and cisplatin we will begin to understand the roles and regulation of competing DSB repair processes. Specific aims include: 1. To characterize the LOH frequency and spectrum of DAP-resistant (DAPR) skin fibroblasts and T cells in Aprtneo/+ mice after in utero or adult exposure to ionizing radiation (IR). 2. To investigate the effect of mitomycin C on LOH in Aprtneo/+ mice. 3. To introduce deficiency for each of the MMR gene products and note effects on the MR stringency requirement for DNA sequence homology. 4. To investigate whether DSB and MMR repair pathways both participate in repair of damage induced by mitomycin C or cisplatin. 5. To introduce Ku70 deficiency to test whether or not NHEJ and HR have overlapping functions. 6. To introduce DNA-PKcs deficiency to test whether or not Ku and DNA-PKcs participate in distinct as well as common DSB repair pathways. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NAVELBINE AND CISPLATIN IN PATIENTS WITH ADVANCED BREAST CANCER Principal Investigator & Institution: Hochster, Howard S.; Assistant Professor; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2002; Project Start 01-DEC-2001; Project End 30-NOV-2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NEURAL BASIS OF LEARNED FOOD AVERSION AND NAUSEA Principal Investigator & Institution: Horn, Charles C.; Monell Chemical Senses Center 3500 Market St Philadelphia, Pa 19104
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Timing: Fiscal Year 2004; Project Start 01-JUN-2004; Project End 31-MAY-2009 Summary: (provided by applicant): Some medications produce nausea and vomiting that may lead to loss of appetite and reduced food intake, which can negatively affect recovery from disease. Nausea and vomiting are frequently observed with use of cytotoxic chemotherapy agents. Little is known about the neural pathways and mechanism for detecting toxins. Gastrointestinal (GI) sensory nerve fibers play an important role in the initiation of vomiting, and may also be involved in the stimulation of nausea. The present proposal will focus on identifying the pathways and neurochemistry of GI vagal and spinal afferent fibers and brain nuclei that are activated by toxins. To address this issue experiments will be conducted to examine the effects of cisplatin (a chemotherapy agent) and lithium chloride (LiCI) (treatments that produce nausea in humans) on visceral afferent nerve activity and brain and spinal cord Fos expression. Studies will determine: (1) the properties (neurotransmitter receptors, stretch-sensitivity, site of innervation in the stomach and intestine) of vagal and spinal afferent fibers responsive to cisplatin and LiCI using a novel application of single-unit neurophysiology, (2) the brainstem and spinal cord sites that are activated by cisplatin and LiCI treatment using Fos expression, (3) the peripheral neural pathways involved in brain Fos expression produced by cisplatin and LiCI using lesions of the vagus and GI spinal nerves, and (4) the neurotransmitter receptors that play a role in the brain Fos response produced by cisplatin and LiCI treatment. An understanding of the physiology of toxin detection may contribute to nausea treatment in a large number of clinical situations, including cancer chemotherapy, diabetic gastroparesis, anorexia nervosa, ischemic gastropathy, chronic intestinal obstruction, abdominal malignancy, and functional dyspepsia. Effective treatment of nausea may substantially improve the quality of life for patients with chronic disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NF KAPPA B MEDIATED CHEMORESISTANCE IN HUMAN LUNG CANCER Principal Investigator & Institution: Jones, David R.; Surgery; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2002; Project Start 05-AUG-2000; Project End 31-JUL-2005 Summary: Lung cancer is the most common cause of cancer death in both men and women. Eighty percent of all newly diagnosed lung cancers are non-small cell lung cancers (NSCLC), and over 75 percent present with advanced stage disease. For this reason as well as the predilection for distant recurrence after complete resection, most patients are treated with chemotherapy alone or in combination with other modalities. Unfortunately, the majority of NSCLC are chemoresistant despite treatment regimens with second or third generation of chemotherapeutic agents. Tumor chemoresistance has been attributed to the ability of cells to overcome programmed cell death (apoptosis). Recently, it has been established that chemotherapy upregulates the NFkappaB transcription factor and this is associated with cellular resistance to chemotherapy-induced apoptosis. With this understanding, experiments were performed to determine whether NF-kappaB provided a similar cell survival signal in NSCLC cell lines following the addition of gemcitabine and cisplatin, two genotoxic agents commonly used to treat NSCLC. Preliminary data demonstrates that these chemotherapeutic agent induce NF-kappaB transcriptional activity. More importantly, the loss of NF- kappaB sensitizes NSCLC cell lines to chemotherapy-induced apoptosis. Although cell death induced by chemotherapy involves death receptor pathways in certain cell types, chemotherapy- induced apoptosis in NSCLC cells did not involve
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either Fas- or caspase-8-dependent death receptor pathways. In contrast, NF- kappaB was required to overcome mitochondrial-mediated apoptosis following chemotherapy addition. In addition, ceramide has recently been shown to inhibit the anti-apoptotic P13K/Akt pathway as well as activate NFkappaB. Since the loss of NF- kappaB activity sensitizes NSCLC cells to chemotherapy-induced apoptosis, the major goal of this proposal is to examine the cell signaling mechanisms governing apoptosis and chemoresistance following the addition of chemotherapy. To achieve this objective, we will use established (by the P.I.) cell lines which lack NF-kappaB activity and compare them to controls. These cells will be exposed to chemotherapeutic agents and apoptotic and anti-apoptotic signaling pathways will be examined in vitro. The specific aims of the proposal are to: 1) establish whether chemotherapy kills NSCLC cells through mitochondrial-dependent mechanisms, 2) determine whether the redox status of the cell is responsible for modulating NF-kappaB-dependent cell survival in response to chemotherapy, and 3) determine the role of ceramide as both a pro- and anti-apoptotic mediator following chemotherapy. These studies will provide important insight into how chemotherapy activates apoptotic pathways, as well as mechanisms by which tumors become chemoresistant through upregulation of NF-kappaB. The ultimate goal of this study is to provide the necessary background for the initiation of novel treatment strategies designed to treat patients with advanced lung cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NON-INVASIVE MONITORING OF TUMOR SPECIFIC T CELL ABLATION Principal Investigator & Institution: Mccarthy, Timothy; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 31-MAY-2002; Project End 31-MAR-2007 Summary: (provided by applicant): Immune surveillance is a process by which T lymphocytes of the immune system detect and destroy transformed cells before they can become a threat to the host. This general idea is strongly supported by data directly demonstrating the presence of mutated proteins in some tumor cells that can serve as targets for immunological responses and tumor destruction. Thus, many tumors are visible to the immune system. Despite this, some tumors that are potentially visible by way of expressing mutated proteins still evade the immune response and kill the host. The process of tumor rejection by T lymphocytes requires the migration of the T cells from the blood into the tumor mass where contact dependent cytotoxic mechanisms and concentrated delivery of cytokines can be effective against the tumor. We hypothesize that one mechanism of failure of the immune response to reject tumors is failure to migrate to the tumor. To test this hypothesis we propose to image T cell migration to tumors using a targeted transgenic mouse and tumor model system combined with whole animal imaging technologies including MicroPET and MRI. The specific model is based on the DUC18 transgenic mouse that produces T cells that are focused on an antigen produced by the CMS-5 tumor cell. In preliminary experiments, we have shown that DUCl8 T cells efficiently reject the CMS-5 tumor implanted in mice. Thus, a critical next step is to study the migration of DUC18 T cells in live tumor bearing mice using radiotracer molecular imaging techniques. The project is divided into three specific aims. First; to use our MicroPET/MR techniques to study cell-mediated ablation kinetics of the implanted tumor model. Second; to investigate optical techniques to study tumor rejection and finally; to extend this research to include T cell ablation of a metastatic lung tumor model. DUCl8 T cells will be radiolabeled either internally or on surface receptors with targeted 64Cu chelates. Serial imaging of the radiolabeled cells will be
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achieved using MicroPET and co-registered with high-resolution MR images of the mice. This will allow for accurate measurement of the kinetics of cell distribution and tumor volume and subsequent MicroPET/MR imaging will be used to follow the ablation process over the following days. In addition, we will cross-validate new optical probes to monitor the process of T cell tumor ablation in these genetically engineered mice in vivo. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NOVEL INORGANIC NUCLEASES Principal Investigator & Institution: Cowan, James A.; Professor; Chemistry; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2007 Summary: (provided by applicant): Traditional drug development has focused primarily on protein targets. This reflects the diverse structural and catalytic roles of cellular proteins that provide for opportune targets in metabolic and infectious disease. The complexity of protein structure also affords an opportunity for highly selective recognition by organic molecules, using spatial and bonding constraints to map drugs to protein targets. Such approaches have been successfully used in the treatment of disease states that derive from structural or catalytic perturbations of enzyme function. The role of inorganic chemistry in drug development has been severely limited and metal ions have been recruited into drug design only peripherally, either as a target for binding of an organic ligand through coordination to the metal cofactor of a metalloprotein, or, rarely, as an active complex. DNA has also served as a focus of investigation for drug development, and in this case cisplatin is an example of one of the most prominent applications of inorganic complexes in the treatment of disease. However, DNA poses significant problems with regard to recognition of specific sequences. Typically this requires the use of complementary oligonucleotides with an attached metal complex and such an approach severely limits the scope of what can be usefully developed. A third target, RNA, has not previously received the intensity of recognition afforded to the other two, although many structural and chemical features of RNA make it attractive as a drug target. Most important, there is no cellular repair mechanism for RNA As a result of the many disease states caused by RNA viruses, compounds that are capable of specific or selective binding to RNA should be considered in developing effective chemotherapeutic treatments. Copper aminoglycosides are demonstrated to be highly efficient cleavage catalysts for DNA and RNA targets. Such catalysts mediate both oxidative and hydrolytic pathways and their cleavage reactions display enzymelike Michaelis-Menten kinetic behavior. Both in vitro and in vivo cleavage of RNA targets have been demonstrated, and this proposal seeks to expand our understanding of the chemical mechanisms underlying the selective binding and cleavage of RNA targets and improve develop their use as bona fide inorganic drugs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PHARMACOLOGY AND DRUG RESISTANCE Principal Investigator & Institution: Colvin, Oliver Michael.; Professor; Duke University Durham, Nc 27710 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2008 Summary: (provided by applicant): The anti-tumor effect and the toxicity of any regimen are obviously related to the concentrations of the active components of the drugs to which tumor and normal tissues are exposed. It has been shown that
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pharmacokinetic-based individual dose modulation of busulfan can reduce the incidence of veno-occlusive disease and ensure adequate therapeutic drug exposure for allogeneic cell engraftment. We also know that other chemotherapy agents and auxiliary drugs such as antiemetics will interfere with the metabolism and pharmacokinetics of the agents used in the high-dose cyclophosphamide, cisplatin, BCNU (CPB) regimen. Therefore, the first Specific Aim of this project is to evaluate and implement methods to conduct pharmacokinetic-based dose individualization of CPB. We are pursuing this by a three tiered strategy of: dose individualization based on the pharmacokinetics of CPB in an individual patient; use of relatively innocuous metabolic probes to predict CPB exposure; and pre-screening patients? DNA for polymorphisms in genes which are thought to control the metabolism of CPB. The latter effort is being conducted through collaboration with our project on the Duke breast cancer SPORE grant. The goal of this work will be to reduce inter-patient variability and thus variance in outcome/toxicity. In addition, such a platform will provide us with a more consistent patient group to test innovative strategies directed at reversal of drug resistance, as outlined below. The extent and duration of cytoreduction produced by any regimen is undoubtedly related to the drug sensitivity of the patient?s tumor. Data suggest that some patients would benefit from inhibition of resistance-related enzymes such as O 6 -methyl transferase, while others may benefit from (and tolerate) additional dose escalation. Aim 2 intends to conduct clinical trials to explore both of these strategies with a goal of improving the efficacy of high-dose chemotherapy without worsening its therapeutic index. The characteristics of patients being enrolled into the mini-allogeneic transplant studies described in Project 2 would suggest that pharmacokinetic variability might be even wider in this population. Aim 3 of this project proposes to conduct a detailed pharmacokinetic/pharmacodynamic evaluation of the cyclophosphamide/fludarabine combination used in this regimen. The focus will be evaluation of factors that may explain and predict inter-patient variability in addition to investigation of relationships between systemic drug exposure and immunosuppression/engraftment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PHASE II RANDOMIZED TRIAL OF CPT-11 AND MITOMYCIN C Principal Investigator & Institution: Villalona, Miguel A.; Associate Professor; Internal Medicine; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2002; Project Start 24-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant): The poor prognosis of patients with advanced gastric and esophageal cancer indicates an obvious need for more effective treatments. Based on a response rate approaching 50% in single institution trials, irinotecan- (CPT11) cisplatin based therapy has been gaining support. However, responses are short lived and a high incidence of significant toxicity has been associated with this regimen. Based on the preclinical findings of others, documenting upregulation of topoisomerase I (Topo I) activity, the target enzyme for CPT-11, after administration of mitomycin C (MMC) and our observation that CPT-11 decreases the levels of DT-Diaphorase (NQ0R), we recently completed a pharmacologically designed phase I study of the combination. Low doses of MMC were used to modulate Topo I and CPT-11 activity. We demonstrated upregulation of expression of the Topo I gene in peripheral blood mononuclear cells (PBMC) after MMC administration, good tolerability and encouraging antitumor activity in patients with refractory solid malignancies that included patients with esophageal and stomach cancer. In this proposal, we plan to study advanced- and previously-untreated patients with esophageal and GE junction adenocarcinomas. A two arm, randomized, phase II trial will compare two schedules of
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sequential MMC and CPT-11 to pick the best of the two schedules for phase III evaluation. As a potential proof-of-concept in humans of the importance of NQ01 mutations, topoisomerase I and carboxylesterase gene expression, as predictors of chemoresistance to MMC and CPT-11, we will obtain tumor tissue and PBMC samples in order to evaluate possible associations between these genes, prognosis and antitumor activity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PHASE III RANDOMIZED STUDY OF INTENSIVE CISPLATIN AND VINBLASTIN +/- AMIFOSTINE Principal Investigator & Institution: Schiller, Joan H.; Professor; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2002; Project Start 01-DEC-2001; Project End 30-NOV-2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PREDICTING RESPONSE TO THERAPY: DETECTION OF ORAL CANCER Principal Investigator & Institution: Carey, Thomas E.; Professor of Otorhinolaryngology; Otolaryngology; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 30-SEP-1999; Project End 31-AUG-2004 Summary: A critical research goal in head and neck oncology is to define the use of chemotherapy plus radiation regimens that allow organ preservation and preserve quality of life. Progress has been limited by the failure of some tumors to respond to chemoradiation, and the lack of predictive markers for identifying those likely to respond. Furthermore, persistent or recurrent disease is often detected late when the effectiveness of salvage treatment options is limited. Oral cancer is a devastating disease for which better therapies are needed. Surgery is effective in some patients but the surgical defects can be functionally and cosmetically unacceptable and many patients recur after surgery. Thus, the development of predictive markers to select patients for appropriate therapy is needed. Our preliminary results suggest that p53 expression or mutation and expression of the apoptosis-blocking proteins, Bcl-2 and Bcl-x, interact to determine responsiveness to chemoradiation. We propose to determine in patients with oral cancers whether chemotherapy response, organ preservation and/or survival is predicted by p53 overexpression and gene mutation, and we will determine how this is influenced by the expression of Bcl-2 and Bcl-x. Our preliminary in vivo and in vitro data support the concept that tumors with mutant p53 are susceptible to cisplatin-based chemotherapy regimens but that those with wild type p53 are resistant. We will test our hypotheses in tumor samples obtained from patients before and after organ sparing therapy and we will test these hypotheses with in vitro experiments using cell lines with known p53 and Bcl-2/Bcl-x status. Specimens from patients undergoing conventional treatment will also be tested to determine how expression and mutation of these genes may influence outcome in the absence of organ sparing procedures. Furthermore, our preliminary data indicate that the presence and persistence of serum antibodies to p53 in patients with head and neck cancer is associated with poor outcome. However, we have also observed that following successful treatment the antibodies disappear and may reappear with relapse. Thus, we plan to investigate the value of antibodies to p53 as a predictive marker for persistence, recurrence, and successful therapy as well as to
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correlate p53 antibody data with p53 mutation data. The information developed in this work should result in new trials that employ predictive markers to select the most appropriate and effective treatment for oral cancer. This together with close monitoring for early recurrence should in turn lead to improved overall survival. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PROGNOSTIC MARKERS IN TRIALS FOR HEAD AND NECK CANCER Principal Investigator & Institution: Cullen, Kevin J.; Director; V T Lombardi Cancer Res Center; Georgetown University Washington, Dc 20057 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-JAN-2004 Summary: (provided by applicant): Our fundamental hypothesis is that readily identifiable biomarkers, including p53, thymidylate synthase and enzymes in the glutathione pathway are critical determinants of response and long term outcome for patients receiving chemotherapy and/or radiation for head and neck cancer. These biomarkers may be developed both as prognostic indicators to guide therapy and as targets for strategies which will enhance the efficacy of cisplatin based chemotherapy in this set of diseases. We present preliminary data which strongly suggest that overexpression of p53, thymidylate synthase and glutathione s-transferase (pi) are associated with poor outcome in patients receiving chemotherapy for head and neck cancer. We believe they can be developed as clinically important markers for patients with head and neck cancer. On the basis of our preliminary data, we propose the following aims: 1. To confirm the prognostic significance of p53, glutathione stransferase and thymidylate synthase in patients participating in clinical trials for head and neck cancer. 2. To confirm the prognostic significance of p53, glutathione stransferase and thymidylate synthase in a control group of patients receiving standard surgery and/or radiation therapy. 3. To develop tissue microarrays based on the samples in specific aims 1 and 2 for focused screening and validation of additional cellular factors as determinants of clinical response and outcome. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PROTEOTOXICITY NEPHROTOXICITY
BIOMARKERS
FOR
CISPLATIN
Principal Investigator & Institution: Flaws, Jodi A.; Associate Professor; Epidemiology and Prev Medicine; University of Maryland Balt Prof School Baltimore, Md 21201 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant):There is a pressing need to better understand the mechanisms of platinum-based anti-cancer drug toxicity to the kidney and to utilize this basic scientific information for the development of biomarkers to detect early manifestations of renal damage in patients treated with these and other nephrotoxic anti-cancer agents. It is our hypothesis that treatment of renal proximal tubule cells to platinum-based drugs will produce specific oxidative cellular effects that will be intrinsically linked to increased excretion of specific oxidized proteins of renal derivation into the urine via chaperoning by specific stress protein families. In vitro studies which will compare the responses of primary cultures of both human and rat kidney cells to cisplatin using a short term dose-response design. These studies will provide a mechanistic basis for testing the hypothesis that stress proteins play a central role in the excretion of specific oxidized proteins from this target cell population. Data from these studies should will also determine whether this proposed mechanism of
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platinum-induced toxicity is similar in rat and human proximal tubule cells. This hypothesis will be further tested via studies involving acute in vivo exposure of rats to platinum- based drugs using a dose-response, time course design. Examination of urine samples from these animals will be focused on those proteins found to be preferentially excreted by the proximal tubule cells in culture. Data from these studies will be essential for understanding the extent to which urinary biomakers derived in rats may be used for predicting platinum-induced human nephrotoxicity. The utility of these new biomarkers for earlier detection of platinum-induced nephrotoxicity in humans will hopefully be evaluated under a future R33 grant application that will apply knowledge derived from these studies to other nephrotoxic anti-cancer agents. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: RADIOIMMUNOTHERAPY Principal Investigator & Institution: Wong, Jeffrey Y.; Staff Radiation Oncologist; City of Hope National Medical Center Duarte, Ca 91010 Timing: Fiscal Year 2002; Project Start 19-APR-2002; Project End 31-MAR-2006 Summary: (provided by applicant): Recent radioimmunotherapy (RIT) clinical trials with 90Y-chimeric T84.66 anti-CEA demonstrate the feasibility of dose-intensification through stem cell support and the feasibility of combining RIT with 5-FU chemotherapy. Results indicate that clinically meaningful outcomes are achievable with cT84.66. Results also demonstrate that the primary limitations of 90Y-cT84.66 are its immunogenicity and hematopoi-etic toxicity which limit the number and frequency of therapy cycles. Further refinements in the antibody construct and in how RIT is combined with other systemic therapies are therefore needed. To more effectively integrate RIT with multi-agent chemotherapy, the next generation of Phase I clinical trials will focus on the most promising areas and will evaluate strategies that: 1) combine RIT with more potent radiosensitizing chemotherapy agents. This should result in chemotherapy doses that are potentially radioenhancing without significantly adding to hematopoietic toxicity; 2) utilize more prolonged continuous infusion chemotherapy schedules that have significantly less hematopoietic toxicity; and 3) incorporate regional delivery of radioenhancing chemotherapy and RIT to further improve on the therapeutic ratio. Trials will also evaluate two improved therapy constructs derived from cT84.66: a humanized version of T84.66 and the minibody, an intermediate molecular weight (80 kD), faster clearing construct. A humanized construct should prove less immunogenic and allow for a greater number of therapy cycles in combination with chemotherapy. The minibody demonstrates even higher tumor/marrow dose ratios compared to cT84.66. Due to faster clearance, it is predicted to have less hematopoietic toxicity and immunogenicity making it better suited for combined modality therapy. Finally, RIT directed toward other breast tumor targets will be evaluated. Specifically, the antiHER2/neu antibody, Herceptin, will be evaluated in biodistribution and Phase I therapy trials radiolabeled with 111In and 90Y. Herceptin has properties that make it attractive for RIT due to its anti-tumor effects, radiation/chemotherapy enhancing effects, and minimal immunogenicity. Project 5 involves the concerted efforts of multiple clinical and basic science Divisions and therefore fully incorporates the multi-disciplinary team approach that is a unique strength of this Program Project. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: RB, P53, & BCL-2 PROTEINS IN APOPTOSIS Principal Investigator & Institution: Weintraub, Steven J.; Assistant Professor; Surgery; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130
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Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2008 Summary: (provided by applicant): The therapeutic value of DNA-damaging antineoplastic agents is dependent upon their ability to induce tumor cell apoptosis while sparing most normal tissues. We recently found that a component of the apoptotic response to these agents in several different types of tumor cells is the deamidation of two asparagines in the unstructured loop of Bcl-xL, and we found that deamidation of these asparagines imparts susceptibility to apoptosis by disrupting the ability of Bcl-xL to block the proapoptotic activity of BH3 domain-only proteins. Conversely, we found that Bcl-xL deamidation is actively suppressed in fibroblasts, and that suppression of deamidation is an essential component of their resistance to DNA damage-induced apoptosis. Finally, we found that at least in some cells, the retinoblastoma protein mediates the suppression of Bcl-xL deamidation. We have begun to define the mechanism by which deamidation of Bcl-XL is regulated. Our data provides evidence that deamidation of Bcl-xL is induced by an upward shift in the cytosolic pH that is induced by cisplatin treatment and that the retinoblastoma protein suppresses Bcl-xL deamidation because it suppresses the increase in pH. Importantly, our data strongly suggests that the increase in pH does not directly cause deamidation of Bcl-xL. Instead, our findings support a mechanism in which the cytosolic pH increase induces deamidation of Bcl-xL by activating an autocatalytic "deamidase" function of Bcl-xL. We propose that this mechanism affords the cell tighter control of Bcl-xL deamidation and allows deamidation to occur at a lower pH and more rapidly than if deamidation were regulated directly by pH. We speculate that a similar mechanism has an important role in the regulation of other proteins. We now propose to (1) characterize the autocatalytic deamidase activity by performing a structure-function analysis of Bcl-xL with respect to this activity; (2) delineate signal transduction pathways that mediate cisplatin-induced cytosolic alkalinization; and (3) examine the potential role of dysregulation of cisplatininduced cytosolic alkalinization and Bcl-xL deamidation in tumor cell resistance to cisplatin. These studies may lead to the identification of cellular targets that allow for the development of more efficacious and less toxic antineoplastic therapies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REGULATION OF P53-MEDIATED APOPTOSIS IN GLIOMAS Principal Investigator & Institution: Lang, Frederick F.; Neurosurgery; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 77030 Timing: Fiscal Year 2003; Project Start 17-JUL-2003; Project End 30-JUN-2008 Summary: (provided by applicant): The tumor suppressor p53 as an ideal therapeutic target for gliomas. The results of our recent phase I clinical trial (PI: F.F. Lang) of adenovirus-p53 gene delivery (Ad-p53), and those of other studies in our laboratory, demonstrate that the anticancer effect of Ad-p53 occurs via apoptosis. The data also show that, whereas glioma cells harboring mutant p53 undergo apoptosis following Adp53 infection, wild-type p53 glioma cells are resistant to Ad-p53-induced apoptosis. Treatment of wild-type p53 glioma cells with DNA damaging agents after Ad-p53 infection results in significant apoptosis. Recent findings from our laboratory indicate that phosphorylation of p53 may be the critical mechanism underlying Ad-p53mediated apoptosis and may explain the resistance of gliomas to conventional therapy. Thus, the hypothesis of this proposal is that site-specific phosphorylation of p53 regulates the induction of Ad-p53-mediated apoptosis in glioma cells, and that p53 phosphorylation can be modulated with DNA-damaging agents to overcome the resistance of wild-type p53 gliomas to conventional therapy. To test this hypothesis we will construct p53 expression vectors in which critical N-terminal serines of p53 are
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mutated either to prevent their phosphorylation or to mimic constitution phosphorylation. By analyzing the apoptotic effects of these constructs on mutant and wildtype p53 gliomas with or without DNA damaging agents as well as in isogenic cell lines we will characterize the N-terminal phosphorylation sites that are critically involved in regulating p53-mediated apoptosis in glioma cells (Aim 1). By analyzing the expression of p53-responsive down-stream targets after transfer of the N-terminal serine mutant constructs into glioma cells, we will determine whether p53 phosphorylation regulates apoptosis by altering the spectrum of p53 responsive genes (Aim 2). To investigate the effects of p53 phosphorylation on Ad-p53-mediated apoptosis in vivo, human xenografts grown intracranially in nude mice will be treated with Ad-p53 with or without radiation or chemotherapy and levels of p53 phosphorylation will be correlated with apoptosis and animal survival. These studies should help define p53 phosphorylation as a therapeutic target and a marker of p53-mediated apoptosis in gliomas. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ROLE OF GRP78 IN ALKYLATING AGENT SENSITIVITY Principal Investigator & Institution: Chatterjee, Satadal; Medicine; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2002; Project Start 01-JAN-1995; Project End 31-JAN-2006 Summary: The continuing studies employing different means to induce glucose regulated stress protein GRP78, such as treating cells with 2-deoxyglucose or 6aminonicotinamide, clearly demonstrate that induction of GRP78 in V79 Chinese hamster cells is associated with potentiation of cytotoxicity inflicted by BCNU, cisplatin or melphalan as determined by clonogenic survival assays. Enhanced sensitivity to these platinating/alkylating agents, observed following GRP78 induction, is associated with an impairment of DNA cross-link repair. Further, this increase in sensitivity associated with up-regulation of GRP78 is also observed in three different human colon cancer cell lines, each bearing genetic defects, such as mutated p53, defective mismatch repair, or deficiency in O6-alkylguanine-DNA-alkyltransferase (AGT). Thus, it appears that the approach of overexpression/upregulation of GRP78, a strong Ca2+-binding protein may be useful in potentiation of cytotoxicity induced by alkylating/platinating agents. The proposal involves an investigation to determine the mechanisms of association of GRP78 induction with alkylating/platinating in various human cancer cell lines by examining the following specific questions: 1) Is the association true for human cancer cell lines originated from various tissues?; 2) What are the consequences of GRP78 induction on alkylating agent-induced apoptosis?; 3) Does GRP78-dependent increased sensitivity stem from impairment in removal of DNA adducts or DNA cross-link repair?; 4) Does GRP78 directly participate in DNA repair? and; 5) Is induced GRP78 itself the cause of increased sensitivity or is it the result of activation, or do pathways that lead to GRP78 induction and augmented sensitivity (e.g., alteration in Ca2+ homeostasis) overlap? The study is expected to provide an increased understanding of the mechanisms of GRP78 modulation of molecular and cellular responses to cancer chemotherapeutic agents that will allow strategies for transferring benchside results to the bedside. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SIGNAL TRANSDUCTION AND CELL DEATH REGULATION Principal Investigator & Institution: Basu, Alakananda; Associate Professor; Molecular Biology and Immunology; University of North Texas Hlth Sci Ctr Fort Worth, Tx 761072699
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Timing: Fiscal Year 2002; Project Start 01-JAN-2001; Project End 31-DEC-2004 Summary: Caspases, a family of cysteine proteases, are central to most cell death programs and therefore present an attractive target for therapeutic interventions. The investigators have shown that the PKC signal transduction pathway regulates anticancer drug sensitivity although the mechanism of regulation is incompletely understood. There are three classes of PKC isozymes-conventional (alpha, beta1, beta2 and gamma), novel (delta, epsilon, eta, theta and mu) and atypical (zeta and lambda / iota). Novel PKC isozymes are substrates for caspases and proteolytic activation of these isozymes has been linked to cell death. The preliminary study showed that PKC can also influence activation of caspases by apoptotic stimuli, suggesting that the PKC signal transduction pathway can be targeted to increase cell death by apoptotic stimuli. The investigators hypothesize that PKC functions not only downstream of caspases but also upstream of caspases to regulate caspase activation and cell death by chemotherapeutic drugs and that both the catalytic fragment and holoenzyme of PKC decide cell survival and cell death. The Specific Aims are: (1) to delineate which steps of the cisplatininduced caspase cascade are regulated by PKC; (2) to determine the functional significance of PKC activation and down-regulation on cisplatin-induced cell death and; (3) to establish whether deregulation in the PKC signal transduction pathway affects caspase activation and cisplatin resistance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SIGNIFICANCE OF GGT EXPRESSION IN TUMORS Principal Investigator & Institution: Hanigan, Marie H.; Associate Professor; Cell Biology; University of Oklahoma Hlth Sciences Ctr Health Sciences Center Oklahoma City, Ok 73126 Timing: Fiscal Year 2002; Project Start 01-AUG-1992; Project End 31-MAR-2004 Summary: (adapted verbatim from the investigator's abstract) Cisplatin is the most effective chemotherapy drug for the treatment of ovarian cancer. Its usefulness in the clinic is restricted by dose-limiting nephrotoxicity and the development of drugresistance within the tumor. During the previous funding period our studies demonstrated that the nephrotoxicity of cisplatin is due to the metabolism of cisplatinglutathione conjugate through a GGT- mediated pathway in the kidney. We further demonstrated that this GGT-mediated toxicity is specific to the kidney. When GGT was transfected into tumor cells it reduced the toxicity of cisplatin rather than increasing it as was seen in the kidney. These findings indicate that there are two distinct mechanisms of cisplatin toxicity. The delineation of these two mechanisms would provide the opportunity to inhibit the side effects of cisplatin without compromising its antitumor activity. The current proposal focuses on defining the mechanisms by which cisplatin exerts its toxic effects and identifying the mechanism by which tumor cells develop resistance to cisplatin. The first specific aim is to further characterize the unstable cisplatin-glutathione conjugate that is a substrate for GGT and follow its metabolism within the kidney. A series of cisplatin-glutathione conjugates will be tested as substrates for GGT-mediated activation to nephrotoxins by LLC-PK1 cells and human renal proximal tubule cells. Cisplatin-glutathione conjugates will be isolated by HPLC and their structure determined by Mass Spectrometry. The pathway by which they are metabolized will be determined with the use of selective inhibitors of enzymes within the pathways. Inhibitors that block the activation of cisplatin in vitro will be tested for their ability to block the nephrotoxicity of cisplatin in vivo. The second specific aim is to identify the mechanism by which tumors become resistant to cisplatin in vivo. Human epithelial ovarian tumors will be propagated in nude mice. Half the mice will be treated
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with cisplatin. Cisplatin resistant tumors will be isolated after several courses of treatment. mRNA will be isolated from these tumors and differentially expressed genes will be isolated by representational differential analysis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SILENCING OF APOPTOTIC PATHWAYS IN TCC BY DNA METHYLATION Principal Investigator & Institution: Jones, Peter A.; Director; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2002; Project Start 13-SEP-2002; Project End 31-AUG-2007 Summary: Revised Abstract: "Silencing of Apoptotic Pathways in TCC by DNA Methylation", is led by Dr. Peter A. Jones and represents the first systematic study investigating the role of epigenetic mechanisms, DNA methylation, and gene silencing in human tumors. The project leader will utilize state-of-the-art genome scanning and quantitative techniques to study methylation changes occurring during bladder carcinogenesis. In the previous review, this project was judged to be of high scientific merit and essentially no significant deficiencies were noted, hence no major alterations in the project have been made. In Specific Aim 1, genes specifically involved in apoptotic pathways in transitional cell carcinomas (TCC) of different grades and stages will be evaluated. The approach of concentrating on a single pathway in methylation and incorporation of environmental factors is innovative. By assessing the timing, magnitude, and potential significance of tumor related DNA methylation during malignant transformation, a better understanding of the cause and effect relationship of these genome-wide alterations with tumor progression will emerge. The goals of this specific aim are well integrated the efforts in Project 3, which will evaluate expression levels of the proteins of these genes. In Specific Aim 2, the methylation status of these same genes will be evaluated in a set of human tumors obtained from the SEER program, which contains significant epidemiologic data. This information will be utilized to explore the relationship between cigarette smoking and DNA methylation status. Specific Aim 2 is also very well integrated with Project 2, in that Project 2 will evaluate the expression of the proteins encoded by the genes evaluated for promoter methylation in Project 1 on the same set of patients. Specific Aim 3 represents a mechanistic approach to evaluate the affect of methylation status on cisplatin-induced apoptosis in different cellular environments. This project is highly likely to be successful in providing new biomarkers for bladder cancer detection and diagnosis and may also impact the clinical management of these tumors. This highly meritorious project received an average merit rating of 1.5 in the previous review, and received the same score (1.5) in the current submission. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SPECIFIC IMMUNOTHERAPY WITH MONOCLONAL ANTIBODIES Principal Investigator & Institution: Bast, Robert C.; Professor of Medicine; None; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 30-SEP-1988; Project End 31-MAR-2005 Summary: (Applicant's Abstract) Overexpression of pl85(c-erbB-2) (HER2) is observed in up to 30 percent of breast and ovarian cancers and is often associated with a poor prognosis. Antibodies reactive with the extracellular domain of HER2 can inhibit growth of cancer cells that overexpress HER2 and can potentiate the activity of cytotoxic drugs including cisplatin, paclitaxel and doxorubicin. Despite FDA approval of the anti-
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HER2 antibody trastuzumab (Herceptin) for clinical use, mechanisms by which antiHER2 antibodies inhibit tumor cell growth and potentiate chemotherapy are not well understood. In our previous studies, treatment of cancer cells that overexpress HER2 with antiHER2 antibodies have induced cell cycle arrest in G1/S and inhibited anchorage independent growth. Binding of anti-HER2 antibody upregulated p27K1P1, downregulated cyclin E and CDK2, and increased association of p27K1P1 with CDK2. Anti-HER2 antibody inhibited the interaction of HER2 with HER3, downregulated constitutive activity of phosphinositol-3-kinase (P13 kinase) and blocked heregulin induced signaling through P13 kinase to AKT and P70S6 kinases. The aims of the current proposal include: 1) to define the mechanisms by which specific unconjugated anti-HER2 antibodies inhibit growth of tumor cells that overexpress HER2; 2) to determine the mechanisms by which anti-p 185 HER2 antibodies potentiate the activity of paclitaxel; and 3) to define the interaction of HER2/HER3 driven activation of P13 kinase with endogenous abnormalities of the P13 kinase pathway. We will test the hypothesis that cell cycle arrest, inhibition of clonogenic growth, inhibition of angiogenesis and potentiation of chemotherapy relate to inhibition of signaling through the P13 kinase pathway. As a fraction of ovarian and breast cancers exhibit amplification of P13 kinase subunits, amplification of AKT and mutation of the PTEN lipid phosphatase that dephosphorylates phosphatidylinositol 3,4,5 P3, we also predict that the impact of anti-HER2 antibodies will depend upon the particular alterations in P13 kinase signaling within individual cancers. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ST.LOUIS-CAPE GIRARDEAU CCOP Principal Investigator & Institution: Henry, Patrick H.; Chairman; St.Louis-Cape Girardeau Ccop 12800 Corporate Hill Dr St. Louis, Mo 63131 Timing: Fiscal Year 2002; Project Start 01-JUN-1987; Project End 31-MAY-2007 Summary: (provided by applicant): The St. Louis-Cape Girardeau CCOP is a consortium of four hospitals in two separate bi-state health service areas serving parts of eastern Missouri and western Illinois. The Investigators from the St. Louis Metropolitan area are affiliated with one or both of the two hospitals in the consortium and have worked together for the past eighteen years in cancer treatment research protocols and more recently, in cancer control research studies. The Cape Girardeau Investigators have worked with CCOP for the past nine years and are affiliated with two hospitals in that city. During the next five years we expect to accrue at least sixty credits per year for cancer treatment research protocols of the NSABP and SWOG and at least seventy five credits (new participants and follow-up) per year for cancer control and prevention studies. These cancer control credits will be derived primarily from our participation in the Breast Cancer Prevention Trial-1, Prostate Cancer Prevention Trial-1 and the Breast Cancer Prevention Trial-2. We will continue to provide high quality data to the Southwest Oncology Group and the National Surgical Adjuvant Breast and Bowel Project which are our research bases, utilizing the data management system developed during the past eighteen years. In summary, we will continue our excellent performance of the past eighteen years in cancer treatment research studies and extend our more recent participation in cancer control and prevention trials. The past experience and capabilities of the Investigators and Clinical Research Associates provides a strong base for continuing development of this Community Clinical Oncology Program. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SUBSTANCES
STRATEGIES
FOR
EFFICIENT
ROUTES
TO
BIOACTIVE
Principal Investigator & Institution: Burke, Steven D.; Professor; Chemistry; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 31-MAR-2007 Summary: (provided by applicant): We will develop and demonstrate a powerful new strategy for bicyclic acetal synthesis and elaboration. We will apply this ketalization/ring-closing metathesis technique to the synthesis of four natural products of varying structure to illustrate its versatility. Key attributes of this strategy that act in concert to afford extremely short synthetic routes to the chosen targets are:. Subunit convergence by intermolecular ketalization (a reliable, high-yielding net dehydration);. Intramolecular C-C bond formation via ring-closing metathesis;. Production of a dissymmetric bicyclic acetal from a C2-symmetric diene-diol;. Conformational locking of a dihydropyran within the bridged bicyclic acetal, allowing exploitation of steric and stereoelectronic biases for hydropyran functionalization;. Potential for chain elaboration in two directions in the residual vinyl group of the diene-diol and the ketone "R" group in convergence subunits;. Internal masking of three functional groups (hydroxyl, hydroxyl, and carbonyl), thus avoiding extra steps for protection and deprotection. We will synthesize the targets below by expeditious sequences enabled by these considerations:. 20-Deoxybryostatins, representative of the clinically-significant bryostatin class of anticancer agents;. Didemniserinolipid B, containing the 6,8dioxabicyclo[3.2.1]octane skeleton common in bioactive agents;. Thromboxane B2(TXBz)., natural degradation product of platelet aggregation mediator TXA2and model for clinical development of thrombosis inhibitors for cardiovascular disease treatment;. Kendomycin, a recently isolated ansa macrocyclic quinone methide that has exhibited biological activity as an endothelin receptor antagonist, as an antibacterial against MRSA strains, and as a potent anticancer agent with cytotoxicities similar or superior to doxorubicin and cisplatin against several cell lines. The proposed syntheses are onethird to one-half as long as comparative benchmarks for these targets, illustrating the effectiveness of this developing strategy for dramatically affecting synthetic efficiency. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: STUDY OF A FACTP140-SSRP1-ASSOCIATED P53 KINASE Principal Investigator & Institution: Lu, Hua; Associate Professor; Biochem and Molecular Biology; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2002; Project Start 10-JAN-2002; Project End 31-DEC-2006 Summary: The overall objective of this proposal is to understand the molecular and biochemical basis underlying the regulation of the p53 tumor suppressor protein in mammalian systems. Our approach is to focus on a specific cellular process that modifies the properties of the p53 protein and thus its functions in response to DNA damage caused by UV radiation or cisplatin treatment. Hence, utilizing p53 as a probe, we have identified and purified a stress-responsive kinase complex that specifically targets serine 392 which is evolutionarily conserved and plays a critical role in regulating p53 activity. This newly identified kinase complex contains chromatin-related transcriptional elongation factor FACTp140/SSRP1 and the alpha, alpha' and beta subunits of casein kinase II (CKII). Molecular delineation of its role in regulating p53 function will shed light on the mechanisms of DNA damage-induced p53 signaling. Three specific aims are to dissect the mechanisms of p53 regulation by this kinase in response to DNA damage in experimental and biological contexts. 1) To determine how
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the substrate selectivity of the FACTp140/SSRP1-associated p53 kinase complex is achieved. Using the C-terminal domain of p53 as a substrate, the serine 392 kinase will be purified and characterized from UV- or cisplatin-treated HeLa cell nuclear extracts using conventional chromatography and affinity columns. Kinetic analysis of this kinase will be performed to examine the biochemical mechanism of its substrate specificity. Molecular, biochemical and cell biological methods will be developed to determine protein-protein interactions among the components of the complex and their association with p53 in vitro and in vivo. Interacting domains will be mapped, and the effect of deletion mutants of these kinase components on the substrate selectivity will be assessed. 2) To determine the mechanism by which the FACTp140-SSRP1-associated p53 kinase is activated in response to DNA damage. The activation of this kinase in cells after DNA damage or transcriptional attenuation will be analyzed. Co- localization of the p53 S392 kinase components after DNA damage and the effect of cisplatin-damaged DNA on the assembly and activity of this kinase complex in vitro will be analyzed. The effects of dominant negative mutants of FACTp140 or of SSRP1 on the p53 S392 phosphorylation will be assessed after DNA damage. 3) To determine whether the FACTp140-SSRP1-associated p53 kinase regulates p53 stability and activity after DNA damage. The effects of this kinase on MDM2-mediated p53 ubiquitination in vitro and in vivo, p53 stability and transcriptional activity- will be evaluated in various cells after DNA damage. These studies will systematically elucidate the novel multi- subunit protein kinase complex and will also contribute to a better understanding of a different p53 regulation mechanism in response to DNA damage. This investigation has important implications for anti-cancer drug development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SYNERGISTIC LYMPHOMAS
CHEMO
RADIOIMMUNOTHERAPY
FOR
B
Principal Investigator & Institution: Johnson, Timothy A.; Medicine; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2005 Summary: The long-term objectives of this proposal are 1) to improve therapy for nonHodgkin's lymphoma using combinations of radioimmunotherapy and chemotherapy and 2) to discern the intracellular mechanisms responsible for the synergistic cytotoxicity mediated by these two therapeutic modalities. Preliminary data demonstrate marked synergism in vitro between Iodine-131-radiolabeled anti-CD20 antibody and nucleoside analogs; moderate synergism with topoisomerase inhibitors; and non synergism with cisplatin or 4-hydroxycyclophosphamide. The specific aims of this proposal are four-fold. First, we will test the hypothesis that nucleoside analogs are a more potent class of radiosensitizing drugs for use with I-131-anti-CD20 antibodies than other drug classes using human-derived lymphoma cell lines in vitro. Conclusions will be confirmed in three different in vitro cytotoxic assays, including a clonogenic outgrowth assay, and data will be analyzed by a rigorous isobolographic methodology. Second, we will investigate the mechanisms involved in the potent synergism observed with the nucleoside analogs by assaying well-established effects of the analogs, including the induction of apoptosis, the enhancement of radiation- induced DNA damage, and the incorporation of nucleoside analog into repair DNA. Third, we will investigate the role of Fs-dependent apoptosis in the synergism between anti-CD20 radioimmunotherapy and nucleoside analogs. Fas-dependent and Fas-independent signaling will be studied in experiments employing specific anti-Fas receptor and antiFas ligand blocking antibodies, soluble protein inhibitors of the caspase proteins, and
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Cisplatin
immunoblotting of activated forms of caspase 3 (CPP32), caspase 8 (FLICE), and poly(ADP-ribose) polymerase. Fourth, the most promising combinations of radiolabeled anti-CD20 antibody and chemotherapy will be tested for efficacy in two mouse tumor xenograft models, including a subcutaneous tumor model in nude mice and a disseminated tumor model in SCID mice. The proposed studies will be performed in the laboratory of Dr. Oliver Press at the University of Washington. The large patient base and intense focus on the treatment of lymphomas and other hematologic malignancies at both the University of Washington and the Fred Hutchinson Cancer Research Center and the expertise of the radioimmunotherapy group at these institutions will facilitate rapid translation of promising combinations of radioimmunotherapy and chemotherapy into clinical trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TARGETING ADENOVIRUS VECTORS TO OVARIAN CANCER Principal Investigator & Institution: King, C Richter.; Vice President, Research; Genvec, Inc. 65 W Watkins Mill Rd Gaithersburg, Md 20878 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2006 Summary: (provided by applicant): Despite significant improvements in the management of ovarian cancer, approximately 13,900 women per year in the United States are expected to ultimately fail standard therapies and die. Peritoneal spread is the major route of dissemination and leads to significant morbidity. Therefore, ovarian cancer is well suited for the application of adenoviral anti-cancer treatments because they permit a regional administration of the vector into the peritoneal cavity with exposure of disseminated lesions to a locally high concentration of vector. However, a major disadvantage of current adenovirus vectors is that they efficiently transduce nontarget, mesothelial cells that line all the major organs in the peritoneal cavity while inefficiently transducing ovarian cancer cells. This suboptimal efficiency and specificity results because the target cancer cells often do not express high levels of the primary adenovirus receptor, the Coxsackie-Adenovirus Receptor (CAR), while the non-target mesothelial cells are efficiently transduced in a CAR-dependent manner. We have made significant strides in increasing the specificity of adenovirus vectors for cancer applications. We have created two targeted adenovirus vectors that are simultaneously mutated to avoid binding to CAR and genetically redirected for binding to either alphavbeta3/5 or alphavbeta6 integrin receptors, which are both highly expressed in ovarian cancers. Our preliminary data indicates that these vectors will avoid CARmediated gene transfer to healthy mesothelial tissue while efficiently targeting tumor cells that express either alphavbeta3/5 or alphavbeta6 integrin receptors. Our overall objective in the proposed studies is to identify a targeted lead vector expressing the therapeutic transgene for tumor necrosis factor-alpha (TNF) for the treatment of ovarian cancer. This lead must demonstrate significant anti-tumor activity with an acceptable toxicity profile in at least 2 preclinical models designed to closely mimic the clinical application. We will first test the hypothesis that the in vitro and in vivo efficiency and specificity of gene delivery are improved through targeting using vectors carrying marker genes (Specific Aim 1). We will then construct alphavbeta3/5 or alphavbeta6 targeted vectors carrying the transgene for TNF. We will test the feasibility of these vectors as clinical leads by determining whether they display appropriate anti-tumor activities and toxicity profiles according to predefined criteria (Specific Aim 2). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TARGETING AKT/NF-KAPPA BETA FOR PANCREATIC CANCER THERAPY Principal Investigator & Institution: Sarkar, Fazlul H.; Professor; Pathology; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2008 Summary: (provided by applicant): Pancreatic neoplasia is the fifth most common cancer in the United States. Its etiology is largely unknown and no curative treatment is presently available. Over-expression of epidermal growth factor receptor (EGFR) occurs in approximately 90% of human pancreatic cancer. EGFR over-expression or activation leads to the activation of Akt and NF-kappaB signaling pathways, suggesting that these pathways are important therapeutic targets for pancreas cancer. Activation of Akt/NFkappaB in pancreatic cancer induces downstream target genes, such as uPA, VEGF, IL-8 and Bcl-xl that may mediate its cardinal clinical features of locally aggressive growth, metastasis, and chemotherapy resistance. We have recently observed that genistein is a potent inhibitor of Akt/NF-kappaB pathway and inducer of apoptotic cell death. Our microarray data from cells treated with genistein showed inactivation of NF-kappaB downstream genes that are important in angiogenesis, invasion and metastasis (Cancer Letters 186:157, 2002). In addition, we have recently discovered a new cDNA that codes for ERRP. ERRP is believed to attenuate the EGFR function by sequestration of EGFR ligands, and that the ERRP could be upregulated by genistein treatment of pancreatic cancer cells. Our results also suggest that treatment of pancreatic cancer cells with either genistein or ERRP or their combinations may induce apoptotic cell death, and may also sensitize pancreatic cancer cells to commonly used chemotherapeutic agents, such as cisplatin and gemcitabine. Collectively, these findings strongly suggest that the inactivation of the EGFR/Akt/NF-kappaB pathways should be very important for devising therapeutic strategies for pancreatic cancer, which could be accomplished by our novel approach (genistein and ERRP treatment). Based on our preliminary data, we hypothesize that ERRP is a negative regulator of EGFR that inhibits proliferation and stimulates apoptosis by attenuating EGFR signaling. We further hypothesize that inactivation of Akt/NF-kappaB signaling, which is a downstream signaling pathway of EGFR, by genistein may potentiate the activity of ERRP treatment in pancreatic cancer cells, and may also sensitize these cells to cisplatin and/or gemcitabine. To test our hypothesis, we will determine how ERRP inactivates EGFR signaling, and also determine the effects of ERRP and genistein on cell growth inhibition and induction of apoptosis, and correlate these results with inactivation of Akt and NF-kappaB. Moreover, we will determine the cause and effect relationships between cell growth inhibition and apoptosis inducing activity of genistein and ERRP with Akt/NF-kappaB signaling, by gene transfection experiments. We will also test whether the inactivation of Akt/NF-kappaB by genistein and/or ERRP could sensitize pancreatic cancer cells to cisplatin and gemcitabine-induced apoptosis. Finally, we will test whether the treatment effects of these agents alone or in combinations with or without cisplatin and gemcitabine will inhibit tumor growth in SCID xenografts. These results will provide mechanistic as well as pre-clinical data in support of our hypotheses and may open new and novel avenues for the treatment of human pancreatic cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TELOMERASE SPECIFIC CASPASE TRANSFER FOR GLIOMAS Principal Investigator & Institution: Kondo, Seiji; Neurosurgery; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 31-AUG-2002
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Cisplatin
Summary: (provided by applicant): Our efforts to treat malignant gliomas are focused on methods to transfer the caspase genes to tumors. Because the apoptotic pathway may be disrupted in tumors and caspases are the mainstay of apoptosis programs, this approach is one of the most promising strategies for cancer gene therapy. However, if caspases were transduced to normal brain cells, they will undergo apoptosis. To restrict induction of apoptosis to tumor cells, we need to establish a tumor specific expression system of caspases. Telomerase is a particularly attractive target for the tumor-targeting system. It is because a vast majority of malignant gliomas have telomerase activity, while most normal brain cells do not. Activation of telomerase is tightly regulated at the transcriptional level of the telomerase catalytic subunit (hTERT). Therefore, we hypothesize that by using the hTERT promoter-driven vector system, the expression of caspases can be restricted to telomerase-positive malignant gliomas. In preliminary studies, we constructed the caspase-8 (initiator caspase) or rev-caspase-6 (executioner caspase) expression vector with the hTERT promoter (hTERT/caspase-8 or rev-caspase6) and demonstrated that each construct induced apoptosis in telomerase-positive malignant glioma cells, but not in cultured astrocytes lacking telomerase. Furthermore, the growth of subcutaneous tumors in nude mice was significantly suppressed by the treatment with the hTERT/rev-caspase-6. Additionally, the antitumor effect of hTERT/caspase-8 or rev-caspase-6 was enhanced by the combination with anticancer drug, cisplatin. The goal of this proposal is to investigate whether treatment with the hTERT/caspase-8 or rev-caspase-6 construct is an effective approach for telomerasepositive malignant gliomas using an experimental model of human malignant gliomas. The specific aims are: 1) to select tumor model systems for the in vivo treatment with hTERT/caspase-8 or rev-caspase-6 construct, 2) to investigate the antitumor effect of the hTERT/caspase-8 or rev-caspase-6 construct on intracranial tumors, 3) to investigate their in vitro and in vivo antitumor efficacy combined with conventional therapy (cisplatin, temozolomide, or gamma-irradiation), and 4) to investigate the molecular mechanisms underlying the effect of the hTERT/caspase-8 or rev-caspase-6. A unique focus of this work is the emphasis on the telomerase-specific gene transfer of caspases. We anticipate that the studies described in the current proposal will lead to a novel and promising targeting approach for malignant gliomas expressing telomerase activity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: THERAPEUTIC TARGETING OF HSP90-DEPENDENT SIGNALING Principal Investigator & Institution: Karnitz, Larry M.; Associate Professor; Mayo Clinic Coll of Medicine, Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2009 Summary: (provided by applicant): Despite the recent identification of additional drugs with activity in ovarian cancer, including gemcitabine, topotecan and liposomal doxorubicin, the vast majority of patients with stage Ill/IV ovarian cancer succumb to this disease. This observation highlights the need for improved methods to circumvent drug resistance in ovarian cancer. Emerging evidence suggests that many of the same changes that contribute to the development of ovarian cancer might also contribute to drug resistance. Signaling from the cell surface receptors HER2/neu and insulin-like growth factor receptor (IGFR) activates the phosphatidylinositol-3 (PI3) kinase/Akt pathway, which inhibits apoptosis, and the Ras/Raf/MEK/Erk pathway, which enhances proliferation. In addition, checkpoint kinase signaling that is activated by replication stress and DNA damage plays a critical role in determining whether cells will restore homeostasis or undergo apoptosis. Interestingly, the ongoing activity of the heat shock protein 90 (HSP90) chaperone complex is critical for the stability and
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function of components of all of these pathways. The central hypothesis underlying this project is that HSP90 directed therapy would overcome chemotherapy resistance in ovarian cancer through inhibition of proliferation and survival signaling. Our preliminary studies demonstrate that 17-allylamino-17- demethoxygeldanamycin (17AAG) or geldanamycin (GA) causes downregulation of HER2, IGFR, and Akt in multiple ovarian cancer cells. Additional experiments demonstrate that 17-AAG inhibits the activation of checkpoint kinase 1 (Chk1) and enhances the cytotoxicity of gemcitabine in OVCAR-3 cells. Finally, our ongoing phase I study has demonstrated that 17-AAG successfully targets the HSP90 complex in patients at therapeutically achievable doses and that 17-AAG can be combined with cisplatin and gemcitabine in the clinical setting. We now propose to 1) to determine how HSP90 participates in gemcitabine-triggered Chk1 signaling in ovarian cancer cells; 2) assess the extent to which 17-AAG sensitizes various ovarian cancer cells to gemcitabine, cisplatin, and topotecan and determine whether differences in sensitization reflect variations in HSP90 chaperone complex function and/or levels of HSP90 clients; and 3) to evaluate the clinical and biologic effects of 17-AAG alone and when combined with gemcitabine or cisplatin in ovarian cancer patients. Collectively, these studies will provide information about the ability to alter the response of ovarian cancer cells to chemotherapeutic agents in vitro and in the clinical setting. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: THERAPEUTIC/MECHANISTIC ROLE OF APE1 IN GERM CELL TUMORS Principal Investigator & Institution: Kelley, Mark R.; Associate Director; Pediatrics; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2003; Project Start 05-AUG-2003; Project End 31-JUL-2008 Summary: (provided by applicant): Therapy for disseminated germ cell tumors (GCT) has been successful with 70-80% of patients being cured with front line chemotherapy. However, for those 20-30% of patients with extra-gonadal primaries or refractory disease, the response to therapy is poor with only 3-30% surviving disease-free after second line agents. One approach to treating resistant disease is the development of strategies to augment the chemotherapeutic agents that have been so successful in the majority of GCT patients. Little is known about the role of DNA repair systems in GCT's except that efficient repair appears to make tumor cells resistant to therapy. We have observed that GCT's express high levels of Ape1/ref-1 compared to normal tissues. Ape1/ref-1 is a multifunctional protein with DNA base excision repair (BER) activity and redox activity required for activation of specific transcription factors including Fos, Jun, NFkappaB, HIF-1alpha (hypoxia inducible factor), p53, and PAX5. This novel combination of functions links Ape1/ref-1 with resistance to many of the therapeutic agents (bleomycin, cisplatin, radiation, and VP-16) used to treat GCT's by acting as direct substrates for BER or indirectly by altering signaling through transcription factors regulated by Ape1/ref-l. Based on this information, we hypothesize: High level expression of Ape1/ref-1 in GCT's is a functional marker of disease which 1) is predictive of high risk disease and 2) can be manipulated to gain a therapeutic advantage. The major thrust of this proposal is to characterize the molecular biology of Ape1/ref-1 in GCT's as it relates to the clinical course of patients and the response of GCT cells to therapeutic agents. To approach this goal, we have developed four Specific Aims: Specific Aim1: Determine the relative expression of, Ape1/ref-1in good prognosis and high-risk GCT's. This takes advantage of the wealth of clinical GCT material
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available at Indiana University. Specific Aim 2: What is the role of Ape1/ref-1 in GCT progression and development, including cell growth, apoptosis, cell cycle, and differentiation? That is how does the high level expression of Ape1/ref-1, including over-expression of repair, redox, and nuclear localization domain mutants independently affect the ability of GCT cells to grow as cancer cells. Specific Aim 3: How do changes in the redox status of Ape1/ref-1 affect repair function? Using site-specific mutants, determine which cysteine residues specifically control repair function of Ape1/ref-l? Specific Aim 4: How do alterations in the repair and redox functioning of Ape1/ref-1 affect the response of GCT cells to therapeutic agents? Using what we learn in Aims 2 & 3, how can we alter the resistance of GCT cells to therapeutic agents. Through these analyses, we hope to determine the underlying mechanisms by which Ape1/ref-1 function is linked to the progression of testicular cancer. If any mutants are shown to sensitize the GCT cell lines to chemo-/IR agents, as expected, this will set the stage for future gene therapy approaches to sensitize GCT's to therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: METASTASIS
TISSUE
SPECIFIC
GENE
THERAPY
FOR
PULMONARY
Principal Investigator & Institution: Kao, Chinghai; Associate Professor; Urology; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2002; Project Start 04-JAN-2001; Project End 31-DEC-2003 Summary: (Applicant's Abstract) The major goal of this application is to develop a new treatment modality for pulmonary metastasis. Malignant cells usually gain access to the bloodstream through thin-walled venous tumor vessels and grow in solid cores from which fragments or tumor cells may break off to form tumor emboli. Such emboli tend to lodge in the first capillary beds they encounter. Therefore, the lung is a common metastatic side of many human tumors that spread via the hematogenous route. Effective therapy for patients with pulmonary metastases is lacking. To improve the treatment of these lethal sequelae of cancer, the applicant developed a novel tissuespecific gene therapy modality to treat pulmonary metastasis using osteosarcoma as an ideal model system. The objective of this application is to enhance the efficacy of the applicant's tissue-specific gene-therapy approach and develop a novel gene-delivery technique for the treatment of pulmonary metastases. They hypothesis to be tested is: pulmonary metastases can be treated by tissue/tumor-specific promoter-based toxic gene therapy with recombinant adenovirus as a gene delivery vehicle. Treatment efficacy can be enhanced by 1) combining with chemotherapeutic agents, and 2) improving localized delivery of therapeutic agents using an isolated-single-lungperfusion technique. To test these hypotheses the applicant proposes the following studies. (I) To study the possible benefit of combining gene therapy with chemotherapy, the beneficial effect of four commonly used chemotherapeutic agents, methotrexate, ifosfamide, doxorubicin and cisplatin, on herpes simplex virus thymidine kinase mediated cell- and tumor-kill will be evaluated. The doses of adenovirus, prodrugs, and chemotherapeutic agents for optimal therapeutic efficacy and the sequence of treatment will be studied. (II) To investigate the interaction between toxic gene therapy and chemotherapy, he will study the effect of chemotherapeutic agents on adenovirus mediated transgene expression, the effect of adenoviral gene expression on chemotherapy, and the collaborative efficacy of TK/prodrug and chemotherapeutic agent mediated cell-kill. In particular, the applicant will investigate the potential interference of virus attachment to its receptor and transportation to the nuclei. (III) To
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increase the local virus concentration and virus-target cell contact time, he will establish an isolated-single-lung-perfusion technique for locoregional delivery of adenovirus and evaluate its therapeutic advantage. He will also evaluate gene transduction efficacy of adenovirus delivered by the isolated-single-lung-perfusion technique. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TRANSLATIONAL RESEARCH IN BREAST CANCER Principal Investigator & Institution: Overmoyer, Beth A.; Medicine; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2002; Project Start 01-SEP-2000; Project End 31-AUG-2005 Summary: The goal of this grant application is to support the development of a mentored-career that focuses on building a foundation of mechanism-based Phase I/II therapeutic trials directed at breast cancer. It is the intent of this application to utilize currently established research relationships, which supports a mentoring environment in the design and administration of Phase I/II trials, and provides background education in the basics of scientific reason. Therapeutic trials will be designed which integrate experts in pharmacokinetic and pharmacodynamic analysis, mechanisms of apoptosis, and angiogenesis, with clinicians specializing in the treatment of breast cancer at the Ireland Cancer Center (ICC) at University Hospitals of Cleveland (UHC) and Case Western Reserve University (CWRU). With the mentoring of Dr. Scot Remick, Director of the Developmental Therapeutics Program, the investigator will test the hypothesis that the therapeutic response of breast cancer to cytotoxic treatment will be enhanced through the addition of novel therapies. Two studies will form the foundation of this hypothesis. Specific Aim 1: To enhance the disease-free and overall survival of patients with inflammatory breast cancer receiving doxorubicin with the addition of an angiogenesis inhibitor (SU5416). To determine if there is a correlation between disease response and changes in plasma markers of angiogenesis, tumor microvascular density, and tumor blood flow. Specific Aim 2: To enhance the disease response of advanced/metastatic breast cancer and other solid tumors to cisplatin and paclitaxel treatment with the addition of a retinoid, fenretinide (4HPR). To determine if there is a correlation between disease response and changes in tumor tissue retinoid receptor activation and level of apoptosis. This study will also determine if 4-HPR therapy induces in vivo expression of TIG3, a novel gene involved with apoptosis, in treated patients, and confirm that its level of expression correlates with disease response. A Phase II breast cancer trial will follow the completion of this Phase I protocol. These studies will provide a foundation for active participation of collaborative laboratories, resulting in a successful career developing a mechanism-based therapeutic research program in breast cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TRANSLATIONAL STUDIES OF NOVEL SELECTIVE CDK2 INHIBITORS Principal Investigator & Institution: Shapiro, Geoffrey I.; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2003; Project Start 19-SEP-2003; Project End 30-JUN-2008 Summary: Cyclin-dependent kinase (cdk)2 is a core enzyme of the cell cycle machinery, and has been shown to affect cell cycle progression during multiple phases, including G1, S and G2. Deregulated cdk2 activity is common in human cancer, including NSCLC, and its inhibition results in both cell cycle arrest and apoptosis. Several cdk2 inhibitor
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compounds, including BMS-387032 (Bristol-Myers Squibb) and PNU-252808 (Pharmacia) are in early phase I and late preclinical development, respectively. In the first specific aim, the response of a panel of NSCLC cell lines to these compounds will be characterized and the inhibition of phosphorylation of cdk2 targets, such as Rb and p27 Kips, will be confirmed. Appropriately paired cell lines will also be examined to determine whether apoptosis induced by these compounds is selective for transformed cells. In addition, a variety of genetically engineered cell types will be used to determine if apoptosis occurs by p53, E2F-1-p73 or p27[Kip1]-dependent pathways. In specific aim 2, pharmacodynamic assays will be designed to assess the activity of these compounds in plasma, in tumor samples and in proliferating surrogate tissues. First, methodology will be developed to assay the ability of drug-containing plasma to inhibit the proliferation of stimulated peripheral blood mononuclear cells. Second, anti-Rb and anti-p27[Kip1]-phosphospecific antibodies will be adapted for immunohistochemistry so that inhibition of cdk2-mediated phosphorylation of these targets can be confirmed in tumor fine needle aspirates, buccal smears and skin biopsies. Finally, noninvasive measures of cdk2 activity, including 18FDG and 18FLT-PET scanning will be piloted in xenograft models. These pharmacodynamic assays will be incorporated into a companion study that will accompany ongoing and planned phase I trials with cdk2 inhibitor agents. In specific aim 3, the potential synergy of these compounds with standard DNA- and microtubule-damaging chemotherapy agents will be explored, in order to guide the rational design of phase I combination clinical trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TREATMENT OF CHILDHOOD CANCER Principal Investigator & Institution: Brecher, Martin L.; Roswell Park Cancer Institute Corp Buffalo, Ny 14263 Timing: Fiscal Year 2002; Project Start 01-JUL-1980; Project End 31-DEC-2002 Summary: Cooperative trials in pediatric cancer patients have played a major role in the remarkable improvement in cure of childhood cancers. Because most childhood cancers are rare, it is only through this mechanism that adequate numbers of patients can be accrued in reasonable lengths of time for randomized controlled studies. The Department of Pediatrics at Roswell Park Cancer Institute (RPCI) has actively participated in cooperative group trials via the Pediatric Oncology Group (POG) to answer treatment questions which would be impossible to answer were we to conduct only single institution studies. Some pediatric solid tumors are so rare that national intergroup studies are required. We also participate in these intergroup studies. RPCI investigators are coordinators for a number of POG protocols including front-line studies for the treatment of advanced Hodgkin's disease, advanced small non- cleaved cell lymphoma, non-rhabdomyosarcoma soft tissue sarcomas, acute lymphoblastic leukemia in relapse, the National Wilms Tumor Study, brain tumors in infants, and the Intergroup Ewing's Sarcoma Study. Roswell Park investigators have also developed POG phase II studies of continuous infusion 5-fluouracil and the combination of cisplatin, ifosfamide and etoposide. Roswell Park investigators chair the Wilms Tumor Committee, the Neuroscience Subcommittee of the Brain Tumor Committee, and cochair the Pathology Discipline Core Committee, as well as being active on a number of other POG Core Committees. They have made major contributions over the last few years in the areas of solid tumor oncology, neuro- oncology and the treatment of lymphoid malignancies. We are strongly committed to the interdisciplinary approach to pediatric cancer and have established collaboration with the necessary clinical specialties including Radiation Medicine, Pediatric Surgery, Pediatric Neurology,
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Neurosurgery, and Orthopedic Surgery, as well as with researchers in immunology, pharmacology and molecular biology. As more children are cured of their cancers, the identification and prevention, when feasible, of complications of therapy have become imperative. We have been a major contributor to the identification and understanding of the long-term medical and psychosocial effects of the treatment of leukemia, Hodgkin's disease, and a number of solid tumors, both through the cooperative group mechanism and through institutional studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: UROKINASE RECEPTOR-INITIATED CELL-SIGNALING Principal Investigator & Institution: Gonias, Steven L.; Professor; Pathology; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: (provided by applicant): Binding of urokinase-type plasminogen activator (uPA) to its receptor, uPAR, activates diverse cell-signaling pathways, including the Ras-ERKJMAP kinase pathway, and thereby regulates cell migration, growth, and apoptosis. uPAR-initiated cell-signaling is sensitive to low concentrations of uPA and requires as few as 3x103 copies of cell-surface uPAR. Furthermore, in aggressive cancer cells, an autocrine pathway may be established in which binding of endogeneouslyproduced uPA to uPAR is responsible for maintaining a high basal level of activated ERK. We hypothesize that uPAR-initiated cell-signaling is a major determinant of cancer cell aggressiveness in vivo. The major goal of this research project is to elucidate the uPA-uPAR cell-signaling system. Specific Aim 1 focuses on the basic biochemistry of uPAR-initiated cell-signaling. Studies are proposed to characterize the kinetics of uPARligation in relation to cell-signaling, determine how the cell integrates uPAR- and integrin-initiated cell-signaling responses, determine the function of complementary pathways such as the Ras-ERK and RhoRho-kinase pathways, and identify feedbackloops that shut-down cell-signaling after uPAR ligation. We will also address the possibility that uPAR may regulate cell-signaling, in part by uPA-independent mechanisms. In Specific Aim 2, we will test our hypothesis that uPA-initiated cellsignaling reflects the activity of a biochemical system that includes plasminogen, plasminogen activator inhibitor-1(PAI-1), other Serpins, and LDL receptor homologues, such as the VLDL receptor (VLDLr). A major goal of Specific Aim 2 is to reconstitute uPAR-initiated cell-signaling in vitro with components that may regulate cell-signaling in vivo. In Specific Aim 3, translational studies are proposed to characterize the uPAuPAR cell-signaling system as a target for the development of novel anticancer therapeutics. We will study the activity of antibodies that block uPA-binding to uPAR alone and in combination with herceptin, cisplatin or etoposide. We will also develop novel chimeric receptors that may rapidly catabolize uPA, decreasing the amount of uPA available to ligate uPAR. The proposed studies offer the potential to elucidate properties of uPA and PAL-1 that are not currently understood, further our understanding of this key cell-regulatory system, and generate novel strategies for treating cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: VITAMIN D IN PROSTATE CANCER: TUMOR VASCULATURE EFFECTS Principal Investigator & Institution: Trump, Donald L.; Professor; Roswell Park Cancer Institute Corp Buffalo, Ny 14263
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Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): We have demonstrated that the most active vitamin D moiety 1,25 dihydroxycholecalciferol (calcitriol) has significant antiproliferative activity in vivo and in vitro. Calcitriol induces G0/G1 arrest, modulates p27/p21, induces apoptosis and enhances the antitumor activity of cisplatin, carboplatin, paclitaxel and docetaxel. In vitro and in vivo, dexamethasone (dex) potentiates calcitriolmediated antitumor activity and vitamin D receptor (VDR) ligand binding in vitro and in vivo and enhances VDR protein expression. Calcitriol/dex also suppress activated mitogen-activated protein kinase (MAPK), Ert 1/2) activity and phosphorylated Akt (PAkt). In a phase II clinical trial of hormone refractory prostate cancer with high dose oral calcitriol and dex, we observed a 50 percent reduction in serum prostate specific antigen (PSA) in 28 percent of patients with no hypercalcemia; modulation of VDR and other potential markers of calcitriol activity in peripheral blood monocytes. We have preliminary data indicating that calcitriol and dex induces apoptosis, modulates cell cycle, decreases P-Erk 1/2 and P-Ark and significantly up-regulated VDR expression of tumor-derived endothelial cells (TDEC) as compared to endothelial cells isolated from normal tissues (aortic). These studies suggest that the mechanism(s) of calcitriol/dex antitumor activity may involve effects on intratumor vasculature. We propose to examine this hypothesis by the following Specific Aims: 1) to determine the mechanisms involved in calcitriol/dex effects in TDEC isolated from prostate tumors as compared to normal by examining: a) effects on apoptosis and cell cycle; b) effects on invasiveness, motility, and angiogenesis; and c) whether activities require calcitriol binding to the VDR; 2) To determine the prostate tumor models the role of TDEC in calcitriol/dex antitumor effects by determining: a) effects on the vasculature within the tumor; b) effects on TDEC isolated from animals treated with calcitriol; and c) whether a relationship exists between modulation of effects on TDEC and antitumor effects and 3) To evaluate oral calcitriol (12mg QDx3) and/or dex (4mg QDx4) administered weekly x 4 to patients with localized prostate cancer immediately prior to prostatectomy to determine: a) effects on tumor endothelial cells; b) effects of cell cycle status, apoptosis markers and prostatic intraepithelial neoplasia (PIN) and c) prostate specific antigen (PSA) response. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: VITAMINS AND PREVENTION OF CANCER PROGRESSION Principal Investigator & Institution: Johanning, Gary L.; Nutrition Sciences; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2003; Project Start 16-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant): One contribution toward the goal preventing cancer progression would be to identify environmental factors such as nutrients that may contribute to cancer survivorship. The optimal vitamin nutriture of cancer patients is not well established, and the role of vitamins in preventing the recurrence of clinically overt cancer has not been widely evaluated. Our preliminary data provide evidence that rapid depletion of the vitamin folic acid is associated with increased resistance of cultured human lung cancer and ovarian cells to the chemotherapeutic agent cisplatin. The overall goal of this project is to examine the hypothesis that folic acid influences the resistance in lung cancer cells to the action of cisplatin. We hypothesize, based on our preliminary data, that folate will prevent intrinsic and acquired resistance to cisplatin. To test this hypothesis, we propose the following two specific aims: Specific Aim 1: To determine whether altered folic acid concentrations can prevent or reverse resistance to the chemotherapeutic agent cisplatin. Specific Aim 2: To evaluate the mechanisms by
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which folic acid alters resistance to cisplatin. In the first specific aim, we will evaluate whether supplementation with folic acid decreases the resistance to cisplatin. We will test folate and cisplatin in several lung cancer cell lines. In Specific Aim 2, we will attempt to determine the mechanism by which folate supplementation decreases resistance by evaluating the effect of folate supplementation on levels of metabolites commonly associated with the development of resistance, and on expression of genes associated with development of resistance. If our studies are successful, a rationale for clinical trials aimed at evaluating the influence of vitamin status on resistance to chemotherapy in cancer patients would be established. If vitamin supplementation is ultimately found to decrease resistance to chemotherapeutic agents, then a simple and inexpensive approach to prevent, at least in part, the resistance that limits the effectiveness of chemotherapy will be realized. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
E-Journals: PubMed Central3 PubMed Central (PMC) is a digital archive of life sciences journal literature developed and managed by the National Center for Biotechnology Information (NCBI) at the U.S. National Library of Medicine (NLM).4 Access to this growing archive of e-journals is free and unrestricted.5 To search, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Pmc, and type “cisplatin” (or synonyms) into the search box. This search gives you access to fulltext articles. The following is a sample of items found for cisplatin in the PubMed Central database: •
A polymerase chain reaction-based method to detect cisplatin adducts in specific genes. by Jennerwein MM, Eastman A.; 1991 Nov 25; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=329126
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Acquired cisplatin resistance in human ovarian cancer cells is associated with enhanced repair of cisplatin-DNA lesions and reduced drug accumulation. by Parker RJ, Eastman A, Bostick-Bruton F, Reed E.; 1991 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=329864
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Acridine-modified, clamp-forming antisense oligonucleotides synergize with cisplatin to inhibit c-Myc expression and B16-F0 tumor progression. by Stewart DA, Xu X, Thomas SD, Miller DM.; 2002 Jun 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=117175
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Antitumorigenic Evaluation of Thalidomide Alone and in Combination with Cisplatin in DBA2/J Mice. by Ruddy JM, Majumdar SK.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=139116
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Adapted from the National Library of Medicine: http://www.pubmedcentral.nih.gov/about/intro.html.
With PubMed Central, NCBI is taking the lead in preservation and maintenance of open access to electronic literature, just as NLM has done for decades with printed biomedical literature. PubMed Central aims to become a world-class library of the digital age. 5 The value of PubMed Central, in addition to its role as an archive, lies in the availability of data from diverse sources stored in a common format in a single repository. Many journals already have online publishing operations, and there is a growing tendency to publish material online only, to the exclusion of print.
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Biochemical basis for cisplatin and 5-fluorouracil synergism in human ovarian carcinoma cells. by Scanlon KJ, Newman EM, Lu Y, Priest DG.; 1986 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=387045
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Crystal structure of a double-stranded DNA containing a cisplatin interstrand crosslink at 1.63 A resolution: hydration at the platinated site. by Coste F, Malinge JM, Serre L, Shepard W, Roth M, Leng M, Zelwer C.; 1999 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=148391
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DNA damage by anti-cancer agents resolved at the nucleotide level of a single copy gene: evidence for a novel binding site for cisplatin in cells. by Grimaldi KA, McAdam SR, Souhami RL, Hartley JA.; 1994 Jun 25; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=331679
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Exposure of Human Ovarian Carcinoma to Cisplatin Transiently Sensitizes the Tumor Cells for Liposome-Mediated Gene Transfer. by Son K, Huang L.; 1994 Dec 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=45500
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Gleevec (STI-571) inhibits lung cancer cell growth (A549) and potentiates the cisplatin effect in vitro. by Zhang P, Gao WY, Turner S, Ducatman BS.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=149413
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High resistance to cisplatin in human ovarian cancer cell lines is associated with marked increase of glutathione synthesis. by Godwin AK, Meister A, O'Dwyer PJ, Huang CS, Hamilton TC, Anderson ME.; 1992 Apr 1; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=48805
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HMG-domain proteins specifically inhibit the repair of the major DNA adduct of the anticancer drug cisplatin by human excision nuclease. by Huang JC, Zamble DB, Reardon JT, Lippard SJ, Sancar A.; 1994 Oct 25; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=45026
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Human nucleotide excision repair in vitro: repair of pyrimidine dimers, psoralen and cisplatin adducts by HeLa cell-free extract. by Sibghatullah, Husain I, Carlton W, Sancar A.; 1989 Jun 26; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=318007
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Increased gene-specific repair of cisplatin interstrand cross-links in cisplatin-resistant human ovarian cancer cell lines. by Zhen W, Link CJ Jr, O'Connor PM, Reed E, Parker R, Howell SB, Bohr VA.; 1992 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=360224
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Influence of Cisplatin Intrastrand Crosslinking on the Conformation, Thermal Stability, and Energetics of a 20-mer DNA Duplex. by Poklar N, Pilch DS, Lippard SJ, Redding EA, Dunham SU, Breslauer KJ.; 1996 Jul 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=38793
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p53-dependent and -independent responses to cisplatin in mouse testicular teratocarcinoma cells. by Zamble DB, Jacks T, Lippard SJ.; 1998 May 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=27612
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Protective effect of piperacillin against the nephrotoxicity of cisplatin in rats. by Hayashi T, Watanabe Y, Kumano K, Kitayama R, Muratani T, Yasuda T, Saikawa I, Katahira J, Kumada T, Shimizu K.; 1989 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=172470
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Rapid changes of nucleotide excision repair gene expression following UVirradiation and cisplatin treatment of Dictyostelium discoideum. by Yu SL, Lee SK, Alexander H, Alexander S.; 1998 Jul 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=147717
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Rapid gene-specific repair of cisplatin lesions at the human DUG/DHFR locus comprising the divergent upstream gene and dihydrofolate reductase gene during early G1 phase of the cell cycle assayed by using the exonucleolytic activity of T4 DNA polymerase. by Rampino NJ, Bohr VA.; 1994 Nov 8; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=45149
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Role of promoter hypermethylation in Cisplatin treatment response of male germ cell tumors. by Koul S, McKiernan JM, Narayan G, Houldsworth J, Bacik J, Dobrzynski DL, Assaad AM, Mansukhani M, Reuter VE, Bosl GJ, Chaganti RS, Murty VV.; 2004; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=420487
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Steroid hormones induce HMG1 overexpression and sensitize breast cancer cells to cisplatin and carboplatin. by He Q, Liang CH, Lippard SJ.; 2000 May 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18508
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Study of the interaction of DNA with cisplatin and other Pd(II) and Pt(II) complexes by atomic force microscopy. by Onoa GB, Cervantes G, Moreno V, Prieto MJ.; 1998 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=147433
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The effect of chromatin structure on cisplatin damage in intact human cells. by Davies NP, Hardman LC, Murray V.; 2000 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=102687
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The ORD1 gene encodes a transcription factor involved in oxygen regulation and is identical to IXR1, a gene that confers cisplatin sensitivity to Saccharomyces cerevisiae. by Lambert JR, Bilanchone VW, Cumsky MG.; 1994 Jul 19; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=44396
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TNF-[alpha] mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity. by Ramesh G, Reeves WB.; 2002 Sep 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151130
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Uptake of the anticancer drug cisplatin mediated by the copper transporter Ctr1 in yeast and mammals. by Ishida S, Lee J, Thiele DJ, Herskowitz I.; 2002 Oct 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=137878
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YB-1 promotes strand separation in vitro of duplex DNA containing either mispaired bases or cisplatin modifications, exhibits endonucleolytic activities and binds several DNA repair proteins. by Gaudreault I, Guay D, Lebel M.; 2004; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=373280
The National Library of Medicine: PubMed One of the quickest and most comprehensive ways to find academic studies in both English and other languages is to use PubMed, maintained by the National Library of Medicine.6 The advantage of PubMed over previously mentioned sources is that it covers a greater number of domestic and foreign references. It is also free to use. If the publisher has a Web site that offers full text of its journals, PubMed will provide links to that site, as well as to sites offering other related data. User registration, a subscription fee, or some other type of fee may be required to access the full text of articles in some journals. To generate your own bibliography of studies dealing with cisplatin, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “cisplatin” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for cisplatin (hyperlinks lead to article summaries): •
A combination immunochemotherapy of 5-fluorouracil, cisplatin, leucovorin, and OK-432 for advanced and recurrent gastric carcinoma. Author(s): Yoshikawa T, Tsuburaya A, Kobayashi O, Sairenji M, Motohashi H, Noguchi Y. Source: Hepatogastroenterology. 2003 November-December; 50(54): 2259-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14696512
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A double-blind, crossover, randomized comparison of granisetron and ramosetron for the prevention of acute and delayed cisplatin-induced emesis in patients with gastrointestinal cancer: is patient preference a better primary endpoint? Author(s): Koizumi W, Tanabe S, Nagaba S, Higuchi K, Nakayama N, Saigenji K, Nonaka M, Yago K. Source: Chemotherapy. 2003 December; 49(6): 316-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14671433
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A novel biweekly schedule with cisplatin and gemcitabine in advanced non-small cell lung cancer. Author(s): Lopez-Vivanco G, Fuente N, Barcelo R, Rubio I, Munoz A, Mane JM, PerezHoyos T, Viteri A, Ferreiro J. Source: Int J Clin Pharmacol Res. 2003; 23(1): 9-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14621068
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PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web sites of participating publishers. Publishers that participate in PubMed supply NLM with their citations electronically prior to or at the time of publication.
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A novel time-course cDNA microarray analysis method identifies genes associated with the development of cisplatin resistance. Author(s): Whiteside MA, Chen DT, Desmond RA, Abdulkadir SA, Johanning GL. Source: Oncogene. 2004 January 22; 23(3): 744-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14737109
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A phase II study of gemcitabine and cisplatin in chemotherapy-naive, unresectable gall bladder cancer. Author(s): Doval DC, Sekhon JS, Gupta SK, Fuloria J, Shukla VK, Gupta S, Awasthy BS. Source: British Journal of Cancer. 2004 April 19; 90(8): 1516-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15083178
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A phase II study of weekly cisplatin, 6S-stereoisomer leucovorin and fluorouracil as first-line chemotherapy for elderly patients with advanced gastric cancer. Author(s): Graziano F, Santini D, Testa E, Catalano V, Beretta GD, Mosconi S, Tonini G, Lai V, Labianca R, Cascinu S. Source: British Journal of Cancer. 2003 October 20; 89(8): 1428-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14562012
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A prescription and administration error of cisplatin: a case report. Author(s): Pourrat X, Antier D, Crenn I, Calais G, Jonville-Bera AP, Rouleau A. Source: Pharmacy World & Science : Pws. 2004 April; 26(2): 64-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15085939
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A randomised clinical trial of radiotherapy plus cisplatin versus radiotherapy alone in stage III non-small cell lung cancer. Author(s): Cakir S, Egehan I. Source: Lung Cancer (Amsterdam, Netherlands). 2004 March; 43(3): 309-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15165089
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Activating transcription factor 4 increases the cisplatin resistance of human cancer cell lines. Author(s): Tanabe M, Izumi H, Ise T, Higuchi S, Yamori T, Yasumoto K, Kohno K. Source: Cancer Research. 2003 December 15; 63(24): 8592-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14695168
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Adjuvant and neoadjuvant therapy for gastric cancer using epirubicin/cisplatin/5fluorouracil (ECF) and alternative regimens before and after chemoradiation. Author(s): Leong T, Michael M, Foo K, Thompson A, Lim Joon D, Weih L, Ngan S, Thomas R, Zalcberg J. Source: British Journal of Cancer. 2003 October 20; 89(8): 1433-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14562013
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Are serial CA 19-9 kinetics helpful in predicting survival in patients with advanced or metastatic pancreatic cancer treated with gemcitabine and cisplatin? Author(s): Stemmler J, Stieber P, Szymala AM, Schalhorn A, Schermuly MM, Wilkowski R, Helmberger T, Lamerz R, Stoffregen C, Niebler K, Garbrecht M, Heinemann V. Source: Onkologie. 2003 October; 26(5): 462-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14605463
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Bacterial meningitis observed in a phase I trial of vinorelbine, cisplatin and thoracic radiotherapy for non-small cell lung cancer: report of a case and discussion on doselimiting toxicity. Author(s): Sekine I, Matsuda T, Saisho T, Watanabe H, Yamamoto N, Kunitoh H, Ohe Y, Tamura T, Kodama T, Saijo N. Source: Japanese Journal of Clinical Oncology. 2000 September; 30(9): 401-5. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11095138
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BBR 3464: a novel triplatinum complex, exhibiting a preclinical profile of antitumor efficacy different from cisplatin. Author(s): Manzotti C, Pratesi G, Menta E, Di Domenico R, Cavalletti E, Fiebig HH, Kelland LR, Farrell N, Polizzi D, Supino R, Pezzoni G, Zunino F. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2000 July; 6(7): 2626-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10914703
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Beta-hydroxyisovalerylshikonin and cisplatin act synergistically to inhibit growth and to induce apoptosis of human lung cancer DMS114 cells via a tyrosine kinasedependent pathway. Author(s): Xu Y, Kajimoto S, Nakajo S, Nakaya K. Source: Oncology. 2004; 66(1): 67-75. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15031601
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BGP-15 - a novel poly(ADP-ribose) polymerase inhibitor - protects against nephrotoxicity of cisplatin without compromising its antitumor activity. Author(s): Racz I, Tory K, Gallyas F Jr, Berente Z, Osz E, Jaszlits L, Bernath S, Sumegi B, Rabloczky G, Literati-Nagy P. Source: Biochemical Pharmacology. 2002 March 15; 63(6): 1099-111. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11931842
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Bilateral blindness and lumbosacral myelopathy associated with high-dose carmustine and cisplatin therapy. Author(s): Wang MY, Arnold AC, Vinters HV, Glasgow BJ. Source: American Journal of Ophthalmology. 2000 September; 130(3): 367-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11020424
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Biochemical and molecular mechanisms of cisplatin resistance. Author(s): Siddik ZH. Source: Cancer Treat Res. 2002; 112: 263-84. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12481720
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Biochemical modulation of Cisplatin mechanisms of action: enhancement of antitumor activity and circumvention of drug resistance. Author(s): Fuertes MA, Alonso C, Perez JM. Source: Chemical Reviews. 2003 March; 103(3): 645-62. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12630848
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Biodegradable polymer-mediated intratumoral delivery of cisplatin for treatment of human head and neck squamous cell carcinoma in a chimeric mouse model. Author(s): Chen FA, Kuriakose MA, Zhou MX, DeLacure MD, Dunn RL. Source: Head & Neck. 2003 July; 25(7): 554-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12808659
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Biological effects of ultrasound exposure on adriamycin-resistant and cisplatinresistant human ovarian carcinoma cell lines in vitro. Author(s): Yu T, Bai J, Hu K, Wang Z. Source: Ultrasonics Sonochemistry. 2004 April; 11(2): 89-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15030785
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Biweekly low-dose sequential gemcitabine, 5-fluorouracil, leucovorin, and cisplatin (GFP): a highly active novel therapy for metastatic adenocarcinoma of the exocrine pancreas. Author(s): Araneo M, Bruckner HW, Grossbard ML, Frager D, Homel P, Marino J, DeGregorio P, Mortazabi F, Firoozi K, Jindal K, Kozuch P. Source: Cancer Investigation. 2003; 21(4): 489-96. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14533437
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Bleomycin, actinomycin-D, and cisplatin treatment of ovarian germ-cell malignancies contributes to reducing adverse drug reactions. Author(s): Sumi T, Ishiko O, Yoshida H, Ogita S. Source: Oncol Rep. 2000 November-December; 7(6): 1235-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11032921
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BNP7787, a novel protector against platinum-related toxicities, does not affect the efficacy of cisplatin or carboplatin in human tumour xenografts. Author(s): Boven E, Verschraagen M, Hulscher TM, Erkelens CA, Hausheer FH, Pinedo HM, van der Vijgh WJ. Source: European Journal of Cancer (Oxford, England : 1990). 2002 May; 38(8): 1148-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12008205
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Body-surface area-based dosing does not increase accuracy of predicting cisplatin exposure. Author(s): de Jongh FE, Verweij J, Loos WJ, de Wit R, de Jonge MJ, Planting AS, Nooter K, Stoter G, Sparreboom A. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2001 September 1; 19(17): 3733-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11533095
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Bolus and infusional 5-fluorouracil combined with cisplatin in advanced gastric cancer. Author(s): Barone C, Cassano A, Landriscina M, Longo R, Astone A, Pozzo C. Source: Oncol Rep. 2000 November-December; 7(6): 1305-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11032934
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Bone or cartilage invasion by advanced head and neck cancer: intra-arterial supradose cisplatin chemotherapy and concomitant radiotherapy for organ preservation. Author(s): Samant S, Robbins KT, Kumar P, Ma JZ, Vieira F, Hanchett C. Source: Archives of Otolaryngology--Head & Neck Surgery. 2001 December; 127(12): 1451-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11735813
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Changes in biophysical parameters of plasma membranes influence cisplatin resistance of sensitive and resistant epidermal carcinoma cells. Author(s): Liang XJ, Yin JJ, Zhou JW, Wang PC, Taylor B, Cardarelli C, Kozar M, Forte R, Aszalos A, Gottesman MM. Source: Experimental Cell Research. 2004 February 15; 293(2): 283-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14729466
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Chemoembolization with cisplatin, lipiodol and Gelfoam and subsequent systemic chemotherapy with cisplatin and interferon in patients with hepatocellular carcinoma: a non-randomized prospective study. Author(s): Baur M, Walter R, Gebauer A, Tscholakoff D, Lochs H, Muhlbacher F, Turetschek K, Binder R, Hudec M, Gangl A, Ferenci P, Dittrich C. Source: International Journal of Oncology. 2003 September; 23(3): 811-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12888922
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Cisplatin and fluorouracil concurrent to radiotherapy in nasopharyngeal cancer: is the schedule compatible? Author(s): Licitra L, Bossi P, Locati L, Zunino F. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2004 January 15; 22(2): 377; Author Reply 377-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14722048
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Cisplatin as initial chemotherapy in ovarian carcinosarcomas: a Gynecologic Oncology Group study. Author(s): Tate Thigpen J, Blessing JA, DeGeest K, Look KY, Homesley HD; Gynecologic Oncology Group. Source: Gynecologic Oncology. 2004 May; 93(2): 336-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15099942
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Cisplatin resistance is associated with deregulation in protein kinase C-delta. Author(s): Huang J, Mohanty S, Basu A. Source: Biochemical and Biophysical Research Communications. 2004 April 16; 316(4): 1002-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15044084
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Cisplatin-induced apoptosis in Hep3B cells: mitochondria-dependent and independent pathways. Author(s): Kim JS, Lee JM, Chwae YJ, Kim YH, Lee JH, Kim K, Lee TH, Kim SJ, Park JH. Source: Biochemical Pharmacology. 2004 April 15; 67(8): 1459-68. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15041463
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Cisplatin-induced apoptosis in HL-60 human promyelocytic leukemia cells: differential expression of BCL2 and novel apoptosis-related gene BCL2L12. Author(s): Floros KV, Thomadaki H, Lallas G, Katsaros N, Talieri M, Scorilas A. Source: Annals of the New York Academy of Sciences. 2003 December; 1010: 153-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15033711
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Cisplatin-induced apoptosis in melanoma cells: role of caspase-3 and caspase-7 in Apaf-1 proteolytic cleavage and in execution of the degradative phases. Author(s): Del Bello B, Valentini MA, Comporti M, Maellaro E. Source: Annals of the New York Academy of Sciences. 2003 December; 1010: 200-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15033720
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Cisplatin-induced ubiquitination of RNA polymerase II large subunit and suppression of induction by 7-hydroxystaurosporine (UCN-01). Author(s): Yang LY, Jiang H, Rangel KM, Plunkett W. Source: Oncol Rep. 2003 September-October; 10(5): 1489-95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12883729
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Combined S-1 and cisplatin preoperative chemotherapy for patients with advanced gastric cancer: report of five cases. Author(s): Nakane Y, Inoue K, Michiura T, Nakai K, Sato M, Baden T, Okumura S, Yamamichi K. Source: Hepatogastroenterology. 2004 January-February; 51(55): 289-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15011888
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Comparison of ondansetron with metoclopramide in prevention of acute emesis associated with low dose & high dose cisplatin chemotherapy. Author(s): Bhatia A, Tripathi KD, Sharma M. Source: The Indian Journal of Medical Research. 2003 July; 118: 33-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14748464
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Comparison of oral versus intravenous ramosetron in prevention of acute cisplatininduced emesis: a randomized controlled trial. Author(s): Tantipalakorn C, Srisomboon J, Thienthong H, Pantusart A, Suprasert P, Saereesongkhun C, Eamtang S, Sutthichat A, Pautad N. Source: J Med Assoc Thai. 2004 February; 87(2): 119-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15061293
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Concurrent chemoradiotherapy with daily low dose intra-arterial cisplatin plus 5fluorouracil for stage IV nasopharyngeal cancer. Author(s): Kohno N, Ohno Y, Kitahara S, Tamura E, Tanabe T, Murata Y, Kawaida M. Source: Singapore Med J. 2003 August; 44(8): 410-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14700420
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Concurrent chemoradiotherapy with gemcitabine and cisplatin after incomplete (R1) resection of locally advanced pancreatic carcinoma. Author(s): Wilkowski R, Thoma M, Duhmke E, Rau HG, Heinemann V. Source: International Journal of Radiation Oncology, Biology, Physics. 2004 March 1; 58(3): 768-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14967432
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Concurrent cisplatin-based chemotherapy plus radiotherapy for cervical cancer: a meta-analysis. Author(s): Lukka H, Johnston M. Source: Clin Oncol (R Coll Radiol). 2004 April; 16(2): 160-1. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15074747
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Concurrent cisplatin-based chemotherapy plus radiotherapy for cervical cancer: a meta-analysis. Author(s): Green JA. Source: Clin Oncol (R Coll Radiol). 2004 February; 16(1): 82. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14768764
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Conflicting effects of caffeine on apoptosis and clonogenic survival of human K1 thyroid carcinoma cell lines with different p53 status after exposure to cisplatin or UVc irradiation. Author(s): Deplanque G, Ceraline J, Lapouge G, Dufour P, Bergerat JP, Klein-Soyer C. Source: Biochemical and Biophysical Research Communications. 2004 February 20; 314(4): 1100-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14751246
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Death receptor 5 and Bcl-2 protein expression as predictors of tumor response to gemcitabine and cisplatin in patients with advanced non-small-cell lung cancer. Author(s): Han JY, Hong EK, Choi BG, Park JN, Kim KW, Kang JH, Jin JY, Park SY, Hong YS, Lee KS. Source: Medical Oncology (Northwood, London, England). 2003; 20(4): 355-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14716031
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Decreased pyruvate kinase M2 activity linked to cisplatin resistance in human gastric carcinoma cell lines. Author(s): Yoo BC, Ku JL, Hong SH, Shin YK, Park SY, Kim HK, Park JG. Source: International Journal of Cancer. Journal International Du Cancer. 2004 February 10; 108(4): 532-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14696117
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Defective stress kinase and Bak activation in response to ionizing radiation but not cisplatin in a non-small cell lung carcinoma cell line. Author(s): Viktorsson K, Ekedahl J, Lindebro MC, Lewensohn R, Zhivotovsky B, Linder S, Shoshan MC. Source: Experimental Cell Research. 2003 October 1; 289(2): 256-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14499626
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Defining the function of XPC protein in psoralen and cisplatin-mediated DNA repair and mutagenesis. Author(s): Chen Z, Xu XS, Yang J, Wang G. Source: Carcinogenesis. 2003 June; 24(6): 1111-21. Epub 2003 March 28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12807748
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Depletion of endogenous nitric oxide enhances cisplatin-induced apoptosis in a p53dependent manner in melanoma cell lines. Author(s): Tang CH, Grimm EA. Source: The Journal of Biological Chemistry. 2004 January 2; 279(1): 288-98. Epub 2003 October 23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14576150
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Development of cross-resistance between heat and cisplatin or hydroxyurea treatments in FaDu squamous carcinoma cells. Author(s): Yang WL, Yang-Biggs G, Wu Y, Ye X, Gallos G, Owen RP, Ravikumar TS. Source: The Journal of Surgical Research. 2003 May 1; 111(1): 143-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12842459
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Diabetes mellitus following cisplatin treatment. Author(s): Nan DN, Fernandez-Ayala M, Vega Villegas ME, Garcia-Castano A, Rivera F, Lopez-Brea M, Gonzalez-Macias J. Source: Acta Oncologica (Stockholm, Sweden). 2003; 42(1): 75-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12665335
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Different mechanisms for gamma-glutamyltransferase-dependent resistance to carboplatin and cisplatin. Author(s): Daubeuf S, Balin D, Leroy P, Visvikis A. Source: Biochemical Pharmacology. 2003 August 15; 66(4): 595-604. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12906924
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Differential involvement of neurotransmitters through the time course of cisplatininduced emesis as revealed by therapy with specific receptor antagonists. Author(s): Hesketh PJ, Van Belle S, Aapro M, Tattersall FD, Naylor RJ, Hargreaves R, Carides AD, Evans JK, Horgan KJ. Source: European Journal of Cancer (Oxford, England : 1990). 2003 May; 39(8): 1074-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12736106
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Disruption of the Fanconi anemia-BRCA pathway in cisplatin-sensitive ovarian tumors. Author(s): Taniguchi T, Tischkowitz M, Ameziane N, Hodgson SV, Mathew CG, Joenje H, Mok SC, D'Andrea AD. Source: Nature Medicine. 2003 May; 9(5): 568-74. Epub 2003 April 07. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12692539
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Distortion product otoacoustic emissions test is useful in children undergoing cisplatin treatment. Author(s): Toral-Martinon R, Shkurovich-Bialik P, Collado-Corona MA, Mora-Magana I, Goldgrub-Listopad S, Shkurovich-Zaslavsky M. Source: Archives of Medical Research. 2003 May-June; 34(3): 205-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14567400
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DNA microarray analysis of the correlation between gene expression patterns and acquired resistance to 5-FU/cisplatin in gastric cancer. Author(s): Kim HK, Choi IJ, Kim HS, Kim JH, Kim E, Park IS, Chun JH, Kim IH, Kim IJ, Kang HC, Park JH, Bae JM, Lee JS, Park JG. Source: Biochemical and Biophysical Research Communications. 2004 April 9; 316(3): 781-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15033468
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DNA topology: topological transformation of DNA by reaction of cisplatin-DNA-core histone complexes with human DNA topoisomerase. Author(s): Kobayashi S, Nakagawa S, Uehara N, Hamashima H, Tanaka A. Source: Nucleic Acids Res Suppl. 2002; (2): 283-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12903215
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Docetaxel, cisplatin, 5-fluorouracil (TPF)-based induction chemotherapy for head and neck cancer and the case for sequential, combined-modality treatment. Author(s): Haddad R, Tishler RB, Norris CM, Mahadevan A, Busse P, Wirth L, Goguen LA, Sullivan CA, Costello R, Case MA, Posner MR. Source: The Oncologist. 2003; 8(1): 35-44. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12604730
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Dose escalation study of tezacitabine in combination with cisplatin in patients with advanced cancer. Author(s): Flaherty KT, Stevenson JP, Gallagher M, Giantonio B, Algazy KM, Sun W, Haller DG, O'Dwyer PJ. Source: Cancer. 2003 April 15; 97(8): 1985-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12673728
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Down-regulation and altered localization of gamma-catenin in cisplatin-resistant adenocarcinoma cells. Author(s): Liang XJ, Shen DW, Gottesman MM. Source: Molecular Pharmacology. 2004 May; 65(5): 1217-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15102950
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Dual action of cyclin-dependent kinase inhibitors: induction of cell cycle arrest and apoptosis. A comparison of the effects exerted by roscovitine and cisplatin. Author(s): Wesierska-Gadek J, Gueorguieva M, Horky M. Source: Polish Journal of Pharmacology. 2003 September-October; 55(5): 895-902. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14704484
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Effects of electrogenetherapy with p53wt combined with cisplatin on curvival of human tumor cell lines with different p53 status. Author(s): Cemazar M, Grosel A, Glavac D, Kotnik V, Skobrne M, Kranjc S, Mir LM, Andre F, Opolon P, Sersa G. Source: Dna and Cell Biology. 2003 December; 22(12): 765-75. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14683587
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Efficacy of cisplatin and cyclophosphamide combination for recurrent and metastatic carcinoma of the uterine cervix. Author(s): Eralp Y, Saip P, Sakar B, Tas F, Aydiner A, Topuz E. Source: Eur J Gynaecol Oncol. 2003; 24(3-4): 323-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12807249
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Efficacy of droperidol in the prevention of cisplatin-induced delayed emesis: a double-blind, randomised parallel study. Author(s): Minegishi Y, Ohmatsu H, Miyamoto T, Niho S, Goto K, Kubota K, Kakinuma R, Kudoh S, Nishiwaki Y. Source: European Journal of Cancer (Oxford, England : 1990). 2004 May; 40(8): 1188-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15110882
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Efficacy of intraperitoneal cisplatin as consolidation therapy in patients with pathologic complete remission following front-line therapy for epithelial ovarian cancer. Consolidative intraperitoneal cisplatin in ovarian cancer. Author(s): Topuz E, Eralp Y, Saglam S, Saip P, Aydiner A, Berkman S, Yavuz E. Source: Gynecologic Oncology. 2004 January; 92(1): 147-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14751150
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Efficacy, safety and pharmacokinetics of palonosetron in patients receiving highly emetogenic cisplatin-based chemotherapy: a dose-ranging clinical study. Author(s): Eisenberg P, MacKintosh FR, Ritch P, Cornett PA, Macciocchi A. Source: Annals of Oncology : Official Journal of the European Society for Medical Oncology / Esmo. 2004 February; 15(2): 330-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14760130
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Efficiency of extension of mismatched primer termini across from cisplatin and oxaliplatin adducts by human DNA polymerases beta and eta in vitro. Author(s): Bassett E, Vaisman A, Havener JM, Masutani C, Hanaoka F, Chaney SG. Source: Biochemistry. 2003 December 9; 42(48): 14197-206. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14640687
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Elderly patients with advanced non-small cell lung cancer. A pase II study with weekly cisplatin and gemcitabine. Author(s): Berardi R, Porfiri E, Scartozzi M, Lippe P, Silva RR, Nacciarriti D, Menichetti ET, Tummarello D, Carle F, Piga A, Cellerino R. Source: Oncology. 2003; 65(3): 198-203. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14657592
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Enhanced chemosensitivity of bladder cancer cells to cisplatin by suppression of clusterin in vitro. Author(s): Chung J, Kwak C, Jin RJ, Lee CH, Lee KH, Lee SE. Source: Cancer Letters. 2004 January 20; 203(2): 155-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14732223
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Enhanced susceptibility of oral squamous cell carcinoma cell lines to FAS-mediated apoptosis by cisplatin and 5-fluorouracil. Author(s): Iwase M, Watanabe H, Kondo G, Ohashi M, Nagumo M. Source: International Journal of Cancer. Journal International Du Cancer. 2003 September 10; 106(4): 619-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12845662
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Evaluation of cisplatin + 5-FU, carboplatin + 5-FU, and ifosfamide + epirubicine regimens using the micronuclei test and nuclear abnormalities in the buccal mucosa. Author(s): Torres-Bugarin O, Ventura-Aguilar A, Zamora-Perez A, Gomez-Meda BC, Ramos-Ibarra ML, Morgan-Villela G, Gutierrez-Franco A, Zuniga-Gonzalez G. Source: Mutation Research. 2003 August 5; 539(1-2): 177-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12948826
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Expression of p53 protein as a predictor of the response to 5-fluorouracil and cisplatin chemotherapy in human gastrointestinal cancer cell lines evaluated with apoptosis by use of thin layer collagen gel. Author(s): Matsuhashi N, Saio M, Matsuo A, Sugiyama Y, Saji S. Source: International Journal of Oncology. 2004 April; 24(4): 807-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15010816
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Factors predicting response and survival in 149 patients with unresectable hepatocellular carcinoma treated by combination cisplatin, interferon-alpha, doxorubicin and 5-fluorouracil chemotherapy. Author(s): Akcali Z, Akin E, Ozyilkan O. Source: Cancer. 2002 November 1; 95(9): 2038-9; Author Reply 2039. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12404300
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Factors predicting response and survival in 149 patients with unresectable hepatocellular carcinoma treated by combination cisplatin, interferon-alpha, doxorubicin and 5-fluorouracil chemotherapy. Author(s): Leung TW, Tang AM, Zee B, Yu SC, Lai PB, Lau WY, Johnson PJ. Source: Cancer. 2002 January 15; 94(2): 421-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11905412
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Failure of activation of caspase-9 induces a higher threshold for apoptosis and cisplatin resistance in testicular cancer. Author(s): Mueller T, Voigt W, Simon H, Fruehauf A, Bulankin A, Grothey A, Schmoll HJ. Source: Cancer Research. 2003 January 15; 63(2): 513-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12543810
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Farnesyl transferase inhibitor SCH66336 is cytostatic, pro-apoptotic and enhances chemosensitivity to cisplatin in melanoma cells. Author(s): Smalley KS, Eisen TG. Source: International Journal of Cancer. Journal International Du Cancer. 2003 June 10; 105(2): 165-75. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12673674
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Fate of RNA polymerase II stalled at a cisplatin lesion. Author(s): Tremeau-Bravard A, Riedl T, Egly JM, Dahmus ME. Source: The Journal of Biological Chemistry. 2004 February 27; 279(9): 7751-9. Epub 2003 December 12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14672951
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Feasibility of combination chemotherapy with cisplatin and etoposide for haemodialysis patients with lung cancer. Author(s): Watanabe R, Takiguchi Y, Moriya T, Oda S, Kurosu K, Tanabe N, Tatsumi K, Nagao K, Kuriyama T. Source: British Journal of Cancer. 2003 January 13; 88(1): 25-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12556954
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Filgrastim support during combination chemotherapy using cisplatin, doxorubicin, and cyclophosphamide to treat advanced or recurrent endometrial cancer: a clinical study and literature review. Author(s): Hall DJ, Martin DA, Kincaid K. Source: Eur J Gynaecol Oncol. 2003; 24(6): 481-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14658586
Studies
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Final results of a randomized phase III trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in advanced gastric cancer: A trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group. Author(s): Vanhoefer U, Rougier P, Wilke H, Ducreux MP, Lacave AJ, Van Cutsem E, Planker M, Santos JG, Piedbois P, Paillot B, Bodenstein H, Schmoll HJ, Bleiberg H, Nordlinger B, Couvreur ML, Baron B, Wils JA. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2000 July; 18(14): 2648-57. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10894863
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First-line chemotherapy with cisplatin plus fractionated temozolomide in recurrent glioblastoma multiforme: a phase II study of the Gruppo Italiano Cooperativo di Neuro-Oncologia. Author(s): Brandes AA, Basso U, Reni M, Vastola F, Tosoni A, Cavallo G, Scopece L, Ferreri AJ, Panucci MG, Monfardini S, Ermani M; Gruppo Italiano Cooperativo di Neuro-Oncologia. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2004 May 1; 22(9): 1598-604. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15117981
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First-line gemcitabine with cisplatin or epirubicin in advanced non-small-cell lung cancer: a phase III trial. Author(s): Wachters FM, Van Putten JW, Kramer H, Erjavec Z, Eppinga P, Strijbos JH, de Leede GP, Boezen HM, de Vries EG, Groen HJ. Source: British Journal of Cancer. 2003 October 6; 89(7): 1192-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14520444
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Fractionated administration of irinotecan and cisplatin for treatment of extensivedisease small-cell lung cancer: a phase II study. Author(s): Takigawa N, Fujiwara K, Ueoka H, Kiura K, Tabata M, Hiraki A, Shibayama T, Segawa Y, Kamei H, Hiraki S, Tanimoto M, Harada M. Source: Anticancer Res. 2003 January-February; 23(1B): 557-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12680145
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Fractionated administration of irinotecan and cisplatin for treatment of non-small-cell lung cancer: a phase II study of Okayama Lung Cancer Study Group. Author(s): Ueoka H, Tanimoto M, Kiura K, Tabata M, Takigawa N, Segawa Y, Takata I, Eguchi K, Okimoto N, Harita S, Kamei H, Shibayama T, Watanabe Y, Hiraki S, Harada M. Source: British Journal of Cancer. 2001 July 6; 85(1): 9-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11437395
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Freeze dried ondansetron: first observations with the fast dissolving oral antiemetic Zofran Zydis for the prophylaxis of the cisplatin-induced emesis in gynecological cancer patients. Author(s): Lehoczky O, Udvary J, Pulay T. Source: Neoplasma. 2002; 49(2): 126-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12088106
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Front-line paclitaxel/cisplatin-based chemotherapy in brain metastases from nonsmall-cell lung cancer. Author(s): Cortes J, Rodriguez J, Aramendia JM, Salgado E, Gurpide A, Garcia-Foncillas J, Aristu JJ, Claver A, Bosch A, Lopez-Picazo JM, Martin-Algarra S, Brugarolas A, Calvo E. Source: Oncology. 2003; 64(1): 28-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12457029
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Front-line treatment of advanced non-small-cell lung cancer with MTA (LY231514, pemetrexed disodium, ALIMTA) and cisplatin: a multicenter phase II trial. Author(s): Manegold C, Gatzemeier U, von Pawel J, Pirker R, Malayeri R, Blatter J, Krejcy K. Source: Annals of Oncology : Official Journal of the European Society for Medical Oncology / Esmo. 2000 April; 11(4): 435-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10847462
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gamma-Glutamyl transpeptidase catalyses the extracellular detoxification of cisplatin in a human cell line derived from the proximal convoluted tubule of the kidney. Author(s): Paolicchi A, Sotiropuolou M, Perego P, Daubeuf S, Visvikis A, Lorenzini E, Franzini M, Romiti N, Chieli E, Leone R, Apostoli P, Colangelo D, Zunino F, Pompella A. Source: European Journal of Cancer (Oxford, England : 1990). 2003 May; 39(7): 996-1003. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12706370
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Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 1. Author(s): Giaccone G, Herbst RS, Manegold C, Scagliotti G, Rosell R, Miller V, Natale RB, Schiller JH, Von Pawel J, Pluzanska A, Gatzemeier U, Grous J, Ochs JS, Averbuch SD, Wolf MK, Rennie P, Fandi A, Johnson DH. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2004 March 1; 22(5): 777-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14990632
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Geldanamycin and its 17-allylamino-17-demethoxy analogue antagonize the action of Cisplatin in human colon adenocarcinoma cells: differential caspase activation as a basis for interaction. Author(s): Vasilevskaya IA, Rakitina TV, O'Dwyer PJ. Source: Cancer Research. 2003 June 15; 63(12): 3241-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12810654
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Gemcitabine and cisplatin as induction chemotherapy for patients with unresectable Stage IIIA-bulky N2 and Stage IIIB nonsmall cell lung carcinoma: an Italian Lung Cancer Project Observational Study. Author(s): Cappuzzo F, Selvaggi G, Gregorc V, Mazzoni F, Betti M, Rita Migliorino M, Novello S, Maestri A, De Marinis F, Darwish S, De Angelis V, Nelli F, Bartolini S, Scagliotti GV, Tonato M, Crino L. Source: Cancer. 2003 July 1; 98(1): 128-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12833465
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Gemcitabine and Cisplatin is a highly effective combination chemotherapy in patients with advanced cancer of the gallbladder. Author(s): Malik IA, Aziz Z, Zaidi SH, Sethuraman G. Source: American Journal of Clinical Oncology : the Official Publication of the American Radium Society. 2003 April; 26(2): 174-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12714891
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Gemcitabine and cisplatin versus vinorelbine and cisplatin versus ifosfamide+gemcitabine followed by vinorelbine and cisplatin versus vinorelbine and cisplatin followed by ifosfamide and gemcitabine in stage IIIB-IV non small cell lung carcinoma: a prospective randomized phase III trial of the Gruppo Oncologico Italia Meridionale. Author(s): Gebbia V, Galetta D, Caruso M, Verderame F, Pezzella G, Valdesi M, Borsellino N, Pandolfo G, Durini E, Rinaldi M, Loizzi M, Gebbia N, Valenza R, Tirrito ML, Varvara F, Colucci G; Gruppo Ocologico Italia Meridionale. Source: Lung Cancer (Amsterdam, Netherlands). 2003 February; 39(2): 179-89. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12581571
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Gemcitabine combined with cisplatin as first-line treatment in patients 60 years or older with epithelial ovarian cancer: a phase II study. Author(s): Bauknecht T, Hefti A, Morack G, Villena-Heinsen C, Wallwiener D, Elling D, Minckwitz GV, Mansouri K, Blatter J, Breitbach GP. Source: International Journal of Gynecological Cancer : Official Journal of the International Gynecological Cancer Society. 2003 March-April; 13(2): 130-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12657112
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Gemcitabine combined with cisplatin as first-line treatment in patients with epithelial ovarian cancer: a phase II study. Author(s): Belpomme D, Krakowski I, Beauduin M, Petit T, Canon JL, Janssens J, Gauthier S, De Pauw A, Moreau V, Kayitalire L. Source: Gynecologic Oncology. 2003 October; 91(1): 32-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14529659
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Gemcitabine plus cisplatin in adjuvant regimen for bladder cancer. Toxicity evaluation. Author(s): Meliani E, Lapini A, Serni S, Corvino C, Carini M. Source: Urologia Internationalis. 2003; 71(1): 37-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12845258
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Gemcitabine plus cisplatin vs. gemcitabine plus carboplatin in stage IIIb and IV nonsmall cell lung cancer: a phase III randomized trial. Author(s): Zatloukal P, Petruzelka L, Zemanova M, Kolek V, Skrickova J, Pesek M, Fojtu H, Grygarkova I, Sixtova D, Roubec J, Horenkova E, Havel L, Prusa P, Novakova L, Skacel T, Kuta M. Source: Lung Cancer (Amsterdam, Netherlands). 2003 September; 41(3): 321-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12928123
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Gemcitabine, cisplatin and methylprednisolone chemotherapy (GEM-P) is an effective regimen in patients with poor prognostic primary progressive or multiply relapsed Hodgkin's and non-Hodgkin's lymphoma. Author(s): Chau I, Harries M, Cunningham D, Hill M, Ross PJ, Archer CD, Norman AR, Wotherspoon A, Koh DM, Gill K, Uzzell M, Prior Y, Catovsky D. Source: British Journal of Haematology. 2003 March; 120(6): 970-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12648066
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Gemcitabine, cisplatin and vinorelbine as induction chemotherapy followed by radical therapy in stage III non-small-cell lung cancer: a multicentre study of galicianlung-cancer-group. Author(s): Leon L, Cueva-Banuelos JF, Huidobro G, Firvida JL, Amenedo M, Lazaro M, Romero C, Estevez SV, Baron FJ, Grande C, Garcia Mata J, Gonzalez A, Castellanos J, Gomez A, Caeiro M, Rodriguez MR, Casal J; Galician Lung Cancer Group. Source: Lung Cancer (Amsterdam, Netherlands). 2003 May; 40(2): 215-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12711124
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Gemcitabine, dexamethasone and cisplatin is an active and non-toxic chemotherapy regimen in relapsed or refractory Hodgkin's disease: a phase II study by the National Cancer Institute of Canada Clinical Trials Group. Author(s): Baetz T, Belch A, Couban S, Imrie K, Yau J, Myers R, Ding K, Paul N, Shepherd L, Iglesias J, Meyer R, Crump M. Source: Annals of Oncology : Official Journal of the European Society for Medical Oncology / Esmo. 2003 December; 14(12): 1762-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14630682
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Gene expression profile of metastatic colon cancer cells resistant to cisplatin-induced apoptosis. Author(s): Huerta S, Harris DM, Jazirehi A, Bonavida B, Elashoff D, Livingston EH, Heber D. Source: International Journal of Oncology. 2003 March; 22(3): 663-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12579322
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Glutathione S-transferase pi amplification is associated with cisplatin resistance in head and neck squamous cell carcinoma cell lines and primary tumors. Author(s): Cullen KJ, Newkirk KA, Schumaker LM, Aldosari N, Rone JD, Haddad BR. Source: Cancer Research. 2003 December 1; 63(23): 8097-102. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14678959
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Hammerhead ribozyme against gamma-glutamylcysteine synthetase attenuates resistance to ionizing radiation and cisplatin in human T98G glioblastoma cells. Author(s): Tani M, Goto S, Kamada K, Mori K, Urata Y, Ihara Y, Kijima H, Ueyama Y, Shibata S, Kondo T. Source: Japanese Journal of Cancer Research : Gann. 2002 June; 93(6): 716-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12079521
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Hammerhead ribozyme against gamma-glutamylcysteine synthetase sensitizes human colonic cancer cells to cisplatin by down-regulating both the glutathione synthesis and the expression of multidrug resistance proteins. Author(s): Iida T, Kijima H, Urata Y, Goto S, Ihara Y, Oka M, Kohno S, Scanlon KJ, Kondo T. Source: Cancer Gene Therapy. 2001 October; 8(10): 803-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11687904
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Hepatic arterial infusion (HAI) of cisplatin and systemic fluorouracil in the treatment of unresectable colorectal liver metastases. Author(s): Mancini R, Tedesco M, Garufi C, Filippini A, Arcieri S, Caterino M, Pizzi G, Cortesi E, Spila A, Sperduti I, Cosimelli M. Source: Anticancer Res. 2003 March-April; 23(2C): 1837-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12820466
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Hepatic arterial infusion of 5-fluorouracil and cisplatin for unresectable or recurrent hepatocellular carcinoma with tumor thrombus of the portal vein. Author(s): Itamoto T, Nakahara H, Tashiro H, Haruta N, Asahara T, Naito A, Ito K. Source: Journal of Surgical Oncology. 2002 July; 80(3): 143-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12115797
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High curative resection rate with weekly cisplatin, 5-fluorouracil, epidoxorubicin, 6Sleucovorin, glutathione, and filgastrim in patients with locally advanced, unresectable gastric cancer: a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD). Author(s): Cascinu S, Scartozzi M, Labianca R, Catalano V, Silva RR, Barni S, Zaniboni A, D'Angelo A, Salvagni S, Martignoni G, Beretta GD, Graziano F, Berardi R, Franciosi V; Italian Group for the Study of Digestive Tract Cancer (GISCAD). Source: British Journal of Cancer. 2004 April 19; 90(8): 1521-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15083179
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High dose ifosfamide in combination with high dose methotrexate, adriamycin and cisplatin in the neoadjuvant treatment of extremity osteosarcoma: preliminary results of an Italian Sarcoma Group/Scandinavian Sarcoma Group pilot study. Author(s): Bacci G, Ferrari S, Longhi A, Picci P, Mercuri M, Alvegard TA, Saeter G, Donati D, Manfrini M, Lari S, Briccoli A, Forni C; Italian Sarcoma Group/Scandinavian Sarcoma Group. Source: J Chemother. 2002 April; 14(2): 198-206. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12017378
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High response rate to cisplatin/etoposide regimen in childhood low-grade glioma. Author(s): Massimino M, Spreafico F, Cefalo G, Riccardi R, Tesoro-Tess JD, Gandola L, Riva D, Ruggiero A, Valentini L, Mazza E, Genitori L, Di Rocco C, Navarria P, Casanova M, Ferrari A, Luksch R, Terenziani M, Balestrini MR, Colosimo C, Fossati-Bellani F. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2002 October 15; 20(20): 4209-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12377964
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High-dose epirubicin and cisplatin in locally advanced undifferentiated nasopharyngeal carcinoma. Author(s): Onat H, Basaran M, Esassolak M, Bavbek SE, Anacak Y, Kaytan E, Altun M, Haydaroglu A. Source: Clin Oncol (R Coll Radiol). 2002 December; 14(6): 449-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12512965
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Histological complete response in a case of advanced gastric cancer treated by chemotherapy with S-1 plus low-dose cisplatin and radiation. Author(s): Takahashi T, Saikawa Y, Kubota T, Akiba Y, Shigematsu N, Yoshida M, Otani Y, Kumai K, Hibi T, Kitajima M. Source: Japanese Journal of Clinical Oncology. 2003 November; 33(11): 584-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14711984
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Homeodomain-interacting protein kinase-2 activity and p53 phosphorylation are critical events for cisplatin-mediated apoptosis. Author(s): Di Stefano V, Rinaldo C, Sacchi A, Soddu S, D'Orazi G. Source: Experimental Cell Research. 2004 February 15; 293(2): 311-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14729469
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Human colon cancer cells surviving high doses of cisplatin or oxaliplatin in vitro are not defective in DNA mismatch repair proteins. Author(s): Sergent C, Franco N, Chapusot C, Lizard-Nacol S, Isambert N, Correia M, Chauffert B. Source: Cancer Chemotherapy and Pharmacology. 2002 June; 49(6): 445-52. Epub 2002 April 20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12107548
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Human hepatocellular carcinoma cells resist to TRAIL-induced apoptosis, and the resistance is abolished by cisplatin. Author(s): Shin EC, Seong YR, Kim CH, Kim H, Ahn YS, Kim K, Kim SJ, Hong SS, Park JH. Source: Experimental & Molecular Medicine. 2002 May 31; 34(2): 114-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12085986
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Human ovarian cancer and cisplatin resistance: possible role of inhibitor of apoptosis proteins. Author(s): Li J, Feng Q, Kim JM, Schneiderman D, Liston P, Li M, Vanderhyden B, Faught W, Fung MF, Senterman M, Korneluk RG, Tsang BK. Source: Endocrinology. 2001 January; 142(1): 370-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11145600
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Hyperfractionated radiotherapy and concomitant cisplatin for locally advanced laryngeal and hypopharyngeal carcinomas: final results of a single institutional program. Author(s): de la Vega FA, Garcia RV, Dominguez D, Iturre EV, Lopez EM, Alonso SM, Romero P, Sola JM. Source: American Journal of Clinical Oncology : the Official Publication of the American Radium Society. 2003 December; 26(6): 550-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14663370
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Hypersensitivity reaction to carboplatin: successful resolution by replacement with cisplatin. Author(s): Porzio G, Marchetti P, Paris I, Narducci F, Ricevuto E, Ficorella C. Source: Eur J Gynaecol Oncol. 2002; 23(4): 335-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12214738
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Hypersensitivity reaction to cisplatin during chemoradiation therapy for gynecologic malignancy. Author(s): Koren C, Yerushalmi R, Katz A, Malik H, Sulkes A, Fenig E. Source: American Journal of Clinical Oncology : the Official Publication of the American Radium Society. 2002 December; 25(6): 625-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12478013
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Hyperthermic intraoperative intraperitoneal chemotherapy with cisplatin and doxorubicin in patients who undergo cytoreductive surgery for peritoneal carcinomatosis and sarcomatosis: phase I study. Author(s): Rossi CR, Foletto M, Mocellin S, Pilati P, De SM, Deraco M, Cavaliere F, Palatini P, Guasti F, Scalerta R, Lise M. Source: Cancer. 2002 January 15; 94(2): 492-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11900234
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Hyperthermic pleural perfusion with cisplatin: early clinical experience. Author(s): Yellin A, Simansky DA, Paley M, Refaely Y. Source: Cancer. 2001 October 15; 92(8): 2197-203. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11596038
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Hypothermic modulation of doxorubicin, cisplatin and radiation cytotoxicity in vitro. Author(s): Lundgren-Eriksson L, Hultborn R, Henriksson R. Source: Anticancer Res. 2001 September-October; 21(5): 3275-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11848483
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Impaired hydrolysis of cisplatin derivatives to aquated species prevents energydependent uptake in GLC4 cells resistant to cisplatin. Author(s): Pereira-Maia E, Garnier-Suillerot A. Source: Journal of Biological Inorganic Chemistry : Jbic : a Publication of the Society of Biological Inorganic Chemistry. 2003 July; 8(6): 626-34. Epub 2003 May 17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12756611
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In vitro cytoprotective activity of squalene on a bone marrow versus neuroblastoma model of cisplatin-induced toxicity. implications in cancer chemotherapy. Author(s): Das B, Yeger H, Baruchel H, Freedman MH, Koren G, Baruchel S. Source: European Journal of Cancer (Oxford, England : 1990). 2003 November; 39(17): 2556-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14602142
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Increased adenoviral transduction efficacy in human laryngeal carcinoma cells resistant to cisplatin is associated with increased expression of integrin alphavbeta3 and coxsackie adenovirus receptor. Author(s): Ambriovic-Ristov A, Gabrilovac J, Cimbora-Zovko T, Osmak M. Source: International Journal of Cancer. Journal International Du Cancer. 2004 July 10; 110(5): 660-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15146554
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Induction of cell cycle arrest and apoptosis in human cervix carcinoma cells during therapy by cisplatin. Author(s): Schloffer D, Horky M, Kotala V, Wesierska-Gadek J. Source: Cancer Detection and Prevention. 2003; 27(6): 481-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14642557
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Influence of the cisplatin hydration schedule on topotecan pharmacokinetics. Author(s): Gelderblom H, Loos WJ, Sparreboom A, Soepenberg O, de Jonge MJ, van Boven-van Zomeren DM, Verweij J. Source: European Journal of Cancer (Oxford, England : 1990). 2003 July; 39(11): 1542-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12855260
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Inhibition of cisplatin-induced ATR activity and enhanced sensitivity to cisplatin. Author(s): Yazlovitskaya EM, Persons DL. Source: Anticancer Res. 2003 May-June; 23(3B): 2275-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12894503
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Inhibition of phosphorylation of a forkhead transcription factor sensitizes human ovarian cancer cells to cisplatin. Author(s): Arimoto-Ishida E, Ohmichi M, Mabuchi S, Takahashi T, Ohshima C, Hayakawa J, Kimura A, Takahashi K, Nishio Y, Sakata M, Kurachi H, Tasaka K, Murata Y. Source: Endocrinology. 2004 April; 145(4): 2014-22. Epub 2003 December 30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14701673
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Inhibition of pre-mRNA splicing by cisplatin and platinum analogs. Author(s): Schmittgen TD, Ju JF, Danenberg KD, Danenberg PV. Source: International Journal of Oncology. 2003 September; 23(3): 785-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12888918
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Intra-arterial cisplatin in osteosarcoma: same question, different answer. Author(s): Rao BN, Rodriguez-Galindo C. Source: Annals of Surgical Oncology : the Official Journal of the Society of Surgical Oncology. 2003 June; 10(5): 481-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12794009
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Intra-arterial induction high-dose chemotherapy with cisplatin for oral and oropharyngeal cancer: long-term results. Author(s): Kovacs AF. Source: British Journal of Cancer. 2004 April 5; 90(7): 1323-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15054449
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Intraperitoneal cisplatin versus no further treatment: 8-year results of EORTC 55875, a randomized phase III study in ovarian cancer patients with a pathologically complete remission after platinum-based intravenous chemotherapy. Author(s): Piccart MJ, Floquet A, Scarfone G, Willemse PH, Emerich J, Vergote I, Giurgea L, Coens C, Awada A, Vermorken JB. Source: International Journal of Gynecological Cancer : Official Journal of the International Gynecological Cancer Society. 2003 November-December; 13 Suppl 2: 196203. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14656280
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Intratumoral cisplatin/epinephrine gel in advanced head and neck cancer: a multicenter, randomized, double-blind, phase III study in North America. Author(s): Castro DJ, Sridhar KS, Garewal HS, Mills GM, Wenig BL, Dunphy FR 2nd, Costantino PD, Leavitt RD, Stewart ME, Orenberg EK. Source: Head & Neck. 2003 September; 25(9): 717-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12953307
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JM216-, JM118-, and cisplatin-induced cytotoxicity in relation to platinum-DNA adduct formation, glutathione levels and p53 status in human tumour cell lines with different sensitivities to cisplatin. Author(s): Fokkema E, Groen HJ, Helder MN, de Vries EG, Meijer C. Source: Biochemical Pharmacology. 2002 June 1; 63(11): 1989-96. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12093475
Studies
89
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Kinetic characterization of ribozymes directed against the cisplatin resistanceassociated ABC transporter cMOAT/MRP2/ABCC2. Author(s): Materna V, Holm PS, Dietel M, Lage H. Source: Cancer Gene Therapy. 2001 March; 8(3): 176-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11332988
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Kinetic study on the reaction of cisplatin with metallothionein. Author(s): Hagrman D, Goodisman J, Dabrowiak JC, Souid AK. Source: Drug Metabolism and Disposition: the Biological Fate of Chemicals. 2003 July; 31(7): 916-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12814969
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Kinetics of cisplatin binding to cellular DNA and modulations by thiol-blocking agents and thiol drugs. Author(s): Sadowitz PD, Hubbard BA, Dabrowiak JC, Goodisman J, Tacka KA, Aktas MK, Cunningham MJ, Dubowy RL, Souid AK. Source: Drug Metabolism and Disposition: the Biological Fate of Chemicals. 2002 February; 30(2): 183-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11792689
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Kinetics of plasma platinum in a hemodialysis patient receiving repeated doses of cisplatin. Author(s): Hirai K, Ishiko O, Sumi T, Kanaoka Y, Ogita S. Source: Oncol Rep. 2000 November-December; 7(6): 1243-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11032923
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Lack of impact of platinum dose intensity on the outcome of ovarian cancer patients. 10-year results of a prospective randomised phase III study comparing carboplatincisplatin with cyclophosphamide-cisplatin. Author(s): Dittrich Ch, Sevelda P, Salzer H, Obermair A, Speiser P, Breitenecker G, Schemper M, Kaider A; Austrian Ovarian Cancer Study Group. Source: European Journal of Cancer (Oxford, England : 1990). 2003 May; 39(8): 1129-40. Erratum In: Eur J Cancer. 2004 March; 40(4): 627. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12736113
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Lhermitte's sign following oxaliplatin-containing chemotherapy in a cisplatinpretreated ovarian cancer patient. Author(s): Ciucci G, De Giorgi U, Leoni M, Bianchedi G. Source: European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies. 2003 May; 10(3): 328-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12752412
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Long-lasting complete remission of a patient with cervical cancer FIGO IVB treated by concomitant chemobrachyradiotherapy with ifosfamide and cisplatin and consolidation chemotherapy--a case report. Author(s): Vrdoljak E, Hamm W, Omrcen T, Prskalo T. Source: Eur J Gynaecol Oncol. 2004; 25(2): 247-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15032295
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Long-term follow-up of hepatic arterial chemoembolization with cisplatin suspended in iodized oil for hepatocellular carcinoma. Author(s): Maeda S, Shibata J, Fujiyama S, Tanaka M, Noumaru S, Sato K, Tomita K. Source: Hepatogastroenterology. 2003 May-June; 50(51): 809-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12828090
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Long-term survival in osteosarcoma patients following retinoblastoma using doxorubicin, cisplatin, and methotrexate. Author(s): Stine KC, Saylors RL, Saccente S, Becton DL. Source: Medical and Pediatric Oncology. 2003 July; 41(1): 77-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12764753
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Long-term survival in phase II trials of gemcitabine plus cisplatin for advanced transitional cell cancer. Author(s): Stadler WM, Hayden A, von der Maase H, Roychowdhury D, Dogliotti L, Seymour L, Kaufmann D, Moore M. Source: Urologic Oncology. 2002 July-August; 7(4): 153-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12474531
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Long-term survival of patients with advanced/recurrent carcinoma of cervix and vagina after neoadjuvant treatment with methotrexate, vinblastine, doxorubicin, and cisplatin with or without the addition of molgramostim, and review of the literature. Author(s): Long HJ 3rd, Rayson S, Podratz KC, Abu-Ghazaleh S, Suman V, Hartmann LC, Levitt R, Nair S, Hatfield AK, Knost JA. Source: American Journal of Clinical Oncology : the Official Publication of the American Radium Society. 2002 December; 25(6): 547-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12477995
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Long-term survivors of ovarian malignancies after cisplatin-based chemotherapy; cardiovascular risk factors and signs of vascular damage. Author(s): de Vos FY, Nuver J, Willemse PH, van der Zee AG, Messerschmidt J, Burgerhof JG, de Vries EG, Gietema JA. Source: European Journal of Cancer (Oxford, England : 1990). 2004 March; 40(5): 696700. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15010070
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Loss of drug-induced activation of the CD95 apoptotic pathway in a cisplatinresistant testicular germ cell tumor cell line. Author(s): Spierings DC, de Vries EG, Vellenga E, de Jong S. Source: Cell Death and Differentiation. 2003 July; 10(7): 808-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12815464
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Low toxic neoadjuvant cisplatin, 5-fluorouracil and folinic acid in locally advanced gastric cancer yields high R-0 resection rate. Author(s): Menges M, Schmidt C, Lindemann W, Ridwelski K, Pueschel W, Jungling B, Feifel G, Schilling M, Stallmach A, Zeitz M. Source: Journal of Cancer Research and Clinical Oncology. 2003 July; 129(7): 423-9. Epub 2003 June 27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12836016
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Low-dose chemotherapy of cisplatin and 5-fluorouracil or doxorubicin via implanted fusion port for unresectable hepatocellular carcinoma. Author(s): Murata K, Shiraki K, Kawakita T, Yamamoto N, Okano H, Nakamura M, Sakai T, Deguchi M, Ohmori S, Nakano T. Source: Anticancer Res. 2003 March-April; 23(2C): 1719-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12820447
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Low-dose cisplatin plus oral tegafur and uracil for the treatment of lung metastases of hepatocellular carcinoma. Author(s): Maeda T, Itasaka H, Takenaka K, Matsumata T, Shimada M, Ikeda T, Sugimachi K. Source: Hepatogastroenterology. 2003 September-October; 50(53): 1583-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14571791
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Low-dose gemcitabine plus cisplatin in previously treated, relapsed non-Hodgkin's lymphoma. Author(s): Wong SF, Lindgren T, Hsu D, Tran G. Source: American Journal of Hematology. 2003 August; 73(4): 298. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12879441
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Low-dose mitomycin C, etoposide, and cisplatin for invasive vulvar Paget's disease. Author(s): Watanabe Y, Hoshiai H, Ueda H, Nakai H, Obata K, Noda K. Source: International Journal of Gynecological Cancer : Official Journal of the International Gynecological Cancer Society. 2002 May-June; 12(3): 304-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12060453
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Lung function changes and pulmonary complications in patients with stage III nonsmall cell lung cancer treated with gemcitabine/cisplatin as part of combined modality treatment. Author(s): Maas KW, van der Lee I, Bolt K, Zanen P, Lammers JW, Schramel FM. Source: Lung Cancer (Amsterdam, Netherlands). 2003 September; 41(3): 345-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12928125
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Marked activity of irofulven toward human carcinoma cells: comparison with cisplatin and ecteinascidin. Author(s): Poindessous V, Koeppel F, Raymond E, Comisso M, Waters SJ, Larsen AK. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2003 July; 9(7): 2817-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12855662
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Mass spectrometric studies of cisplatin-induced changes of hemoglobin. Author(s): Mandal R, Kalke R, Li XF. Source: Rapid Communications in Mass Spectrometry : Rcm. 2003; 17(24): 2748-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14673822
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Mature survival results with preoperative cisplatin, protracted infusion 5fluorouracil, and 44-Gy radiotherapy for esophageal cancer. Author(s): Kleinberg L, Knisely JP, Heitmiller R, Zahurak M, Salem R, Burtness B, Heath EI, Forastiere AA. Source: International Journal of Radiation Oncology, Biology, Physics. 2003 June 1; 56(2): 328-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12738305
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Mediastinal growing teratoma syndrome after cisplatin-based chemotherapy and radiotherapy for intracranial germinoma. Author(s): Iwata H, Mori Y, Takagi H, Shirahashi K, Shinoda J, Shimokawa K, Hirose H. Source: The Journal of Thoracic and Cardiovascular Surgery. 2004 January; 127(1): 291-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14752454
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Mislocalization of membrane proteins associated with multidrug resistance in cisplatin-resistant cancer cell lines. Author(s): Liang XJ, Shen DW, Garfield S, Gottesman MM. Source: Cancer Research. 2003 September 15; 63(18): 5909-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14522917
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Modulation of Janus kinase 2 by cisplatin in cancer cells. Author(s): Song H, Sondak VK, Barber DL, Reid TJ, Lin J. Source: International Journal of Oncology. 2004 April; 24(4): 1017-26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15010843
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Molecular mechanisms of hyperthermia- and cisplatin-induced cytotoxicity in T cell leukemia. Author(s): Mauz-Korholz C, Dietzsch S, Schippel P, Banning U, Korholz D. Source: Anticancer Res. 2003 May-June; 23(3B): 2643-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12894552
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Molecular mechanisms underlying the interaction between ZD1839 ('Iressa') and cisplatin/5-fluorouracil. Author(s): Magne N, Fischel JL, Tiffon C, Formento P, Dubreuil A, Renee N, Formento JL, Francoual M, Ciccolini J, Etienne MC, Milano G. Source: British Journal of Cancer. 2003 August 4; 89(3): 585-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12888834
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Monocular visual loss in a patient undergoing cisplatin chemotherapy. Author(s): Gonzalez F, Menendez D, Gomez-Ulla F. Source: International Ophthalmology. 2001; 24(6): 301-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14750566
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Neoadjuvant chemotherapy for osteosarcoma of the extremities with metastases at presentation: recent experience at the Rizzoli Institute in 57 patients treated with cisplatin, doxorubicin, and a high dose of methotrexate and ifosfamide. Author(s): Bacci G, Briccoli A, Rocca M, Ferrari S, Donati D, Longhi A, Bertoni F, Bacchini P, Giacomini S, Forni C, Manfrini M, Galletti S. Source: Annals of Oncology : Official Journal of the European Society for Medical Oncology / Esmo. 2003 July; 14(7): 1126-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12853357
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Neoadjuvant chemotherapy in squamous cell carcinoma of the esophagus using low dose continuous infusion 5-fluorouracil and cisplatin: results of a prospective study. Author(s): Aroori S, Parshad R, Kapoor A, Gupta SD, Kumar A, Chattophadyay TK. Source: Indian Journal of Cancer. 2004 January-March; 41(1): 3-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15105572
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Neoadjuvant chemotherapy with cisplatin, 5-FU, and leucovorin (PLF) in locally advanced gastric cancer: a prospective phase II study. Author(s): Ott K, Sendler A, Becker K, Dittler HJ, Helmberger H, Busch R, Kollmannsberger C, Siewert JR, Fink U. Source: Gastric Cancer : Official Journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association. 2003; 6(3): 159-67. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14520529
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Neoadjuvant chemotherapy with ifosfamide and cisplatin combination in advanced head and neck cancer: a retrospective analysis of 519 patients: a single institution experience. Author(s): Pai VR, Mazumdar AT, Deshmukh CD, Bakshi AV, Parikh DM, Parikh PM, Mistry RC, Pathak KA. Source: Medical Oncology (Northwood, London, England). 2003; 20(1): 1-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12665677
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Neuroprotective effect of vitamin E supplementation in patients treated with cisplatin chemotherapy. Author(s): Pace A, Savarese A, Picardo M, Maresca V, Pacetti U, Del Monte G, Biroccio A, Leonetti C, Jandolo B, Cognetti F, Bove L. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 March 1; 21(5): 927-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12610195
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Neurotoxicity of platinum compounds: comparison of the effects of cisplatin and oxaliplatin on the human neuroblastoma cell line SH-SY5Y. Author(s): Donzelli E, Carfi M, Miloso M, Strada A, Galbiati S, Bayssas M, GriffonEtienne G, Cavaletti G, Petruccioli MG, Tredici G. Source: Journal of Neuro-Oncology. 2004 March-April; 67(1-2): 65-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15072449
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Non-Q-Wave acute anterior myocardial infarction associated with 5-fluorouracil and cisplatin chemotherapy. Author(s): Erol MK, Acikel M, Senocak H. Source: Southern Medical Journal. 2003 January; 96(1): 99. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12602729
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Nuclear-factor kappa B (NF-kappa B)-inducible nitric oxide synthase (iNOS/NOS II) pathway damages the stria vascularis in cisplatin-treated mice. Author(s): Watanabe K, Inai S, Jinnouchi K, Bada S, Hess A, Michel O, Yagi T. Source: Anticancer Res. 2002 November-December; 22(6C): 4081-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12553036
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Nucleotide excision repair pathways involved in Cisplatin resistance in non-smallcell lung cancer. Author(s): Rosell R, Taron M, Barnadas A, Scagliotti G, Sarries C, Roig B. Source: Cancer Control : Journal of the Moffitt Cancer Center. 2003 July-August; 10(4): 297-305. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12915808
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O6-methyl-guanine-DNA methyltransferase methylation in serum and tumor DNA predicts response to 1,3-bis(2-chloroethyl)-1-nitrosourea but not to temozolamide plus cisplatin in glioblastoma multiforme. Author(s): Balana C, Ramirez JL, Taron M, Roussos Y, Ariza A, Ballester R, Sarries C, Mendez P, Sanchez JJ, Rosell R. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2003 April; 9(4): 1461-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12684420
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Optimization of 5-fluorouracil (5-FU)/cisplatin combination chemotherapy with a new schedule of leucovorin, 5-FU and cisplatin (LV5FU2-P regimen) in patients with biliary tract carcinoma. Author(s): Taieb J, Mitry E, Boige V, Artru P, Ezenfis J, Lecomte T, Clavero-Fabri MC, Vaillant JN, Rougier P, Ducreux M. Source: Annals of Oncology : Official Journal of the European Society for Medical Oncology / Esmo. 2002 August; 13(8): 1192-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12181241
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Overexpression of cMOAT (MRP2/ABCC2) is associated with decreased formation of platinum-DNA adducts and decreased G2-arrest in melanoma cells resistant to cisplatin. Author(s): Liedert B, Materna V, Schadendorf D, Thomale J, Lage H. Source: The Journal of Investigative Dermatology. 2003 July; 121(1): 172-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12839578
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Overexpression of mutated MRP4 in cisplatin resistant small cell lung cancer cell line: collateral sensitivity to azidothymidine. Author(s): Savaraj N, Wu C, Wangpaichitr M, Kuo MT, Lampidis T, Robles C, Furst AJ, Feun L. Source: International Journal of Oncology. 2003 July; 23(1): 173-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12792791
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P53 mutation correlates with cisplatin sensitivity in head and neck squamous cell carcinoma lines. Author(s): Bradford CR, Zhu S, Ogawa H, Ogawa T, Ubell M, Narayan A, Johnson G, Wolf GT, Fisher SG, Carey TE. Source: Head & Neck. 2003 August; 25(8): 654-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12884349
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Pharmacokinetics and preliminary clinical data of the novel chemoprotectant BNP7787 and cisplatin and their metabolites. Author(s): Verschraagen M, Boven E, Ruijter R, van der Born K, Berkhof J, Hausheer FH, van der Vijgh WJ. Source: Clinical Pharmacology and Therapeutics. 2003 August; 74(2): 157-69. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12891226
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Phase I/II study of combination therapy of oral fluorinated pyrimidine compound S-1 with low-dose cisplatin in patients with unresectable and/or recurrent advanced gastric cancer: a novel study design to evaluate safety and efficacy. Author(s): Morita S, Ohashi Y, Hirakawa K, Nakata B, Saji S, Sakamoto J. Source: Japanese Journal of Clinical Oncology. 2004 March; 34(3): 159-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15078913
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Phase II study of gemcitabine, cisplatin, and infusional fluorouracil in advanced pancreatic cancer. Author(s): El-Rayes BF, Zalupski MM, Shields AF, Vaishampayan U, Heilbrun LK, Jain V, Adsay V, Day J, Philip PA. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 August 1; 21(15): 2920-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12885810
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Predicting factors for collection of peripheral blood stem cells in patients with advanced germ cell tumors after cisplatin-based combination chemotherapy. Author(s): Muramaki M, Miyake H, Hara S, Kamidono S, Hara I. Source: Oncol Rep. 2003 September-October; 10(5): 1545-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12883739
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Prediction of 5-fluorouracil and cisplatin synergism for advanced gastrointestinal cancers using a collagen gel droplet embedded culture. Author(s): Mori S, Kunieda K, Sugiyama Y, Saji S. Source: Surgery Today. 2003; 33(8): 577-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12884094
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Quality of life and cisplatin-gemcitabine chemotherapy. Author(s): Mitchell PL. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2000 July; 18(14): 2791-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10894882
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Quality of life in patients diagnosed with primary hepatocellular carcinoma: hepatic arterial infusion of Cisplatin versus 90-Yttrium microspheres (Therasphere). Author(s): Steel J, Baum A, Carr B. Source: Psycho-Oncology. 2004 February; 13(2): 73-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14872525
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Quality-of-life assessment after supradose selective intra-arterial cisplatin and concomitant radiation (RADPLAT) for inoperable stage IV head and neck squamous cell carcinoma. Author(s): Ackerstaff AH, Tan IB, Rasch CR, Balm AJ, Keus RB, Schornagel JH, Hilgers FJ. Source: Archives of Otolaryngology--Head & Neck Surgery. 2002 October; 128(10): 118590. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12365891
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Quantitative analysis of expression levels of bax, bcl-2, and survivin in cancer cells during cisplatin treatment. Author(s): Ikeguchi M, Nakamura S, Kaibara N. Source: Oncol Rep. 2002 September-October; 9(5): 1121-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12168083
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Quantitative effects on c-Jun N-terminal protein kinase signaling determine synergistic interaction of cisplatin and 17-allylamino-17-demethoxygeldanamycin in colon cancer cell lines. Author(s): Vasilevskaya IA, Rakitina TV, O'Dwyer PJ. Source: Molecular Pharmacology. 2004 January; 65(1): 235-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14722256
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Randomized phase I clinical and pharmacologic study of weekly versus twice-weekly dose-intensive cisplatin and gemcitabine in patients with advanced non-small cell lung cancer. Author(s): Crul M, Schoemaker NE, Pluim D, Maliepaard M, Underberg RW, Schot M, Sparidans RW, Baas P, Beijnen JH, Van Zandwijk N, Schellens JH. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2003 September 1; 9(10 Pt 1): 3526-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14506138
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Randomized phase II trial of gemcitabine-cisplatin with or without trastuzumab in HER2-positive non-small-cell lung cancer. Author(s): Gatzemeier U, Groth G, Butts C, Van Zandwijk N, Shepherd F, Ardizzoni A, Barton C, Ghahramani P, Hirsh V. Source: Annals of Oncology : Official Journal of the European Society for Medical Oncology / Esmo. 2004 January; 15(1): 19-27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14679114
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Randomized phase III trial of standard timed doxorubicin plus cisplatin versus circadian timed doxorubicin plus cisplatin in stage III and IV or recurrent endometrial carcinoma: a Gynecologic Oncology Group Study. Author(s): Gallion HH, Brunetto VL, Cibull M, Lentz SS, Reid G, Soper JT, Burger RA, Andersen W; Gynecologic Oncology Group Study. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 October 15; 21(20): 3808-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14551299
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Reducing toxicity of cisplatin in cancer chemotherapy by extracorporeal removal of excess cisplatin. Author(s): Ambruss CM, Karakousis CP, Stadler A, Stadler I, Ambrus JL Jr, Anthone S, Ambrus JL. Source: J Med. 2002; 33(1-4): 119-27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12939112
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Retrospective cost analysis of gemcitabine in combination with cisplatin in non-small cell lung cancer compared to other combination therapies in Europe. Author(s): Schiller J, Tilden D, Aristides M, Lees M, Kielhorn A, Maniadakis N, Bhalla S. Source: Lung Cancer (Amsterdam, Netherlands). 2004 January; 43(1): 101-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14698544
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Role of caspases-3 and -7 in Apaf-1 proteolytic cleavage and degradation events during cisplatin-induced apoptosis in melanoma cells. Author(s): Del Bello B, Valentini MA, Mangiavacchi P, Comporti M, Maellaro E. Source: Experimental Cell Research. 2004 February 15; 293(2): 302-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14729468
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Severe intracellular magnesium and potassium depletion in patients after treatment with cisplatin. Author(s): Lajer H, Bundgaard H, Secher NH, Hansen HH, Kjeldsen K, Daugaard G. Source: British Journal of Cancer. 2003 November 3; 89(9): 1633-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14583761
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Sodium-wasting nephropathy caused by cisplatin in a patient with small-cell lung cancer. Author(s): Iyer AV, Krasnow SH, Dufour DR, Arcenas AS. Source: Clinical Lung Cancer. 2003 November; 5(3): 187-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14667276
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Stress proteins in subcellular structures upon cisplatin treatment and heat shock. Author(s): Mavletova DA, Dvorkin GA. Source: Doklady. Biochemistry and Biophysics. 2003 May-June; 390: 157-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12959069
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Synergistic effects of ICI 182,780 on the cytotoxicity of cisplatin in cervical carcinoma cell lines. Author(s): Garcia-Lopez P, Rodriguez-Dorantes M, Perez-Cardenas E, Cerbon M, Mohar-Betancourt A. Source: Cancer Chemotherapy and Pharmacology. 2004 June; 53(6): 533-40. Epub 2004 January 29. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15138713
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Synthesis and biological evaluation of novel chloroethylaminoanthraquinones with potent cytotoxic activity against cisplatin-resistant tumor cells. Author(s): Pors K, Paniwnyk Z, Ruparelia KC, Teesdale-Spittle PH, Hartley JA, Kelland LR, Patterson LH. Source: Journal of Medicinal Chemistry. 2004 March 25; 47(7): 1856-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15027879
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Thalidomide down-regulates the expression of VEGF and bFGF in cisplatin-resistant human lung carcinoma cells. Author(s): Li X, Liu X, Wang J, Wang Z, Jiang W, Reed E, Zhang Y, Liu Y, Li QQ. Source: Anticancer Res. 2003 May-June; 23(3B): 2481-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12894531
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The initiative role of XPC protein in cisplatin DNA damaging treatment-mediated cell cycle regulation. Author(s): Wang G, Chuang L, Zhang X, Colton S, Dombkowski A, Reiners J, Diakiw A, Xu XS. Source: Nucleic Acids Research. 2004 April 23; 32(7): 2231-40. Print 2004. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15107491
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The oral NK(1) antagonist, aprepitant, given with standard antiemetics provides protection against nausea and vomiting over multiple cycles of cisplatin-based chemotherapy: a combined analysis of two randomised, placebo-controlled phase III clinical trials. Author(s): de Wit R, Herrstedt J, Rapoport B, Carides AD, Guoguang-Ma J, Elmer M, Schmidt C, Evans JK, Horgan KJ. Source: European Journal of Cancer (Oxford, England : 1990). 2004 February; 40(3): 40310. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14746859
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The tumor suppressor p16(INK4a) gene is a regulator of apoptosis induced by ultraviolet light and cisplatin. Author(s): Al-Mohanna MA, Manogaran PS, Al-Mukhalafi Z, A Al-Hussein K, Aboussekhra A. Source: Oncogene. 2004 January 8; 23(1): 201-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14712225
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Toxic cure: Hyperfractionated radiotherapy with concurrent cisplatin and fluorouracil for Stage III and IVA head-and-neck cancer in the community. Author(s): Maguire PD, Meyerson MB, Neal CR, Hamann MS, Bost AL, Anagnost JW, Ungaro PC, Pollock HD, McMurray JE, Wilson EP, Kotwall CA. Source: International Journal of Radiation Oncology, Biology, Physics. 2004 March 1; 58(3): 698-704. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14967423
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Translesion replication in cisplatin-treated xeroderma pigmentosum variant cells is also caffeine-sensitive: features of the error-prone DNA polymerase(s) involved in UV-mutagenesis. Author(s): Yamada K, Takezawa J, Ezaki O. Source: Dna Repair. 2003 August 12; 2(8): 909-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12893087
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Trastuzumab in combination with cisplatin and gemcitabine in patients with Her2overexpressing, untreated, advanced non-small cell lung cancer: report of a phase II trial and findings regarding optimal identification of patients with Her2overexpressing disease. Author(s): Zinner RG, Glisson BS, Fossella FV, Pisters KM, Kies MS, Lee PM, Massarelli E, Sabloff B, Fritsche HA Jr, Ro JY, Ordonez NG, Tran HT, Yang Y, Smith TL, Mass RD, Herbst RS. Source: Lung Cancer (Amsterdam, Netherlands). 2004 April; 44(1): 99-110. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15013588
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Trial of low-dose 5-fluorouracil/cisplatin therapy for advanced extramammary Paget's disease. Author(s): Kariya K, Tsuji T, Schwartz RA. Source: Dermatologic Surgery : Official Publication for American Society for Dermatologic Surgery [et Al.]. 2004 February; 30(2 Pt 2): 341-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14871231
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Tropisetron and dexamethasone administered twice daily for the prevention of acute emesis in patients treated with continuous infusion of Cisplatin-Doxorubicin and high-dose Ifosfamide over 48, 24, and 120 hours. Author(s): Forni C, Loro L, Mazzei T, Beghelli C, Biolchini A, Tremosini M, Triggiani A, Bacci G. Source: Cancer Nursing. 2003 August; 26(4): 331-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12886124
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Ultrastructural change due to acquired cisplatin resistance in human bladder cancer cells. Author(s): Yoon SJ, Park I, Kwak C, Lee E. Source: Oncol Rep. 2003 September-October; 10(5): 1363-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12883708
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Ultrastructural morphology and localisation of cisplatin-induced platinum-DNA adducts in a cisplatin-sensitive and -resistant human small cell lung cancer cell line using electron microscopy. Author(s): Meijera C, van Luyn MJ, Nienhuis EF, Blom N, Mulder NH, de Vries EG. Source: Biochemical Pharmacology. 2001 March 1; 61(5): 573-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11239500
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Uneventful administration of cisplatin to a man with X-linked Charcot-Marie-Tooth disease (CMT). Author(s): Cowie F, Barrett A. Source: Annals of Oncology : Official Journal of the European Society for Medical Oncology / Esmo. 2001 March; 12(3): 422. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11332159
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Unknown primary carcinoma: a feasibility assessment of combination chemotherapy with cisplatin and docetaxel. Author(s): Mukai H, Watanabe T, Ando M, Katsumata N. Source: International Journal of Clinical Oncology / Japan Society of Clinical Oncology. 2003 February; 8(1): 23-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12601538
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Up-front chemotherapy with fotemustine (F) / cisplatin (CDDP) / etoposide (VP16) regimen in the treatment of 33 non-removable glioblastomas. Author(s): Frenay M, Lebrun C, Lonjon M, Bondiau PY, Chatel M. Source: European Journal of Cancer (Oxford, England : 1990). 2000 May; 36(8): 1026-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10885607
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Up-regulation of FLIP in cisplatin-selected HeLa cells causes cross-resistance to CD95/Fas death signalling. Author(s): Kamarajan P, Sun NK, Chao CC. Source: The Biochemical Journal. 2003 November 15; 376(Pt 1): 253-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12911332
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Upstream binding factor up-regulated in hepatocellular carcinoma is related to the survival and cisplatin-sensitivity of cancer cells. Author(s): Huang R, Wu T, Xu L, Liu A, Ji Y, Hu G. Source: The Faseb Journal : Official Publication of the Federation of American Societies for Experimental Biology. 2002 March; 16(3): 293-301. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11874979
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Use of c-myb antisense oligonucleotides to increase the sensitivity of human colon cancer cells to cisplatin. Author(s): Funato T, Satou J, Kozawa K, Fujimaki S, Miura T, Kaku M. Source: Oncol Rep. 2001 July-August; 8(4): 807-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11410788
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Use of high-dose cytarabine to enhance cisplatin cytotoxicity-effects on the response and overall survival rates of advanced head and neck cancer patients. Author(s): Jelic S, Stamatovic Lj, Vucicevic S, Petrovic Z, Kreacic M, Babovic N, Jovanovic N, Mikic A, Gavrilovic D. Source: European Journal of Cancer (Oxford, England : 1990). 2002 July; 38(11): 1478-89. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12110494
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Use of horseradish peroxidase- and fluorescein-modified cisplatin derivatives for simultaneous labeling of nucleic acids and proteins. Author(s): van Gijlswijk RP, Talman EG, Peekel I, Bloem J, van Velzen MA, Heetebrij RJ, Tanke HJ. Source: Clinical Chemistry. 2002 August; 48(8): 1352-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12142394
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Various forms of mutant p53 confer sensitivity to cisplatin and doxorubicin in bladder cancer cells. Author(s): Chang FL, Lai MD. Source: The Journal of Urology. 2001 July; 166(1): 304-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11435891
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Vascular toxicity associated with cisplatin. Author(s): King M, Fernando I. Source: Clin Oncol (R Coll Radiol). 2003 February; 15(1): 36-7. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12602554
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Vinorelbine and cisplatin for the treatment of recurrent and/or metastatic carcinoma of the uterine cervix. Author(s): Gebbia V, Caruso M, Testa A, Mauceri G, Borsellino N, Chiarenza M, Pizzardi N, Palmeri S. Source: Oncology. 2002; 63(1): 31-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12187068
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Vinorelbine and cisplatin in metastatic squamous cell carcinoma of the oesophagus: response, toxicity, quality of life and survival. Author(s): Conroy T, Etienne PL, Adenis A, Ducreux M, Paillot B, Oliveira J, Seitz JF, Francois E, Van Cutsem E, Wagener DJ, Kohser F, Daamen S, Praet M, Gorlia T, Baron B, Wils J; European Organisation for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group. Source: Annals of Oncology : Official Journal of the European Society for Medical Oncology / Esmo. 2002 May; 13(5): 721-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12075740
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Vinorelbine plus cisplatin versus cisplatin plus vindesine and mitomycin C in stage IIIB-IV non-small cell lung carcinoma: a prospective randomized study. Author(s): Gebbia V, Galetta D, Riccardi F, Gridelli C, Durini E, Borsellino N, Gebbia N, Valdesi M, Caruso M, Valenza R, Pezzella G, Colucci G; Gruppo Oncologico Italia Meridionale. Source: Lung Cancer (Amsterdam, Netherlands). 2002 August; 37(2): 179-87. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12140141
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Vinorelbine, cisplatin and continuous infusion of 5-fluorouracil (ViFuP) in metastatic breast cancer patients: a phase II study. Author(s): Nole F, Munzone E, Mandala M, Catania C, Orlando L, Zampino MG, Minchella I, Colleoni M, Peruzzotti G, Marrocco E, Goldhirsch A. Source: Annals of Oncology : Official Journal of the European Society for Medical Oncology / Esmo. 2001 January; 12(1): 95-100. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11249057
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Vinorelbine, ifosfamide and cisplatin as first-line treatment in patients with inoperable non-small cell lung cancer. Author(s): Montalar J, Morales S, Maestu I, Camps C, Vadell C, Garcia R, Yuste AL, Torregrosa D, Segura A. Source: Lung Cancer (Amsterdam, Netherlands). 2001 November; 34(2): 305-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11679190
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Weekly chemotherapy with docetaxel, gemcitabine and cisplatin in advanced transitional cell urothelial cancer: a phase II trial. Author(s): Pectasides D, Glotsos J, Bountouroglou N, Kouloubinis A, Mitakidis N, Karvounis N, Ziras N, Athanassiou A. Source: Annals of Oncology : Official Journal of the European Society for Medical Oncology / Esmo. 2002 February; 13(2): 243-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11886001
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Weekly cisplatin and daily oral etoposide is highly effective in platinum pretreated ovarian cancer. Author(s): van der Burg ME, de Wit R, van Putten WL, Logmans A, Kruit WH, Stoter G, Verweij J. Source: British Journal of Cancer. 2002 January 7; 86(1): 19-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11857006
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Weekly cisplatin and oral etoposide as treatment for relapsed epithelial ovarian cancer. Author(s): Meyer T, Nelstrop AE, Mahmoudi M, Rustin GJ. Source: Annals of Oncology : Official Journal of the European Society for Medical Oncology / Esmo. 2001 December; 12(12): 1705-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11843248
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Weekly gemcitabine and cisplatin chemotherapy: a well-tolerated but ineffective chemotherapeutic regimen in advanced pancreatic cancer patients. A report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD). Author(s): Cascinu S, Labianca R, Catalano V, Barni S, Ferrau F, Beretta GD, Frontini L, Foa P, Pancera G, Priolo D, Graziano F, Mare M, Catalano G. Source: Annals of Oncology : Official Journal of the European Society for Medical Oncology / Esmo. 2003 February; 14(2): 205-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12562645
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Weekly high-dose 5-fluorouracil (5-FU), leucovorin (LV) and bimonthly cisplatin in patients with advanced gastric cancer. Author(s): Lin YC, Chen JS, Wang CH, Wang HM, Chang HK, Liaul CT, Yang TS, Liaw CC, Liu HE. Source: Japanese Journal of Clinical Oncology. 2001 December; 31(12): 605-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11902492
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What is the "best" platinum: cisplatin, carboplatin, or oxaliplatin? Author(s): Lokich J. Source: Cancer Investigation. 2001; 19(7): 756-60. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11577818
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XIAP regulates Akt activity and caspase-3-dependent cleavage during cisplatininduced apoptosis in human ovarian epithelial cancer cells. Author(s): Asselin E, Mills GB, Tsang BK. Source: Cancer Research. 2001 March 1; 61(5): 1862-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11280739
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YB-1 promotes strand separation in vitro of duplex DNA containing either mispaired bases or cisplatin modifications, exhibits endonucleolytic activities and binds several DNA repair proteins. Author(s): Gaudreault I, Guay D, Lebel M. Source: Nucleic Acids Research. 2004 January 12; 32(1): 316-27. Print 2004. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14718551
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CHAPTER 2. NUTRITION AND CISPLATIN Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and cisplatin.
Finding Nutrition Studies on Cisplatin The National Institutes of Health’s Office of Dietary Supplements (ODS) offers a searchable bibliographic database called the IBIDS (International Bibliographic Information on Dietary Supplements; National Institutes of Health, Building 31, Room 1B29, 31 Center Drive, MSC 2086, Bethesda, Maryland 20892-2086, Tel: 301-435-2920, Fax: 301-480-1845, E-mail:
[email protected]). The IBIDS contains over 460,000 scientific citations and summaries about dietary supplements and nutrition as well as references to published international, scientific literature on dietary supplements such as vitamins, minerals, and botanicals.7 The IBIDS includes references and citations to both human and animal research studies. As a service of the ODS, access to the IBIDS database is available free of charge at the following Web address: http://ods.od.nih.gov/databases/ibids.html. After entering the search area, you have three choices: (1) IBIDS Consumer Database, (2) Full IBIDS Database, or (3) Peer Reviewed Citations Only. Now that you have selected a database, click on the “Advanced” tab. An advanced search allows you to retrieve up to 100 fully explained references in a comprehensive format. Type “cisplatin” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.
7
Adapted from http://ods.od.nih.gov. IBIDS is produced by the Office of Dietary Supplements (ODS) at the National Institutes of Health to assist the public, healthcare providers, educators, and researchers in locating credible, scientific information on dietary supplements. IBIDS was developed and will be maintained through an interagency partnership with the Food and Nutrition Information Center of the National Agricultural Library, U.S. Department of Agriculture.
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The following information is typical of that found when using the “Full IBIDS Database” to search for “cisplatin” (or a synonym): •
A phase II study of paclitaxel and cisplatin combination chemotherapy in recurrent or metastatic head and neck cancer. Author(s): University of Instanbul, Institute of Oncology, Medical Oncology Department, Turkey.
[email protected] Source: Basaran, M Bavbek, S E Gullu, I Demirelli, F Sakar, B Tenekeci, N Altun, M Yalcin, S Onat, H J-Chemother. 2002 April; 14(2): 207-13 1120-009X
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Amelioration of cisplatin induced nephrotoxicity in mice by ethyl acetate extract of a polypore fungus, Phellinus rimosus. Author(s): Amala Cancer Research Centre, Amala Nagar, Thrissur, India. Source: Ajith, T A Jose, N Janardhanan, K K J-Exp-Clin-Cancer-Res. 2002 June; 21(2): 213-7 0392-9078
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Combined modality treatment of oral and oropharyngeal cancer including neoadjuvant intraarterial cisplatin and radical surgery followed by concurrent radiation and chemotherapy with weekly docetaxel - three year results of a pilot study. Author(s): Department of Maxillofacial Plastic Surgery, Johann Wolfgang GoetheUniversity Frankfurt Medical School, Frankfurt am Main, Germany.
[email protected] Source: Kovacs, A F Schiemann, M Turowski, B J-Craniomaxillofac-Surg. 2002 April; 30(2): 112-20 1010-5182
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Combining iodine-131 Lipiodol therapy with low-dose cisplatin as a radiosensitiser: preliminary results in hepatocellular carcinoma. Author(s): Department of Nuclear Medicine, Ghent University Hospital, De Pintelaan 185, Belgium.
[email protected] Source: Brans, B Van Laere, K Gemmel, F Defreyne, L Vanlangenhove, P Troisi, R Van Vlierberghe, H Colle, I De Hemptinne, B Dierckx, R A Eur-J-Nucl-Med-Mol-Imaging. 2002 July; 29(7): 928-32 1619-7070
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DNA ploidy and S-phase fraction as predictive factors of response and outcome following neoadjuvant methotrexate, vinblastine, epirubicin and cisplatin (M-VEC) chemotherapy for invasive bladder cancer. Author(s): Department of Urology, University of Ankara, School of Medicine, Turkey. Source: Turkolmez, K Baltaci, S Beduk, Y Muftuoglu, Y Z Gogus, O Scand-J-UrolNephrol. 2002 February; 36(1): 46-51 0036-5599
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Irinotecan plus cisplatin in small-cell lung cancer. Author(s): Division of Medical Oncology, Vanderbilt University Medical Center, Nashville, Tennessee 37232-5536, USA.
[email protected] Source: Sandler, A Oncology-(Huntingt). 2002 September; 16(9 Suppl 9): 39-43 0890-9091
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Irinotecan, cisplatin and mitomycin in inoperable gastro-oesophageal and pancreatic cancers - a new active regimen. Author(s): Department of Medical Oncology, St Bartholomew's Hospital, London EC1A 7BE, UK.
[email protected] Source: Slater, S Shamash, J Wilson, P Gallagher, C J Slevin, M L Br-J-Cancer. 2002 October 7; 87(8): 850-3 0007-0920
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Neoadjuvant chemotherapy with cisplatin and methotrexate in patients with muscleinvasive bladder tumours. Author(s): Department of Oncology, University Hospital Herlev, Copenhagen, Denmark.
[email protected]
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Source: Sengelov, L von der Maase, H Lundbeck, F Barlebo, H Colstrup, H Engelholm, S A Krarup, T Madsen, E L Meyhoff, H H Mommsen, S Nielsen, O S Pedersen, D Steven, K Sorensen, B Acta-Oncol. 2002; 41(5): 447-56 0284-186X •
Nephrotoxicity of heptaplatin: a randomized comparison with cisplatin in advanced gastric cancer. Author(s): Section of Hematology/Oncology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 138-736, Korea. Source: Ahn, J H Kang, Y K Kim, T W Bahng, H Chang, H M Kang, W C Kim, W K Lee, J S Park, J S Cancer-Chemother-Pharmacol. 2002 August; 50(2): 104-10 0344-5704
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Phase II study of docetaxel and cisplatin combination chemotherapy in metastatic or unresectable localized non-small-cell lung cancer. Author(s): Department of Internal Medicine, Korea University, College of Medicine, Seoul, Korea. Source: Kim, Y H Kim, J S Choi, Y H In, K H Park, H S Hong, D S Jeong, T J Lee, Y Y Nam, E Lee, S N Lee, K S Kim, H K Int-J-Clin-Oncol. 2002 April; 7(2): 114-9 1341-9625
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Randomised phase III trial of irinotecan combined with cisplatin for advanced nonsmall-cell lung cancer. Author(s): Department of Clinical Oncology, Osaka City General Hospital, Osaka, Japan.
[email protected] Source: Negoro, S Masuda, N Takada, Y Sugiura, T Kudoh, S Katakami, N Ariyoshi, Y Ohashi, Y Niitani, H Fukuoka, M Br-J-Cancer. 2003 February 10; 88(3): 335-41 0007-0920
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Randomized phase II study of cisplatin with gemcitabine or paclitaxel or vinorelbine as induction chemotherapy followed by concomitant chemoradiotherapy for stage IIIB non-small-cell lung cancer: cancer and leukemia group B study 9431. Author(s): University of Chicago Medical Center and Cancer and Leukemia Group B, Chicago, IL, USA.
[email protected] Source: Vokes, E E Herndon, J E 2nd Crawford, J Leopold, K A Perry, M C Miller, A A Green, M R J-Clin-Oncol. 2002 October 15; 20(20): 4191-8 0732-183X
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Ras-mediated activation of ERK by cisplatin induces cell death independently of p53 in osteosarcoma and neuroblastoma cell lines. Author(s): Department of Pediatric Hematology and Oncology, Justus-LiebigUniversity, 35385 Giessen, Germany.
[email protected] Source: Woessmann, W Chen, X Borkhardt, A Cancer-Chemother-Pharmacol. 2002 November; 50(5): 397-404 0344-5704
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Saponins-mediated potentiation of cisplatin accumulation and cytotoxicity in human colon cancer cells. Source: Gaidi, G. Correia, M. Chauffert, B. Beltramo, J.L. Wagner, H. Lacaille Dubois, M.A. Planta-med. Stuttgart : Georg Thieme Verlag,. January 2002. volume 68 (1) page 7072. 0032-0943
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Secondary leukaemia after treating advanced bladder cancer with methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy and radiotherapy. Author(s): Institut Gustave Roussy, Villejuif, France. Source: Theodore, C Bayle, C Bernheim, A Wibault, P BJU-Int. 2002 September; 90(4): 470-1 1464-4096
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Vitamin E protection from/potentiation of the cytogenetic toxicity of cisplatin in Swiss mice. Author(s): Department of Zoology, Berhampur University, Orissa, India.
[email protected]
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Source: Choudhury, R C Jagdale, M B J-Chemother. 2002 August; 14(4): 397-405 1120009X
Federal Resources on Nutrition In addition to the IBIDS, the United States Department of Health and Human Services (HHS) and the United States Department of Agriculture (USDA) provide many sources of information on general nutrition and health. Recommended resources include: •
healthfinder®, HHS’s gateway to health information, including diet and nutrition: http://www.healthfinder.gov/scripts/SearchContext.asp?topic=238&page=0
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The United States Department of Agriculture’s Web site dedicated to nutrition information: www.nutrition.gov
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The Food and Drug Administration’s Web site for federal food safety information: www.foodsafety.gov
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The National Action Plan on Overweight and Obesity sponsored by the United States Surgeon General: http://www.surgeongeneral.gov/topics/obesity/
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The Center for Food Safety and Applied Nutrition has an Internet site sponsored by the Food and Drug Administration and the Department of Health and Human Services: http://vm.cfsan.fda.gov/
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Center for Nutrition Policy and Promotion sponsored by the United States Department of Agriculture: http://www.usda.gov/cnpp/
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Food and Nutrition Information Center, National Agricultural Library sponsored by the United States Department of Agriculture: http://www.nal.usda.gov/fnic/
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Food and Nutrition Service sponsored by the United States Department of Agriculture: http://www.fns.usda.gov/fns/
Additional Web Resources A number of additional Web sites offer encyclopedic information covering food and nutrition. The following is a representative sample: •
AOL: http://search.aol.com/cat.adp?id=174&layer=&from=subcats
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Family Village: http://www.familyvillage.wisc.edu/med_nutrition.html
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Google: http://directory.google.com/Top/Health/Nutrition/
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Healthnotes: http://www.healthnotes.com/
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Open Directory Project: http://dmoz.org/Health/Nutrition/
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Yahoo.com: http://dir.yahoo.com/Health/Nutrition/
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WebMDHealth: http://my.webmd.com/nutrition
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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html
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The following is a specific Web list relating to cisplatin; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •
Vitamins Vitamin A Source: Healthnotes, Inc.; www.healthnotes.com Vitamin C Source: Healthnotes, Inc.; www.healthnotes.com Vitamin C Source: Prima Communications, Inc.www.personalhealthzone.com Vitamin E Source: Healthnotes, Inc.; www.healthnotes.com
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Minerals Calcium Source: Healthnotes, Inc.; www.healthnotes.com Chondroitin Source: Integrative Medicine Communications; www.drkoop.com Cisplatin Source: Healthnotes, Inc.; www.healthnotes.com Magnesium Source: Healthnotes, Inc.; www.healthnotes.com Potassium Source: Healthnotes, Inc.; www.healthnotes.com Quercetin Source: Integrative Medicine Communications; www.drkoop.com Quercetin Source: Prima Communications, Inc.www.personalhealthzone.com Selenium Source: Healthnotes, Inc.; www.healthnotes.com Selenium Source: Integrative Medicine Communications; www.drkoop.com Zinc Source: Healthnotes, Inc.; www.healthnotes.com
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CHAPTER 3. ALTERNATIVE MEDICINE AND CISPLATIN Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to cisplatin. At the conclusion of this chapter, we will provide additional sources.
National Center for Complementary and Alternative Medicine The National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health (http://nccam.nih.gov/) has created a link to the National Library of Medicine’s databases to facilitate research for articles that specifically relate to cisplatin and complementary medicine. To search the database, go to the following Web site: http://www.nlm.nih.gov/nccam/camonpubmed.html. Select “CAM on PubMed.” Enter “cisplatin” (or synonyms) into the search box. Click “Go.” The following references provide information on particular aspects of complementary and alternative medicine that are related to cisplatin: •
A comparison of the incidence, duration, and degree of the neurologic toxicities of cisplatin-paclitaxel (PT) and cisplatin-cyclophosphamide (PC). Author(s): Bacon M, James K, Zee B. Source: International Journal of Gynecological Cancer : Official Journal of the International Gynecological Cancer Society. 2003 July-August; 13(4): 428-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12911718
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A concurrent chemoirradiation with cisplatin followed by adjuvant chemotherapy with ifosfamide, 5-fluorouracil, and leucovorin for stage IV nasopharyngeal carcinoma. Author(s): Chua DT, Sham JS, Au GK. Source: Head & Neck. 2004 February; 26(2): 118-26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14762880
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A multicenter phase II study of cisplatin and docetaxel (Taxotere) in the first-line treatment of advanced ovarian cancer: a GINECO study. Author(s): Dieras V, Guastalla JP, Ferrero JM, Cure H, Weber B, Winckel P, Lortholary A, Mayer F, Paraiso D, Magherini E, Pujade-Lauraine E. Source: Cancer Chemotherapy and Pharmacology. 2004 June; 53(6): 489-95. Epub 2004 February 07. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14767617
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A multicenter phase II study of the efficacy and safety of docetaxel plus cisplatin in Asian chemonaive patients with metastatic or locally advanced non-small cell lung cancer. Author(s): Ho JC, Tan EH, Leong SS, Wang CH, Sun Y, Li R, Wahid MI, Jusuf A, Liao M, Guan Z, Handoyo P, Huang JS, Chan V, Luna G, Tsang KW, Lam WK; Asian-Pacific Collaborative Group. Source: Respiratory Medicine. 2003 July; 97(7): 796-803. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12854629
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A phase I study of topotecan/paclitaxel alternating with etoposide/cisplatin and thoracic irradiation in patients with limited small cell lung cancer. Author(s): Lu C, Komaki R, Lee JS, Shin DM, Palmer JL, Coldman BJ, Pisters KM, Kurie JM, Fossella FV, Glisson BS. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2003 June; 9(6): 2085-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12796372
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A phase II irinotecan-cisplatin combination in advanced pancreatic cancer. Author(s): Markham C, Stocken DD, Hassan AB. Source: British Journal of Cancer. 2003 November 17; 89(10): 1860-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14612893
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A phase II study of cisplatin and docetaxel administered as three consecutive weekly infusions for advanced non-small-cell lung cancer in elderly patients. Author(s): Ohe Y, Niho S, Kakinuma R, Kubota K, Ohmatsu H, Goto K, Nokihara H, Kunitoh H, Saijo N, Aono H, Watanabe K, Tango M, Yokoyama A, Nishiwaki Y. Source: Annals of Oncology : Official Journal of the European Society for Medical Oncology / Esmo. 2004 January; 15(1): 45-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14679118
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A phase II study of multimodality treatment for locally advanced cervical cancer: neoadjuvant carboplatin and paclitaxel followed by radical hysterectomy and adjuvant cisplatin chemoradiation. Author(s): Duenas-Gonzalez A, Lopez-Graniel C, Gonzalez-Enciso A, Cetina L, Rivera L, Mariscal I, Montalvo G, Gomez E, de la Garza J, Chanona G, Mohar A.
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Source: Annals of Oncology : Official Journal of the European Society for Medical Oncology / Esmo. 2003 August; 14(8): 1278-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12881393 •
A phase II trial of concurrent chemoradiation therapy followed by consolidation chemotherapy with oral etoposide and cisplatin for locally advanced inoperable nonsmall cell lung cancers. Author(s): Park J, Ahn YC, Kim H, Lee SH, Park SH, Lee KE, Lim do H, Park J, Kim K, Jung CW, Im YH, Kang WK, Lee MH, Park K. Source: Lung Cancer (Amsterdam, Netherlands). 2003 November; 42(2): 227-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14568691
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A randomised phase II study of weekly paclitaxel or vinorelbine in combination with cisplatin against inoperable non-small-cell lung cancer previously untreated. Author(s): Chen YM, Perng RP, Shih JF, Lee YC, Lee CS, Tsai CM, Whang-Peng J. Source: British Journal of Cancer. 2004 January 26; 90(2): 359-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14735177
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A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. Author(s): du Bois A, Luck HJ, Meier W, Adams HP, Mobus V, Costa S, Bauknecht T, Richter B, Warm M, Schroder W, Olbricht S, Nitz U, Jackisch C, Emons G, Wagner U, Kuhn W, Pfisterer J; Arbeitsgemeinschaft Gynakologische Onkologie Ovarian Cancer Study Group. Source: Journal of the National Cancer Institute. 2003 September 3; 95(17): 1320-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12953086
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A randomized study of primary bleomycin, vincristine, mitomycin and cisplatin (BOMP) chemotherapy followed by radiotherapy versus radiotherapy alone in stage IIIB and IVA squamous cell carcinoma of the cervix. Author(s): Tabata T, Takeshima N, Nishida H, Hirai Y, Hasumi K. Source: Anticancer Res. 2003 May-June; 23(3C): 2885-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12926129
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A single prior course of BCNU-cisplatin chemotherapy has a significant deleterious effect on mobilization kinetics of otherwise untreated patients. Author(s): Perez-Calvo J, Fernandez O, Aristu JJ, Aramendia JM, Rifon J, Prosper F, Bendandi M, Rocha E, Martin-Algarra S. Source: Bone Marrow Transplantation. 2004 March; 33(5): 499-502. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14716344
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Adjuvant treatment for early ovarian cancer: a randomized phase III trial of intraperitoneal 32P or intravenous cyclophosphamide and cisplatin--a gynecologic oncology group study.
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Author(s): Young RC, Brady MF, Nieberg RK, Long HJ, Mayer AR, Lentz SS, Hurteau J, Alberts DS. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 December 1; 21(23): 4350-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14645424 •
Aggressive simultaneous radiochemotherapy with cisplatin and paclitaxel in combination with accelerated hyperfractionated radiotherapy in locally advanced head and neck tumors. Results of a phase I-II trial. Author(s): Kuhnt T, Becker A, Pigorsch S, Pelz T, Bloching M, Passmann M, Lotterer E, Hansgen G, Dunst J. Source: Strahlentherapie Und Onkologie : Organ Der Deutschen Rontgengesellschaft. [et Al]. 2003 October; 179(10): 673-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14566475
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Alternating chemotherapy with etoposide plus cisplatin and topotecan plus paclitaxel in patients with untreated, extensive-stage small cell lung carcinoma: a phase II trial of the North Central Cancer Treatment Group. Author(s): Jett JR, Hatfield AK, Hillman S, Bauman MD, Mailliard JA, Kugler JW, Morton RF, Marks RS, Levitt R. Source: Cancer. 2003 May 15; 97(10): 2498-503. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12733149
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Alternating doublets: establishing the optimal multifractionated dosing schedule to administer docetaxel, cisplatin, gemcitabine, and vinorelbine in combination. Author(s): Lokich J, Anderson N, Coco F. Source: Cancer Investigation. 2003; 21(6): 830-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14735686
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BGP-15, a hydroximic acid derivative, protects against cisplatin- or taxol-induced peripheral neuropathy in rats. Author(s): Bardos G, Moricz K, Jaszlits L, Rabloczky G, Tory K, Racz I, Bernath S, Sumegi B, Farkas B, Literati-Nagy B, Literati-Nagy P. Source: Toxicology and Applied Pharmacology. 2003 July 1; 190(1): 9-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12831778
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Bleomycin, vincristine, cisplatin/bleomycin, etoposide, cisplatin chemotherapy: an alternating, dose intense regimen producing promising results in untreated patients with intermediate or poor prognosis malignant germ-cell tumours. Author(s): Anthoney DA, McKean MJ, Roberts JT, Hutcheon AW, Graham J, Jones W, Paul J, Kaye SB. Source: British Journal of Cancer. 2004 February 9; 90(3): 601-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14760371
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Butein ameliorates renal concentrating ability in cisplatin-induced acute renal failure in rats. Author(s): Kang DG, Lee AS, Mun YJ, Woo WH, Kim YC, Sohn EJ, Moon MK, Lee HS. Source: Biological & Pharmaceutical Bulletin. 2004 March; 27(3): 366-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14993804
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Carboplatin equals cisplatin: but how do I prescribe it? Author(s): Gore M. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 September 1; 21(17): 3183-5. Epub 2003 July 14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12860965
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Cisplatin and irinotecan (CPT-11) for peritoneal mesothelioma. Author(s): Le DT, Deavers M, Hunt K, Malpica A, Verschraegen CF. Source: Cancer Investigation. 2003; 21(5): 682-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14628425
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Cisplatin and vinorelbine as neoadjuvant chemotherapy in locally advanced cervical cancer: a phase II study. Author(s): Di Vagno G, Cormio G, Pignata S, Scambia G, Di Stefano MG, Tambaro R, Trerotoli P, Serio G, Garganese G, Selvaggi L. Source: International Journal of Gynecological Cancer : Official Journal of the International Gynecological Cancer Society. 2003 May-June; 13(3): 308-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12801261
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Cisplatin as second-line therapy in ovarian carcinoma treated initially with singleagent paclitaxel: a Gynecologic Oncology Group study. Author(s): Thigpen JT, Blessing JA, Olt G, Lentz SS, Bell J. Source: Gynecologic Oncology. 2003 September; 90(3): 581-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=13678728
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Cisplatin in combination with either gemcitabine or irinotecan in carcinomas of unknown primary site: results of a randomized phase II study--trial for the French Study Group on Carcinomas of Unknown Primary (GEFCAPI 01). Author(s): Culine S, Lortholary A, Voigt JJ, Bugat R, Theodore C, Priou F, Kaminsky MC, Lesimple T, Pivot X, Coudert B, Douillard JY, Merrouche Y, Allouache J, Goupil A, Negrier S, Viala J, Petrow P, Bouzy J, Laplanche A, Fizazi K; The Trial for the French Study Group on Carcinomas of Unknown Primary (GEFCAPI 01). Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 September 15; 21(18): 3479-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12972523
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Cisplatin plus etoposide in advanced non-small cell lung cancer patients age of 70 years or older.
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Author(s): Kanat O, Evrensel T, Demiray M, Kurt E, Gonullu G, Arslan M, Manavoglu O, Ozkan A. Source: Lung Cancer (Amsterdam, Netherlands). 2003 August; 41(2): 233-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12871788 •
Cisplatin plus gemcitabine versus a cisplatin-based triplet versus nonplatinum sequential doublets in advanced non-small-cell lung cancer: a Spanish Lung Cancer Group phase III randomized trial. Author(s): Alberola V, Camps C, Provencio M, Isla D, Rosell R, Vadell C, Bover I, RuizCasado A, Azagra P, Jimenez U, Gonzalez-Larriba JL, Diz P, Cardenal F, Artal A, Carrato A, Morales S, Sanchez JJ, de las Penas R, Felip E, Lopez-Vivanco G; Spanish Lung Cancer Group. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 September 1; 21(17): 3207-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12947054
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Cisplatin plus vinorelbine as induction chemotherapy followed by surgery in the treatment of stage IIIB non-small cell lung cancer. Final results of a multicenter phase II study. Author(s): Cigolari S, Curcio C, Maiorino A, Sessa R, Cioffi A, Massimo M. Source: Anticancer Res. 2003 March-April; 23(2C): 1803-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12820462
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Cisplatin versus carboplatin in combination with mitomycin and vinblastine in advanced non small cell lung cancer. A multicenter, randomized phase III trial. Author(s): Paccagnella A, Favaretto A, Oniga F, Barbieri F, Ceresoli G, Torri W, Villa E, Verusio C, Cetto GL, Santo A, De Pangher V, Artioli F, Cacciani GC, Parodi G, Soresi F, Ghi MG, Morabito A, Biason R, Giusto M, Mosconi P, Chiarion Sileni V; GSTVP (Gruppo di Studio Tumori Polmonari del Veneto). Source: Lung Cancer (Amsterdam, Netherlands). 2004 January; 43(1): 83-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14698542
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Cisplatin-based adjuvant chemotherapy in patients with completely resected nonsmall-cell lung cancer. Author(s): Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J; International Adjuvant Lung Cancer Trial Collaborative Group. Source: The New England Journal of Medicine. 2004 January 22; 350(4): 351-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14736927
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Combination with liposome-entrapped, ends-modified raf antisense oligonucleotide (LErafAON) improves the anti-tumor efficacies of cisplatin, epirubicin, mitoxantrone, docetaxel and gemcitabine. Author(s): Pei J, Zhang C, Gokhale PC, Rahman A, Dritschilo A, Ahmad I, Kasid UN.
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Source: Anti-Cancer Drugs. 2004 March; 15(3): 243-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15014358 •
Concurrent cisplatin, paclitaxel, and radiotherapy as preoperative treatment for patients with locoregional esophageal carcinoma. Author(s): Urba SG, Orringer MB, Ianettonni M, Hayman JA, Satoru H. Source: Cancer. 2003 November 15; 98(10): 2177-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14601087
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Concurrent radiochemotherapy with vinorelbine plus cisplatin or carboplatin in patients with locally advanced non-small-cell lung cancer (NSCLC) and an increased risk of treatment complications. Preliminary results. Author(s): Semrau S, Bier A, Thierbach U, Virchow C, Ketterer P, Fietkau R. Source: Strahlentherapie Und Onkologie : Organ Der Deutschen Rontgengesellschaft. [et Al]. 2003 December; 179(12): 823-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14652671
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CPT-11 and cisplatin in the treatment of advanced gastric cancer in Asians. Author(s): Lim WT, Lim ST, Wong NS, Koo WH. Source: J Chemother. 2003 August; 15(4): 400-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12962370
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Docetaxel and cisplatin in patients with advanced gastric cancer: results of Japanese phase I/II study. Author(s): Saitoh S, Sakata Y. Source: Gastric Cancer : Official Journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association. 2002; 5 Suppl 1: 23-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12772883
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Docetaxel and cisplatin with granulocyte colony-stimulating factor (G-CSF) versus MVAC with G-CSF in advanced urothelial carcinoma: a multicenter, randomized, phase III study from the Hellenic Cooperative Oncology Group. Author(s): Bamias A, Aravantinos G, Deliveliotis C, Bafaloukos D, Kalofonos C, Xiros N, Zervas A, Mitropoulos D, Samantas E, Pectasides D, Papakostas P, Gika D, Kourousis C, Koutras A, Papadimitriou C, Bamias C, Kosmidis P, Dimopoulos MA; Hellenic Cooperative Oncology Group. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2004 January 15; 22(2): 220-8. Epub 2003 December 09. Erratum In: J Clin Oncol. 2004 May 1; 22(9): 1771. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14665607
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Durable complete remission after weekly docetaxel administration in a patient with mediastinal non-seminomatous germ-cell tumor refractory to cisplatin-based
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chemotherapy. Author(s): Berruti A, Saini A, Gorzegno G, Tampellini M, Borasio P, Dogliotti L. Source: Annals of Oncology : Official Journal of the European Society for Medical Oncology / Esmo. 2003 October; 14(10): 1589-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14504064 •
Early concurrent chemoradiotherapy with prolonged oral etoposide and cisplatin for limited-stage small-cell lung cancer. Author(s): Lee SH, Ahn YC, Kim HJ, Lim do H, Lee SI, Nam E, Park SH, Park J, Lee KE, Park JO, Kim K, Kim WS, Jung CW, Im YH, Kang WK, Lee MH, Park K. Source: Japanese Journal of Clinical Oncology. 2003 December; 33(12): 620-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14769839
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Ectopic ACTH syndrome due to thymic atypical carcinoid treated with combination chemotherapy of cisplatin and etoposide. Author(s): Takahashi T, Hatao K, Yamashita Y, Tanizawa Y. Source: Intern Med. 2003 December; 42(12): 1197-201. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14714958
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EDTA enhances the antitumor efficacy of intratumoral cisplatin in s.c. grafted rat colon tumors. Author(s): Duvillard C, Ponelle T, Chapusot C, Piard F, Romanet P, Chauffert B. Source: Anti-Cancer Drugs. 2004 March; 15(3): 295-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15014364
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Effect of Aerva lanata on cisplatin and gentamicin models of acute renal failure. Author(s): Shirwaikar A, Issac D, Malini S. Source: Journal of Ethnopharmacology. 2004 January; 90(1): 81-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14698513
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Effect of wild-type and mutant E-cadherin on cell proliferation and responsiveness to the chemotherapeutic agents cisplatin, etoposide, and 5-fluorouracil. Author(s): Fricke E, Hermannstadter C, Keller G, Fuchs M, Brunner I, Busch R, Hofler H, Becker KF, Luber B. Source: Oncology. 2004; 66(2): 150-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15138368
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Effective combination chemotherapy with bimonthly docetaxel and cisplatin with or without hematopoietic growth factor support in patients with advanced gastroesophageal cancer. Author(s): Schull B, Kornek GV, Schmid K, Raderer M, Hejna M, Lenauer A, Depisch D, Lang F, Scheithauer W.
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Source: Oncology. 2003; 65(3): 211-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14657594 •
Effects of the Medicago scutellata trypsin inhibitor (MsTI) on cisplatin-induced cytotoxicity in human breast and cervical cancer cells. Author(s): Lanza A, Tava A, Catalano M, Ragona L, Singuaroli I, Robustelli della Cuna FS, Robustelli della Cuna G. Source: Anticancer Res. 2004 January-February; 24(1): 227-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15015601
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Efficacy of intra-arterial infusion therapy using a combination of cisplatin and docetaxel for recurrent head and neck cancers compared with cisplatin alone. Author(s): Yabuuchi H, Kuroiwa T, Tajima T, Tomita K, Ochiai N, Kawamoto K. Source: Clin Oncol (R Coll Radiol). 2003 December; 15(8): 467-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14690002
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Enhancement of sensitivity to cisplatin by orobol is associated with increased mitochondrial cytochrome c release in human ovarian carcinoma cells. Author(s): Isonishi S, Saitou M, Yasuda M, Ochiai K, Tanaka T. Source: Gynecologic Oncology. 2003 August; 90(2): 413-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12893210
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Escalating doses of paclitaxel and epirubicin in combination with cisplatin in advanced ovarian epithelial carcinoma: a phase I-II study. Author(s): Gebbia V, Di Marco P, Borsellino N, Gebbia N, Valerio MR, Fallica G, Tirrito ML, Valenza R, Citarrella P, Benedetti Panici P. Source: Anti-Cancer Drugs. 2003 June; 14(5): 359-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12782942
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European experience of docetaxel and cisplatin in advanced gastric cancer. Author(s): Roth AD. Source: Gastric Cancer : Official Journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association. 2002; 5 Suppl 1: 27-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12772884
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Gemcitabine and docetaxel after failure of cisplatin-based chemotherapy in patients with carcinoma of unknown primary site. Author(s): Pouessel D, Culine S, Becht C, Romieu G, Fabbro M, Ychou M, Cupissol D, Pinguet F. Source: Anticancer Res. 2003 May-June; 23(3C): 2801-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12926116
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Gemcitabine plus vinorelbine chemotherapy in patients with advanced bladder carcinoma who are medically unsuitable for or who have failed cisplatin-based chemotherapy. Author(s): Turkolmez K, Beduk Y, Baltaci S, Gogus C, Gogus O. Source: European Urology. 2003 December; 44(6): 682-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14644120
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Gemcitabine plus vinorelbine compared with cisplatin plus vinorelbine or cisplatin plus gemcitabine for advanced non-small-cell lung cancer: a phase III trial of the Italian GEMVIN Investigators and the National Cancer Institute of Canada Clinical Trials Group. Author(s): Gridelli C, Gallo C, Shepherd FA, Illiano A, Piantedosi F, Robbiati SF, Manzione L, Barbera S, Frontini L, Veltri E, Findlay B, Cigolari S, Myers R, Ianniello GP, Gebbia V, Gasparini G, Fava S, Hirsh V, Bezjak A, Seymour L, Perrone F. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 August 15; 21(16): 3025-34. Epub 2003 July 01. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12837810
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Gemcitabine, paclitaxel, and cisplatin as induction chemotherapy for patients with biopsy-proven Stage IIIA(N2) nonsmall cell lung carcinoma: a Phase II multicenter study. Author(s): De Marinis F, Nelli F, Migliorino MR, Martelli O, Cortesi E, Treggiari S, Portalone L, Crispino C, Brancaccio L, Gridelli C. Source: Cancer. 2003 October 15; 98(8): 1707-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14534888
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Genistein enhances the cisplatin-induced inhibition of cell growth and apoptosis in human malignant melanoma cells. Author(s): Tamura S, Bito T, Ichihashi M, Ueda M. Source: Pigment Cell Research / Sponsored by the European Society for Pigment Cell Research and the International Pigment Cell Society. 2003 October; 16(5): 470-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12950722
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Glutathione ester but not glutathione protects against cisplatin-induced ototoxicity in a rat model. Author(s): Campbell KC, Larsen DL, Meech RP, Rybak LP, Hughes LF. Source: Journal of the American Academy of Audiology. 2003 April; 14(3): 124-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12859137
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Hepatocyte growth factor sensitizes human ovarian carcinoma cell lines to paclitaxel and cisplatin. Author(s): Rasola A, Anguissola S, Ferrero N, Gramaglia D, Maffe A, Maggiora P, Comoglio PM, Di Renzo MF.
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Source: Cancer Research. 2004 March 1; 64(5): 1744-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14996735 •
Induction chemotherapy with carboplatin/paclitaxel followed by surgery or standard radiotherapy and concurrent daily low-dose cisplatin for locally advanced non-small cell lung cancer (NSCLC). Author(s): De Candis D, Stani SC, Bidoli P, Bedini VA, Potepan P, Navarria P, Aglione S, Bajetta E. Source: American Journal of Clinical Oncology : the Official Publication of the American Radium Society. 2003 June; 26(3): 265-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12796598
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Induction chemotherapy with paclitaxel and cisplatin and CT-based 3D radiotherapy in patients with advanced laryngeal and hypopharyngeal carcinomas--a possibility for organ preservation. Author(s): Pfreundner L, Hoppe F, Willner J, Preisler V, Bratengeier K, Hagen R, Helms J, Flentje M. Source: Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology. 2003 August; 68(2): 163-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12972311
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Induction of thymidine phosphorylase expression by Taxol does not enhance Furtulon sensitivity in a cisplatin-resistant human ovarian carcinoma cell line. Author(s): Hata K, Osaki M, Kanasaki H, Nakayama K, Fujiwaki R, Ito H, Miyazaki K. Source: Anticancer Res. 2003 March-April; 23(2B): 1525-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12820419
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Intraarterial cisplatin with intravenous paclitaxel and ifosfamide as an organpreservation approach in patients with paranasal sinus carcinoma. Author(s): Papadimitrakopoulou VA, Ginsberg LE, Garden AS, Kies MS, Glisson BS, Diaz EM Jr, Clayman G, Morrison WH, Liu DD, Blumenschein G Jr, Lippman SM, Schommer D, Gillenwater A, Goepfert H, Hong WK. Source: Cancer. 2003 November 15; 98(10): 2214-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14601092
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Irinotecan and gemcitabine in patients with advanced non-small cell lung cancer, previously treated with cisplatin-based chemotherapy. A phase II study. Author(s): Pectasides D, Mylonakis N, Farmakis D, Nikolaou M, Koumpou M, Katselis I, Gaglia A, Kostopoulou V, Karabelis A, Kosmas C. Source: Anticancer Res. 2003 September-October; 23(5B): 4205-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14666626
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Irinotecan in patients with relapsed or cisplatin-refractory germ cell cancer: a phase II study of the German Testicular Cancer Study Group. Author(s): Powles T, Shamash J, Berney D, Oliver RT. Source: British Journal of Cancer. 2003 September 15; 89(6): 1140-1; Author Reply 1141-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12966438
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Irinotecan, cisplatin/carboplatin, and COX-2 inhibition in small-cell lung cancer. Author(s): Natale RB. Source: Oncology (Huntingt). 2003 July; 17(7 Suppl 7): 22-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12886870
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Irinotecan/cisplatin followed by 5-FU/paclitaxel/radiotherapy and surgery in esophageal cancer. Author(s): Ajani JA, Faust J, Yao J, Komaki R, Stevens C, Swisher S, Putnam JB, Vaporciyan A, Smythe R, Walsh G, Rice D, Roth J. Source: Oncology (Huntingt). 2003 September; 17(9 Suppl 8): 20-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14569843
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Limited access trial using amifostine for protection against cisplatin- and three-hour paclitaxel-induced neurotoxicity: a phase II study of the Gynecologic Oncology Group. Author(s): Moore DH, Donnelly J, McGuire WP, Almadrones L, Cella DF, Herzog TJ, Waggoner SE; Gynecologic Oncology Group. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 November 15; 21(22): 4207-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14615449
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Long-term follow-up confirms a survival advantage of the paclitaxel-cisplatin regimen over the cyclophosphamide-cisplatin combination in advanced ovarian cancer. Author(s): Piccart MJ, Bertelsen K, Stuart G, Cassidy J, Mangioni C, Simonsen E, James K, Kaye S, Vergote I, Blom R, Grimshaw R, Atkinson R, Swenerton K, Trope C, Nardi M, Kaern J, Tumolo S, Timmers P, Roy JA, Lhoas F, Lidvall B, Bacon M, Birt A, Andersen J, Zee B, Paul J, Pecorelli S, Baron B, McGuire W. Source: International Journal of Gynecological Cancer : Official Journal of the International Gynecological Cancer Society. 2003 November-December; 13 Suppl 2: 1448. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14656271
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Long-term results of first-line sequential high-dose etoposide, ifosfamide, and cisplatin chemotherapy plus autologous stem cell support for patients with advanced metastatic germ cell cancer: an extended phase I/II study of the German Testicular Cancer Study Group. Author(s): Schmoll HJ, Kollmannsberger C, Metzner B, Hartmann JT, Schleucher N, Schoffski P, Schleicher J, Rick O, Beyer J, Hossfeld D, Kanz L, Berdel WE, Andreesen R, Bokemeyer C; German Testicular Cancer Study Group.
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Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 November 15; 21(22): 4083-91. Epub 2003 October 20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14568987 •
Malignant proliferating trichilemmal tumour and CAV (cisplatin, adriamycin, vindesine) treatment. Author(s): Hayashi I, Harada T, Muraoka M, Ishii M. Source: The British Journal of Dermatology. 2004 January; 150(1): 156-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14746636
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Modified rice bran beneficial for weight loss of mice as a major and acute adverse effect of Cisplatin. Author(s): Endo Y, Kanbayashi H. Source: Pharmacology & Toxicology. 2003 June; 92(6): 300-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12787263
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Neoadjuvant docetaxel, cisplatin, 5-fluorouracil before concurrent chemoradiotherapy in locally advanced squamous cell carcinoma of the head and neck versus concomitant chemoradiotherapy: a phase II feasibility study. Author(s): Ghi MG, Paccagnella A, D'Amanzo P, Mione CA, Fasan S, Paro S, Mastromauro C, Carnuccio R, Turcato G, Gatti C, Pallini A, Nascimben O, Biason R, Oniga F, Medici M, Rossi F, Fila G. Source: International Journal of Radiation Oncology, Biology, Physics. 2004 June 1; 59(2): 481-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15145166
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Optimal therapy of advanced ovarian cancer: carboplatin and paclitaxel versus cisplatin and paclitaxel (GOG158) and an update on GOG0182-ICON5. Author(s): Bookman MA, Greer BE, Ozols RF. Source: International Journal of Gynecological Cancer : Official Journal of the International Gynecological Cancer Society. 2003 November-December; 13 Suppl 2: 14955. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14656272
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Optimal therapy of advanced ovarian cancer: carboplatin and paclitaxel vs. cisplatin and paclitaxel (GOG 158) and an update on GOG0 182-ICON5. Author(s): Bookman MA, Greer BE, Ozols RF. Source: International Journal of Gynecological Cancer : Official Journal of the International Gynecological Cancer Society. 2003 November-December; 13(6): 735-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14675308
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Oral vinorelbine in combination with cisplatin: a novel active regimen in advanced non-small-cell lung cancer.
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Author(s): Jassem J, Kosmidis P, Ramlau R, Zarogoulidis K, Novakova L, Breton J, Etienne PL, Seebacher C, Grivaux M, Ojala A, Aubert D, Lefresne F. Source: Annals of Oncology : Official Journal of the European Society for Medical Oncology / Esmo. 2003 November; 14(11): 1634-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14581271 •
Ototoxicity in patients with dose-intensive therapy for cisplatin-resistant germ cell tumors. Author(s): Dubs A, Jacky E, Stahel R, Taverna C, Honegger H. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2004 March 15; 22(6): 1158; Author Reply 1158-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15020620
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Outcome of elderly patients with recurrent or metastatic head and neck cancer treated with cisplatin-based chemotherapy. Author(s): Argiris A, Li Y, Murphy BA, Langer CJ, Forastiere AA. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2004 January 15; 22(2): 262-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14722034
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Outpatient weekly 24-hour infusional adjuvant chemotherapy of cisplatin, 5fluorouracil, and leucovorin for high-risk nasopharyngeal carcinoma. Author(s): Lin JC, Jan JS, Chen KY, Hsu CY, Liang WM, Wang WY. Source: Head & Neck. 2003 June; 25(6): 438-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12784235
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P-CHOP: cisplatin (P) added to the standard CHOP regimen as first-line treatment for aggressive non-Hodgkin lymphoma: a single-institution phase II study. Author(s): Cocconi G, Franciosi V, Dodero A, Bologna A, Vasini G, De Lisi V, Di Blasio B, Ceci G, Camisa R, Cascinu S. Source: American Journal of Clinical Oncology : the Official Publication of the American Radium Society. 2003 December; 26(6): 535-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14663368
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Peripheral neuropathy due to therapy with paclitaxel, gemcitabine, and cisplatin in patients with advanced ovarian cancer. Author(s): Verstappen CC, Postma TJ, Hoekman K, Heimans JJ. Source: Journal of Neuro-Oncology. 2003 June; 63(2): 201-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12825825
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Pharmacokinetic study of cisplatin and infusional etoposide phosphate in advanced breast cancer with correlation of response to topoisomerase IIalpha expression. Author(s): Braybrooke JP, Levitt NC, Joel S, Davis T, Madhusudan S, Turley H, Wilner S, Harris AL, Talbot DC.
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Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2003 October 15; 9(13): 4682-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14581337 •
Phase I dose-finding study of biweekly irinotecan in combination with fixed doses of 5-fluorouracil/leucovorin, gemcitabine and cisplatin (G-FLIP) in patients with advanced pancreatic cancer or other solid tumors. Author(s): Rachamalla R, Malamud S, Grossbard ML, Mathew S, Dietrich M, Kozuch P. Source: Anti-Cancer Drugs. 2004 March; 15(3): 211-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15014353
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Phase I evaluation of sequential topoisomerase targeting with irinotecan/cisplatin followed by etoposide in patients with advanced malignancy. Author(s): Licitra EJ, Vyas V, Nelson K, Musanti R, Beers S, Thomas C, Poplin E, Smith S, Lin Y, Schaaf LJ, Aisner J, Gounder M, Rajendra R, Saleem A, Toppmeyer D, Rubin EH. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2003 May; 9(5): 1673-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12738720
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Phase I study of cisplatin analogue nedaplatin (254-S) and paclitaxel in patients with unresectable squamous cell carcinoma. Author(s): Sekine I, Nokihara H, Horiike A, Yamamoto N, Kunitoh H, Ohe Y, Tamura T, Kodama T, Saijo N. Source: British Journal of Cancer. 2004 March 22; 90(6): 1125-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15026789
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Phase I study of cisplatin, irinotecan, and epirubicin administered every 3 weeks in patients with advanced solid tumours. Author(s): Chen X, Oza AM, Kusenda Z, Yi QL, Kochman D, Moore MJ, Davis AJ, Siu LL. Source: British Journal of Cancer. 2003 August 18; 89(4): 617-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12915867
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Phase I study of weekly alternating therapy with irinotecan/cisplatin and etoposide/cisplatin for patients with small-cell lung cancer. Author(s): Johnson FM, Kurie JM, Peeples BO, Lee JJ, Feng L, Pisters KM, Fossella FV, Papadimitrakopoulou VA, Blumenschein GR, Komaki R, Glisson BS. Source: Clinical Lung Cancer. 2003 July; 5(1): 40-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14596703
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Phase I trial of combined-modality therapy for localized esophageal cancer: escalating doses of continuous-infusion paclitaxel with cisplatin and concurrent radiation
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therapy. Author(s): Brenner B, Ilson DH, Minsky BD, Bains MS, Tong W, Gonen M, Kelsen DP. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2004 January 1; 22(1): 45-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14701767 •
Phase I trial of concomitant vinorelbine, cisplatin, and pelvic irradiation in cervical carcinoma and other advanced pelvic malignancies. Author(s): Mundt AJ, Rotmensch J, Waggoner SE, Yamada SD, Fleming GF. Source: Gynecologic Oncology. 2004 March; 92(3): 801-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14984944
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Phase I trial of escalating-dose irinotecan given weekly with cisplatin and concurrent radiotherapy in locally advanced esophageal cancer. Author(s): Ilson DH, Bains M, Kelsen DP, O'Reilly E, Karpeh M, Coit D, Rusch V, Gonen M, Wilson K, Minsky BD. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 August 1; 21(15): 2926-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12885811
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Phase I/II study of altered schedule of cisplatin and etoposide administration and concurrent accelerated hyperfractionated thoracic radiotherapy for limited-stage small-cell lung cancer. Author(s): Segawa Y, Ueoka H, Kiura K, Tabata M, Takigawa N, Hiraki Y, Watanabe Y, Yonei T, Moritaka T, Hiyama J, Hiraki S, Tanimoto M, Harada M; Okayama Lung Cancer Study Group. Source: Lung Cancer (Amsterdam, Netherlands). 2003 July; 41(1): 13-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12826307
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Phase I/II study of cisplatin combined with weekly paclitaxel in patients with advanced non-small-cell lung cancer. Author(s): Yoshimura N, Kudoh S, Mukohara T, Yamauchi S, Yamada M, Kawaguchi T, Nakaoka Y, Hirata K, Yoshikawa J. Source: British Journal of Cancer. 2004 March 22; 90(6): 1184-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15026799
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Phase I/II study of concurrent twice-weekly paclitaxel and weekly cisplatin with radiation therapy for stage III non-small cell lung cancer. Author(s): Solomon B, Ball DL, Richardson G, Smith JG, Millward M, MacManus M, Michael M, Wirth A, O'Kane C, Muceniekas L, Ryan G, Rischin D. Source: Lung Cancer (Amsterdam, Netherlands). 2003 September; 41(3): 353-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12928126
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Phase I/II study of docetaxel and cisplatin with concurrent thoracic radiation therapy for locally advanced non-small-cell lung cancer. Author(s): Kiura K, Ueoka H, Segawa Y, Tabata M, Kamei H, Takigawa N, Hiraki S, Watanabe Y, Bessho A, Eguchi K, Okimoto N, Harita S, Takemoto M, Hiraki Y, Harada M, Tanimoto M; Okayama Lung Cancer Study Group. Source: British Journal of Cancer. 2003 September 1; 89(5): 795-802. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12942107
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Phase II clinical study of irinotecan and cisplatin as first-line chemotherapy in metastatic or recurrent cervical cancer. Author(s): Chitapanarux I, Tonusin A, Sukthomya V, Charuchinda C, Pukanhapan N, Lorvidhaya V. Source: Gynecologic Oncology. 2003 June; 89(3): 402-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12798702
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Phase II study of cisplatin and 5-fluorouracil (PF) and mitomycin C, vincristine, cisplatin and 5-fluorouracil (MVPF) in patients with metastatic large bowel cancer: an Eastern Cooperative Oncology Group study (EST 1285). Author(s): Pandya KJ, Lefkopoulou M, Petrelli NJ, Vaughn DJ, Smith TJ, Harris JE, Haller DG; Eastern Cooperative Oncology Group. Source: Oncology. 2004; 66(2): 118-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15138363
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Phase II study of cisplatin, ifosfamide, and irinotecan with rhG-CSF support in patients with stage IIIb and IV non-small-cell lung cancer. Author(s): Fujita A, Ohkubo T, Hoshino H, Takabatake H, Tagaki S, Sekine K, Abe S. Source: British Journal of Cancer. 2003 September 15; 89(6): 1008-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12966417
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Phase II study of gemcitabine-cisplatin-paclitaxel triplet as induction chemotherapy in inoperable, locally-advanced non-small cell lung cancer. Author(s): Cappuzzo F, De Marinis F, Nelli F, Calandri C, Maestri A, Benedetti G, Migliorino MR, Cortesi E, Rastelli F, Martelli O, Andruccetti M, Bartolini S, Crino L. Source: Lung Cancer (Amsterdam, Netherlands). 2003 December; 42(3): 355-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14644524
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Phase II study of neo-adjuvant chemotherapy with paclitaxel and cisplatin given every 2 weeks for patients with a resectable squamous cell carcinoma of the esophagus. Author(s): Polee MB, Tilanus HW, Eskens FA, Hoekstra R, Van der Burg ME, Siersema PD, Stoter G, Van der Gaast A. Source: Annals of Oncology : Official Journal of the European Society for Medical Oncology / Esmo. 2003 August; 14(8): 1253-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12881388
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Phase II study of neoadjuvant paclitaxel and cisplatin for operable and locally advanced breast cancer: analysis of 126 patients. Author(s): Ezzat AA, Ibrahim EM, Ajarim DS, Rahal MM, Raja MA, Tulbah AM, AlMalik OA, Al-Shabanah M, Sorbris R. Source: British Journal of Cancer. 2004 March 8; 90(5): 968-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14997191
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Phase II study of the combination of vinorelbine and cisplatin in advanced nonsmall-cell lung cancer. Author(s): Mori K, Kamiyama Y, Kondo T, Kano Y, Tominaga K. Source: Cancer Chemotherapy and Pharmacology. 2004 February; 53(2): 129-32. Epub 2003 November 07. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14605861
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Phase II study of three-dimensional conformal radiotherapy and concurrent mitomycin-C, vinblastine, and cisplatin chemotherapy for Stage III locally advanced, unresectable, non-small-cell lung cancer. Author(s): Lee SW, Choi EK, Lee JS, Lee SD, Suh C, Kim SW, Kim WS, Ahn SD, Yi BY, Kim JH, Noh YJ, Kim SS, Koh Y, Kim DS, Kim WD. Source: International Journal of Radiation Oncology, Biology, Physics. 2003 July 15; 56(4): 996-1004. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12829135
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Phase II study with vinorelbine and cisplatin in advanced non-small cell lung cancer after failure of previous chemotherapy. Author(s): Chen YM, Lee CS, Lin WC, Tsai CM, Perng RP. Source: J Chin Med Assoc. 2003 April; 66(4): 241-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12854877
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Phase II trial of cisplatin/etoposide and concurrent radiotherapy followed by paclitaxel/carboplatin consolidation for limited small-cell lung cancer: Southwest Oncology Group 9713. Author(s): Edelman MJ, Chansky K, Gaspar LE, Leigh B, Weiss GR, Taylor SA, Crowley J, Livingston R, Gandara DR. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2004 January 1; 22(1): 127-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14701775
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Phase II trial of irinotecan plus docetaxel in cisplatin-pretreated relapsed or refractory oesophageal cancer. Author(s): Lordick F, von Schilling C, Bernhard H, Hennig M, Bredenkamp R, Peschel C. Source: British Journal of Cancer. 2003 August 18; 89(4): 630-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12915869
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Phase II trial of neoadjuvant paclitaxel and cisplatin in uterine cervical cancer. Author(s): Park DC, Kim JH, Lew YO, Kim DH, Namkoong SE. Source: Gynecologic Oncology. 2004 January; 92(1): 59-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14751139
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Phase III randomized trial of docetaxel plus cisplatin versus vindesine plus cisplatin in patients with stage IV non-small-cell lung cancer: the Japanese Taxotere Lung Cancer Study Group. Author(s): Kubota K, Watanabe K, Kunitoh H, Noda K, Ichinose Y, Katakami N, Sugiura T, Kawahara M, Yokoyama A, Yokota S, Yoneda S, Matsui K, Kudo S, Shibuya M, Isobe T, Segawa Y, Nishiwaki Y, Ohashi Y, Niitani H; Japanese Taxotere Lung Cancer Study Group. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2004 January 15; 22(2): 254-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14722033
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Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. Author(s): Ozols RF, Bundy BN, Greer BE, Fowler JM, Clarke-Pearson D, Burger RA, Mannel RS, DeGeest K, Hartenbach EM, Baergen R; Gynecologic Oncology Group. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 September 1; 21(17): 3194-200. Epub 2003 July 14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12860964
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Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology Group Study. Author(s): Fleming GF, Brunetto VL, Cella D, Look KY, Reid GC, Munkarah AR, Kline R, Burger RA, Goodman A, Burks RT. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2004 June 1; 22(11): 2159-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15169803
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Phase III trial of gemcitabine and carboplatin versus mitomycin, ifosfamide, and cisplatin or mitomycin, vinblastine, and cisplatin in patients with advanced nonsmall cell lung carcinoma. Author(s): Danson S, Middleton MR, O'Byrne KJ, Clemons M, Ranson M, Hassan J, Anderson H, Burt PA, Fairve-Finn C, Stout R, Dowd I, Ashcroft L, Beresford C, Thatcher N. Source: Cancer. 2003 August 1; 98(3): 542-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12879472
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Phase III trial of methotrexate, vinblastine, doxorubicin, and cisplatin versus carboplatin and paclitaxel in patients with advanced carcinoma of the urothelium. Author(s): Dreicer R, Manola J, Roth BJ, See WA, Kuross S, Edelman MJ, Hudes GR, Wilding G.
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Source: Cancer. 2004 April 15; 100(8): 1639-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15073851 •
Preliminary analysis of RTOG 9708: Adjuvant postoperative radiotherapy combined with cisplatin/paclitaxel chemotherapy after surgery for patients with high-risk endometrial cancer. Author(s): Greven K, Winter K, Underhill K, Fontenesci J, Cooper J, Burke T; Radiation Therapy Oncology Group. Source: International Journal of Radiation Oncology, Biology, Physics. 2004 May 1; 59(1): 168-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15093913
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Preoperative concurrent chemoradiotherapy with cisplatin and docetaxel in patients with locally advanced non-small-cell lung cancer. Author(s): Katayama H, Ueoka H, Kiura K, Tabata M, Kozuki T, Tanimoto M, Fujiwara T, Tanaka N, Date H, Aoe M, Shimizu N, Takemoto M, Hiraki Y. Source: British Journal of Cancer. 2004 March 8; 90(5): 979-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14997193
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Protection by ozone preconditioning is mediated by the antioxidant system in cisplatin-induced nephrotoxicity in rats. Author(s): Borrego A, Zamora ZB, Gonzalez R, Romay C, Menendez S, Hernandez F, Montero T, Rojas E. Source: Mediators of Inflammation. 2004 February; 13(1): 13-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15203559
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Protective Effect of Quercetin on the Evolution of Cisplatin-Induced Acute Tubular Necrosis. Author(s): Francescato HD, Coimbra TM, Costa RS, Bianchi Md M. Source: Kidney & Blood Pressure Research. 2004 April 30 [epub Ahead of Print] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15118361
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Randomised phase II study of docetaxel/cisplatin vs docetaxel/irinotecan in advanced non-small-cell lung cancer: a West Japan Thoracic Oncology Group Study (WJTOG9803). Author(s): Yamamoto N, Fukuoka M, Negoro SI, Nakagawa K, Saito H, Matsui K, Kawahara M, Senba H, Takada Y, Kudoh S, Nakano T, Katakami N, Sugiura T, Hoso T, Ariyoshi Y. Source: British Journal of Cancer. 2004 January 12; 90(1): 87-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14710212
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Randomized phase III study of gemcitabine and vinorelbine versus gemcitabine, vinorelbine, and cisplatin in the treatment of advanced non-small-cell lung cancer: from the German and Swiss Lung Cancer Study Group.
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Author(s): Laack E, Dickgreber N, Muller T, Knuth A, Benk J, Lorenz C, Gieseler F, Durk H, Engel-Riedel W, Dalhoff K, Kortsik C, Graeven U, Burk M, Dierlamm T, Welte T, Burkholder I, Edler L, Hossfeld DK; German and Swiss Lung Cancer Study Group. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2004 June 15; 22(12): 2348-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15197195 •
Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. Author(s): Fossella F, Pereira JR, von Pawel J, Pluzanska A, Gorbounova V, Kaukel E, Mattson KV, Ramlau R, Szczesna A, Fidias P, Millward M, Belani CP. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 August 15; 21(16): 3016-24. Epub 2003 July 01. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12837811
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Relapse-free and overall survival in patients with pathologic stage II nonseminomatous germ cell cancer treated with etoposide and cisplatin adjuvant chemotherapy. Author(s): Kondagunta GV, Sheinfeld J, Mazumdar M, Mariani TV, Bajorin D, Bacik J, Bosl GJ, Motzer RJ. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2004 February 1; 22(3): 464-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14752068
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Reversibility of liver failure secondary to metastatic breast cancer by vinorelbine and cisplatin chemotherapy. Author(s): Sharma RA, Decatris MP, Santhanam S, Roy R, Osman AE, Clarke CB, Khanna S, O'Byrne KJ. Source: Cancer Chemotherapy and Pharmacology. 2003 November; 52(5): 367-70. Epub 2003 July 18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12879281
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RTOG 97-06: initial report of a phase I-II trial of selective bladder conservation using TURBT, twice-daily accelerated irradiation sensitized with cisplatin, and adjuvant MCV combination chemotherapy. Author(s): Hagan MP, Winter KA, Kaufman DS, Wajsman Z, Zietman AL, Heney NM, Toonkel LM, Jones CU, Roberts JD, Shipley WU. Source: International Journal of Radiation Oncology, Biology, Physics. 2003 November 1; 57(3): 665-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14529770
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Scutellaria baicalensis extract decreases cisplatin-induced pica in rats. Author(s): Aung HH, Dey L, Mehendale S, Xie JT, Wu JA, Yuan CS.
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Source: Cancer Chemotherapy and Pharmacology. 2003 December; 52(6): 453-8. Epub 2003 August 27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12942313 •
Second-line chemotherapy with bleomycin, methotrexate, and vinorelbine (BMV) for patients with squamous cell carcinoma of the head, neck and esophagus (SCCHN&E) pretreated with a cisplatin-containing regimen: a phase II study. Author(s): Moroni M, Giannetta L, Gelosa G, Secondino S, Chillura G, Colombo E, Siena S. Source: J Chemother. 2003 August; 15(4): 394-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12962369
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Second-line chemotherapy with low-dose CPT-11 and cisplatin for colorectal cancer resistant to 5-FU-based chemotherapy. Author(s): Yoshimatsu K, Kato H, Ishibashi K, Hashimoto M, Umehara A, Yokomizo H, Yoshida K, Fujimoto T, Iwasaki K, Ogawa K. Source: Cancer Chemotherapy and Pharmacology. 2003 December; 52(6): 465-8. Epub 2003 August 14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12920569
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Selenium and high dose vitamin E administration protects cisplatin-induced oxidative damage to renal, liver and lens tissues in rats. Author(s): Naziroglu M, Karaoglu A, Aksoy AO. Source: Toxicology. 2004 February 15; 195(2-3): 221-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14751677
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Sequencing topotecan and etoposide plus cisplatin to overcome topoisomerase I and II resistance: a pharmacodynamically based Phase I trial. Author(s): Aisner J, Musanti R, Beers S, Smith S, Locsin S, Rubin EH. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2003 July; 9(7): 2504-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12855624
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Should we discard vinorelbine plus cisplatin from the first-line therapy of advanced non-small-cell lung cancer? Author(s): Dediu M. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2004 April 1; 22(7): 1345-7; Author Reply 1347. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15051791
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Silibinin sensitizes human prostate carcinoma DU145 cells to cisplatin- and carboplatin-induced growth inhibition and apoptotic death. Author(s): Dhanalakshmi S, Agarwal P, Glode LM, Agarwal R.
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Source: International Journal of Cancer. Journal International Du Cancer. 2003 September 20; 106(5): 699-705. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12866029 •
Study of paclitaxel and dose escalation of cisplatin in patients with advanced nonsmall cell lung cancer. Author(s): Watanabe H, Yamamoto N, Tamura T, Shimoyama T, Hotta K, Inoue A, Sawada M, Akiyama Y, Kusaba H, Nokihara H, Sekine I, Kunitoh H, Ohe Y, Kodama T, Saijo N. Source: Japanese Journal of Clinical Oncology. 2003 December; 33(12): 626-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14769840
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Successful salvage therapy of resistant gestational trophoblastic disease with etoposide, methotrexate, actinomycin-D, etoposide, cisplatin (EMA/EP). Author(s): Bilgin T, Ozan H, Ozuysal S, Ozkan L. Source: Archives of Gynecology and Obstetrics. 2004 January; 269(2): 159-60. Epub 2002 November 13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14648186
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Survival following intensive preoperative combined modality therapy with paclitaxel, cisplatin, 5-fluorouracil, and radiation in resectable esophageal carcinoma: a phase I report. Author(s): Goldberg M, Farma J, Lampert C, Colarusso P, Coia L, Frucht H, Goosenberg E, Beard M, Weiner LM. Source: The Journal of Thoracic and Cardiovascular Surgery. 2003 October; 126(4): 116873. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14566264
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Tamoxifen inhibits cell proliferation via mitogen-activated protein kinase cascades in human ovarian cancer cell lines in a manner not dependent on the expression of estrogen receptor or the sensitivity to cisplatin. Author(s): Mabuchi S, Ohmichi M, Kimura A, Ikebuchi Y, Hisamoto K, Arimoto-Ishida E, Nishio Y, Takahashi K, Tasaka K, Murata Y. Source: Endocrinology. 2004 March; 145(3): 1302-13. Epub 2003 November 26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14645110
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The effect of Ginkgo extract EGb761 in cisplatin-induced peripheral neuropathy in mice. Author(s): Ozturk G, Anlar O, Erdogan E, Kosem M, Ozbek H, Turker A. Source: Toxicology and Applied Pharmacology. 2004 April 1; 196(1): 169-75. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15050418
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The effects of quercetin vs cisplatin on proliferation and the apoptotic process in A549 and SW1271 cell lines in in vitro conditions. Author(s): Borska S, Gebarowska E, Wysocka T, Drag-Zalesinska M, Zabel M. Source: Folia Morphol (Warsz). 2004 February; 63(1): 103-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15039912
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The expression of metallothionein (MT) and proliferation intensity in ovarian cancers treated with cisplatin and paclitaxel. Author(s): Surowiak P, Kaplenko I, Spaczynski M, Zabel M. Source: Folia Morphol (Warsz). 2003 November; 62(4): 493-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14655150
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Three-arm randomized study of two cisplatin-based regimens and paclitaxel plus gemcitabine in advanced non-small-cell lung cancer: a phase III trial of the European Organization for Research and Treatment of Cancer Lung Cancer Group--EORTC 08975. Author(s): Smit EF, van Meerbeeck JP, Lianes P, Debruyne C, Legrand C, Schramel F, Smit H, Gaafar R, Biesma B, Manegold C, Neymark N, Giaccone G; European Organization for Research and Treatment of Cancer Lung Cancer Group. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 November 1; 21(21): 3909-17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14581415
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Transplantation of neural stem cells into the modiolus of mouse cochleae injured by cisplatin. Author(s): Tamura T, Nakagawa T, Iguchi F, Tateya I, Endo T, Kim TS, Dong Y, Kita T, Kojima K, Naito Y, Omori K, Ito J. Source: Acta Otolaryngol Suppl. 2004 March; (551): 65-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15078082
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Vascular neurotoxicity following chemotherapy with cisplatin, ifosfamide, and etoposide. Author(s): Dietrich J, Marienhagen J, Schalke B, Bogdahn U, Schlachetzki F. Source: The Annals of Pharmacotherapy. 2004 February; 38(2): 242-6. Epub 2003 December 15. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14742759
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Vinflunine potentiates the activity of cisplatin but not 5-fluorouracil in a transplantable murine adenocarcinoma model. Author(s): Shnyder SD, Cooper PA, Gyselinck N, Hill BT, Double JA, Bibby MC. Source: Anticancer Res. 2003 November-December; 23(6C): 4815-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14981930
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Vinorelbine and cisplatin for metastatic breast cancer: a salvage regimen in patients progressing after docetaxel and anthracycline treatment. Author(s): Vassilomanolakis M, Koumakis G, Demiri M, Missitzis J, Barbounis V, Efremidis AP. Source: Cancer Investigation. 2003; 21(4): 497-504. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14533438
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Vinorelbine, ifosfamide, and cisplatin combination as salvage chemotherapy in advanced non-small cell lung cancer. Author(s): Song SY, Kim WS, Kim K, Jung CW, Im YH, Kim HJ, Kang WK, Lee HG, Kwon OJ, Rhee CH, Park CH, Park K. Source: Japanese Journal of Clinical Oncology. 2003 October; 33(10): 509-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14623918
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Weekly administration of irinotecan (CPT-11) plus cisplatin for refractory or relapsed small cell lung cancer. Author(s): Ando M, Kobayashi K, Yoshimura A, Kurimoto F, Seike M, Nara M, Moriyama G, Mizutani H, Hibino S, Gemma A, Okano T, Shibuya M, Kudoh S. Source: Lung Cancer (Amsterdam, Netherlands). 2004 April; 44(1): 121-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15013590
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Weekly chemotherapy with cisplatin, vincristine, doxorubicin, and etoposide is an effective treatment for advanced thymic carcinoma. Author(s): Yoh K, Goto K, Ishii G, Niho S, Ohmatsu H, Kubota K, Kakinuma R, Nagai K, Suga M, Nishiwaki Y. Source: Cancer. 2003 September 1; 98(5): 926-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12942558
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Weekly irinotecan in patients with metastatic gastric cancer failing cisplatin-based chemotherapy. Author(s): Chun JH, Kim HK, Lee JS, Choi JY, Lee HG, Yoon SM, Choi IJ, Ryu KW, Kim YW, Bae JM. Source: Japanese Journal of Clinical Oncology. 2004 January; 34(1): 8-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15020657
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Weekly low dose paclitaxel and cisplatin as first-line chemotherapy for advanced non-small cell lung cancer. Author(s): Kim SW, Suh C, Lee SD, Kim WS, Kim DS, Kim WD, Lee JS. Source: Lung Cancer (Amsterdam, Netherlands). 2003 August; 41(2): 221-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12871786
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Additional Web Resources A number of additional Web sites offer encyclopedic information covering CAM and related topics. The following is a representative sample: •
Alternative Medicine Foundation, Inc.: http://www.herbmed.org/
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AOL: http://search.aol.com/cat.adp?id=169&layer=&from=subcats
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Chinese Medicine: http://www.newcenturynutrition.com/
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drkoop.com: http://www.drkoop.com/InteractiveMedicine/IndexC.html
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Family Village: http://www.familyvillage.wisc.edu/med_altn.htm
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Google: http://directory.google.com/Top/Health/Alternative/
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Healthnotes: http://www.healthnotes.com/
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MedWebPlus: http://medwebplus.com/subject/Alternative_and_Complementary_Medicine
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Open Directory Project: http://dmoz.org/Health/Alternative/
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HealthGate: http://www.tnp.com/
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WebMDHealth: http://my.webmd.com/drugs_and_herbs
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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html
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Yahoo.com: http://dir.yahoo.com/Health/Alternative_Medicine/
The following is a specific Web list relating to cisplatin; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •
General Overview Bone Cancer Source: Integrative Medicine Communications; www.drkoop.com Breast Cancer Source: Healthnotes, Inc.; www.healthnotes.com Cancer Prevention (Reducing the Risk) Source: Prima Communications, Inc.www.personalhealthzone.com Colon Cancer Source: Healthnotes, Inc.; www.healthnotes.com Lung Cancer Source: Healthnotes, Inc.; www.healthnotes.com Lung Cancer Source: Integrative Medicine Communications; www.drkoop.com
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Prostate Cancer Source: Healthnotes, Inc.; www.healthnotes.com •
Herbs and Supplements Alpha-Lipoic Acid Source: Integrative Medicine Communications; www.drkoop.com Beta-Carotene Source: Healthnotes, Inc.; www.healthnotes.com Chemotherapy Source: Healthnotes, Inc.; www.healthnotes.com Cyclophosphamide Source: Healthnotes, Inc.; www.healthnotes.com Cysteine Source: Integrative Medicine Communications; www.drkoop.com Dehydroepiandrosterone (DHEA) Alternative names: DHEA Source: Integrative Medicine Communications; www.drkoop.com DHEA Alternative names: Dehydroepiandrosterone (DHEA) Source: Integrative Medicine Communications; www.drkoop.com Docetaxel Source: Healthnotes, Inc.; www.healthnotes.com Fluorouracil Source: Healthnotes, Inc.; www.healthnotes.com Gamma-Linolenic Acid (GLA) Alternative names: GLA Source: Integrative Medicine Communications; www.drkoop.com GLA Alternative names: Gamma-Linolenic Acid (GLA) Source: Integrative Medicine Communications; www.drkoop.com Glutamine Source: Healthnotes, Inc.; www.healthnotes.com Glutathione Source: Healthnotes, Inc.; www.healthnotes.com Glycyrrhiza Alternative names: Licorice; Glycyrrhiza glabra L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org
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Melatonin Source: Healthnotes, Inc.; www.healthnotes.com Melatonin Source: Prima Communications, Inc.www.personalhealthzone.com Methotrexate Source: Healthnotes, Inc.; www.healthnotes.com Milk Thistle Alternative names: Silybum marianum Source: Integrative Medicine Communications; www.drkoop.com N-Acetyl Cysteine Source: Healthnotes, Inc.; www.healthnotes.com Paclitaxel Source: Healthnotes, Inc.; www.healthnotes.com Silybum Alternative names: Milk Thistle; Silybum marianum (L.) Gaertn. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Silybum Marianum Alternative names: Milk Thistle Source: Integrative Medicine Communications; www.drkoop.com Spleen Extracts Source: Healthnotes, Inc.; www.healthnotes.com St. Mary's Thistle Alternative names: Milk Thistle Source: Integrative Medicine Communications; www.drkoop.com Taurine Source: Healthnotes, Inc.; www.healthnotes.com Thymus Extracts Source: Healthnotes, Inc.; www.healthnotes.com Zingiber Alternative names: Ginger; Zingiber officinale Roscoe Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org
General References A good place to find general background information on CAM is the National Library of Medicine. It has prepared within the MEDLINEplus system an information topic page dedicated to complementary and alternative medicine. To access this page, go to the MEDLINEplus site at http://www.nlm.nih.gov/medlineplus/alternativemedicine.html.
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This Web site provides a general overview of various topics and can lead to a number of general sources.
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CHAPTER 4. DISSERTATIONS ON CISPLATIN Overview In this chapter, we will give you a bibliography on recent dissertations relating to cisplatin. We will also provide you with information on how to use the Internet to stay current on dissertations. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical dissertations that use the generic term “cisplatin” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on cisplatin, we have not necessarily excluded non-medical dissertations in this bibliography.
Dissertations on Cisplatin ProQuest Digital Dissertations, the largest archive of academic dissertations available, is located at the following Web address: http://wwwlib.umi.com/dissertations. From this archive, we have compiled the following list covering dissertations devoted to cisplatin. You will see that the information provided includes the dissertation’s title, its author, and the institution with which the author is associated. The following covers recent dissertations found when using this search procedure: •
Interaction between cisplatin and radiation in the treatment of ovarian cancer cells by LeBlanc, Julie-Maude, MSc from UNIVERSITY OF OTTAWA (CANADA), 2003, 132 pages http://wwwlib.umi.com/dissertations/fullcit/MQ76534
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Investigation of the cytoprotective properties of ebselen (2-phenyl-1,2benzisoselenazol-3(2H)-one) against cisplatin and diethyldithiocarbamate (DDC) toxicity in rat hippocampal astrocytes by Hardej, Diane, PhD from ST. JOHN'S UNIVERSITY (NEW YORK), SCHOOL OF PHARMACY, 2003, 95 pages http://wwwlib.umi.com/dissertations/fullcit/3095074
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Keeping Current Ask the medical librarian at your library if it has full and unlimited access to the ProQuest Digital Dissertations database. From the library, you should be able to do more complete searches via http://wwwlib.umi.com/dissertations.
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CHAPTER 5. PATENTS ON CISPLATIN Overview Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.8 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical patents that use the generic term “cisplatin” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on cisplatin, we have not necessarily excluded non-medical patents in this bibliography.
Patents on Cisplatin By performing a patent search focusing on cisplatin, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We
8Adapted
from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.
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will tell you how to obtain this information later in the chapter. The following is an example of the type of information that you can expect to obtain from a patent search on cisplatin: •
Antitumor agent effect enhancer containing IL-6 antagonist Inventor(s): Mizutani; Youichi (Kyoto, JP), Yoshida; Osamu (Kyoto, JP) Assignee(s): Chugai Seiyaku Kabushiki Kaisha (Tokyo, JP) Patent Number: 6,086,874 Date filed: June 27, 1997 Abstract: The present invention discloses an effect enhancer for antitumor agents, examples of which include platinum compounds such as cisplatin and carboplatin, and mitomycin C, that contains interleukin-6 (IL-6) antagonist, examples of which include antibody to IL-6, antibody to IL-6 receptor, and antibody to gp130 protein. Excerpt(s): The present invention relates to an antitumor agent effect enhancer comprising interleukin-6 antagonist that assists and enhances the effects of antitumor agents in the treatment of tumors. Various drugs such as alkylating agents, metabolism antagonists, antitumor antibiotics and platinum compounds have been used in the past for chemotherapy on human tumors. In the case where remarkable therapeutic effects are not observed when these antitumor agents are used alone, therapeutic methods have been devised in which a plurality of antitumor agents are used concomitantly (Frei, E. III, Cancer Res., 32, 2593-2607, 1992). Tumor cells exhibit various sensitivities to antitumor agents, and certain cells are known to exhibit resistance to therapy by antitumor agents (Magrath, I., New Directions in Cancer Treatment, 1989, SpringerVerlag). Acquisition of resistance to therapy by tumor cells is said to be caused by, for example, the occurrence of multi-drug resistance (MDR) (Tsuruo, T. et al., Cancer Res., 42, 4730-4733, 1982), reduction in cell uptake of antitumor agent (Sherman, S. E. et al., Science, 230, 412, 1985), increased DNA repair activity (Borch, R. F., Metabolism and Action of Anticancer Drugs, Powis, G. & Prough, R. ed., Taylor & Francis, London, 1987, 163-193), or promotion of inactivation of antitumor agent in the cells (Teicher, B. A. et al., Cancer Res., 46, 4379, 1986). In such cases, there are many cases in which the expected therapeutic effects are not observed simply by administering antitumor agent. Renal cell carcinoma exhibits resistance to therapy to antitumor agents such as cisplatin, adriamycin and vinblastine (Kakehi, Y. et al., J. Urol., 139, 862-864, 1988; Kanamaru, H. et al., J. Natl. Cancer Inst., 81, 844-847, 1989; Teicher, B. A. et al., Cancer Res., 47, 388-393, 1987). Platinum compounds such as cisplatin that possess antitumor effects bond with DNA and inhibit DNA synthesis and cell division (Pinto, A. L. et al., Biochica et Biophysica Acta, 780, 167-180, 1985). Web site: http://www.delphion.com/details?pn=US06086874__
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Assay for sensitivity of tumors to DNA-platinating chemotherapy Inventor(s): Dabholkar; Meenakshi (Bethesda, MD), Reed; Eddie (Germantown, MD) Assignee(s): The United States of America as represented by the Department of Health (Washington, DC) Patent Number: 5,705,336 Date filed: March 7, 1995
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Abstract: Assay of the mRNA levels of ERCC1 and XPAC, two genes whose products are involved in DNA repair, provides a method for determining the sensitivity of tumors to treatment by platinum-based chemotherapy. Tumors that are resistant to cisplatin tend to express high levels of the mRNA for ERCC1 which includes exon VIII. In some tumor types, concurrent expression of ERCC1 and XPAC mRNAs is also an indicator of cisplatin resistance. Excerpt(s): The invention relates to assessment of a genetic trait of tumor cells of a patient. The resistance of the tumor cells to chemotherapeutic agents which act by damaging DNA, especially agents which damage DNA in the manner of platinating agents (e.g., cisplatin, carboplatin), is assayed by examining the mRNA expressed from genes involved in DNA repair in humans. Excision repair of bulky DNA adducts, such as those formed by cisplatin, appears to be mediated by an aggregate of genes, with ERCC and XP proteins being involved in DNA damage recognition and excision (1-3). The human DNA repair genes ERCC1 (the human excision repair gene crosscomplementing Chinese hamster ovary (CHO) mutant cell lines of complementation group I) and XPAC (the human excision repair gene that corrects the defect in xeroderma pigmentosum group A cells) have been cloned (4,5). Several studies using mutant human and hamster cell lines that are defective in either of these genes, and their transfected derivatives, and studies in human tumor tissues indicate that the products encoded by these genes are involved in the excision repair of platinum-DNA adducts (6-9). The ERCC1 gene exhibits homology to the yeast RAD10 gene (19), which forms an endonucleolytic complex with RAD1, and is involved in the excision of bulky DNA adducts (11, 12). When transfected into DNA-repair deficient CHO cells, ERCC1 confers cellular resistance to cisplatin along with the ability to repair platinum-DNA adducts (9). Web site: http://www.delphion.com/details?pn=US05705336__ •
Broad specificity DNA damage endonuclease Inventor(s): Avery; Angela M. (Atlanta, GA), Doetsch; Paul W. (Atlanta, GA), Kaur; Balveen (Atlanta, GA) Assignee(s): Emory University (Atlanta, GA) Patent Number: 6,368,594 Date filed: June 8, 1999 Abstract: The present disclosure describes DNA damage endonucleases which exhibit broad specificity with respect to the types of structural aberrations in double stranded DNA. These enzymes recognize double stranded DNA with distortions in structure, wherein the distortions result from photoproducts, alkylation, intercalation, abasic sites, mismatched base pairs, cisplatin adducts and inappropriately incorporated bases (for example, 8-oxoguanine, inosine, xanthine, among others). The UVDE (Uve1p) of Schizosaccharomyces pombe, certain truncated forms of that UVDE (lacking from about 100 to about 250 amino acids of N-terminal sequence) and certain endonucleases from Homo sapiens, Neurospora crassa, Bacillus subtilis, and from Deinococcus radiodurans. The present disclosure further provides methods for cleaving double stranded DNA having structural distortions as set forth herein using the exemplified endonucleases or their stable, functional truncated derivatives. Excerpt(s): The field of the present invention is the area of DNA repair enzymes. In particular, the invention concerns the identification of stable ultraviolet DNA
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endonuclease polypeptide fragments, their nucleotide sequences and recombinant host cells and methods for producing them and for using them in DNA repair processes. Cellular exposure to ultraviolet radiation (UV) results in numerous detrimental effects including cell death, mutation and neoplastic transformation. Studies indicate that some of these deleterious effects are due to the formation of two major classes of bipyrimidine DNA photoproducts, cyclobutane pyrimidine dimers (CPDs) and (6-4) photoproducts (6-4 PPs). (Friedberg et al. [1995] in DNA Repair and Mutagenesis, pp. 24-31, Am. Soc. Microbiol., Washington, D.C.). Organisms have evolved several different pathways for removing CPDs and 6-4 PPs from cellular DNA (Friedberg et al. [1995] supra; Brash et al. [1991] Proc. Natl. Acad. Sci. U.S.A. 8810124-10128). These pathways include direct reversal and various excision repair pathways which can be highly specific or nonspecific for CPDs and 6-4 PPs. For example, DNA photolyases specific for either CPDs or 6-4 PPs have been found in a variety of species and restore the photoproduct bases back to their original undamaged states (Rubert, C. S. [1975] Basic Life Sci. 5A:7387; Kim et al. [1994] J. Biol. Chem. 269:8535-8540; Sancar, G. B. [1990] Mutat. Res. 236:147-160). Excision repair has been traditionally divided into either base excision repair (BER) or nucleotide excision repair (NER) pathways, which are mediated by separate sets of proteins but which both are comprised of DNA incision, lesion removal, gap-filling and ligation reactions (Sancar, A. [1994] Science 266:1954-19560; Sancar, A. and Tang, M. S. [1993] Photochem. Photobiol. 57:905-921). BER N-glycosylase/AP lyases specific for CPDs cleave the N-glycosidic bond of the CPD 5' pyrimidine and then cleave the phosphodiester backbone at the abasic site via a.beta.-lyase mechanism, and have been found in several species including T4 phage-infected Escherichia coli, Micrococcus luteus, and Saccharomyces cerevisiae (Nakabeppu, Y. et al. [1982] J. Biol. Chem. 257:2556-2562; Grafstrom, R. H. et al. [1982] J. Biol. Chem. 257:13465-13474; Hamilton, K. K. et al. [1992] Nature 356:725-728). NER is a widely distributed, lesion non-specific repair pathway which orchestrates DNA damage removal via a dual incision reaction upstream and downstream from the damage site, releasing an oligonucleotide containing the damage and subsequent gap filling and ligation reactions (Sancar and Tang [1993] supra). Web site: http://www.delphion.com/details?pn=US06368594__ •
Chemotherapy of cancer with actyldinaline in combination with gemcitabine capecitabine or cisplatin Inventor(s): Grove; William Richard (Whitmore Lake, MI), Klohs; Wayne Daniel (Ypsilanti, MI), Merriman; Ronald Lynn (Ann Arbor, MI) Assignee(s): Warner-Lambert Company (Morris Plains, NJ) Patent Number: 6,469,058 Date filed: January 19, 2001 Abstract: Acetyldinaline in combination with gemcitabine, a pharmaceutically acceptable salt thereof, capecitabine, or cisplatin is synergistic for treating cancer. Excerpt(s): The invention concerns a method for treating tumors utilizing a combination of known oncolytic agents. The use of the agents together provides unexpectedly greater efficacy than employing the single agents alone. Cancer chemotherapy has advanced dramatically in recent years. Many tumors can be effectively treated utilizing compounds which are either naturally occurring products or synthetic agents. Cancer chemotherapy often entails use of a combination of agents, generally as a means of providing greater therapeutic effects and reducing the toxic effects that are often
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encountered with the individual agents when used alone. We have now discovered a unique combination of known oncolytic agents which exhibits a dramatic synergistic effect. The combination utilizes the agent acetyldinaline, together with either gemcitabine, capecitabine, or cisplatin. The combination is especially effective in treating patients with solid tumors, especially nonsmall cell lung cancer and other advanced solid tumors. Web site: http://www.delphion.com/details?pn=US06469058__ •
Cisplatin and folic acid administered to treat breast cancer Inventor(s): Shaw; Jiajiu (Ann Arbor, MI) Assignee(s): Unitech Pharmaceuticals (Ann Arbor, MI) Patent Number: 6,297,245 Date filed: July 21, 1999 Abstract: A novel pharmaceutical composition, comprising cisplatin and folic acid is disclosed. The preparation of this pharmaceutical composition is also disclosed. The composition may be used to treat cancers and Acquired Immune Deficiency Syndrome (AIDS). Excerpt(s): There is no Federally sponsored research and development in this application. Cisplatin (cis-diamminedichloroplatinum, cis-Pt(NH3)2Cl12, molecular weight 300.05) has been used as a chemotherapeutic agent for many years since the discovery of its anti-tumor activity by B. Rosenberg et al. (Nature, 1965, 205, 698; Nature, 1972, 222, 385). The physician's Desk Reference (PDR) reports that cisplatin (the commercial name is Platinol.RTM.) can be used to treat testicular cancer, ovarian cancer, and bladder cancer. Web site: http://www.delphion.com/details?pn=US06297245__
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Combination cisplatin/tamoxifen therapy for human cancers Inventor(s): Howell; Stephen B. (Del Mar, CA), Mc Clay; Edward F. (Encinitas, CA) Assignee(s): Research Development Foundation (Carson City, NV) Patent Number: 6,288,111 Date filed: June 7, 1995 Abstract: The present invention provides a novel composition of matter useful for the treatment of a wide variety of human cancers. The novel composition is synergistic and cytotoxic and comprised of platinum containing antineoplastic agent and tamoxifen. The present invention also provides for methods of treating cancer. That is, the present invention provides a novel method of treating non-melanoma cancers used the novel pharmacologic combination of the present invention. Other embodiments of the invention provide novel methods of reducing or overcoming resistance that develops to platinum containing antineoplastic agents, such as, cisplatin. Excerpt(s): The present invention relates generally to the fields of medical oncology and the pharmacotherapy of human cancers. More specifically, the present invention relates to novel methods of treating cisplatin resistant or cisplatin non-resistant cancers using a combination of tamoxifen and cisplatin. The treatment of cancer patients with platinum
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coordination complex antineoplastic agents, such as cis-diamminedichloroplatinum (II) (cisplatin) has increased substantially in the last decade. Cisplatin is a antineoplastic agent that has proved useful in the treatment of multiple malignancies including testicular cancer, ovarian cancer, and small cell lung cancer. The mechanism of action is currently unknown but may be related to the ability of cisplatin to bind to DNA and form various types of inter- and intrastrand crosslinks that possibly interfere with both DNA and RNA synthesis. Cancer patients eventually become resistant to treatment with platinum coordination complexes, such as cisplatin. If the patient dies of metastatic cancer, the cells of the metastatic foci are usually also characterized by their extreme resistance to single or combinations of the available chemotherapeutic drugs. In general, drug resistant tumors can be classified as temporary or permanent. The mechanism of resistance to cisplatin is unclear but may be related to decreased drug accumulation, elevation of intracellular concentrations of metallothioneines or glutathione which bind and inactivate cisplatin, or to decreased cisplatin-DNA adduct formation or repair. Web site: http://www.delphion.com/details?pn=US06288111__ •
Combination therapy for advanced cancer Inventor(s): Dugan; Margaret H. (Woodside, NY) Assignee(s): Schering Corporation (Kenilworth, NJ) Patent Number: 5,824,346 Date filed: August 22, 1996 Abstract: There is disclosed a method for treating advanced cancer in patients in need of such treating. Temozolomide and cisplatin are administered in combination in amounts sufficient to achieve a clinical response. Excerpt(s): Despite the numerous advances in cancer treatment, the well-known life style changes that can greatly reduce the risk of cancer, and the early warning signs that some cancers provide, many patients still develop advanced cancer for which no conventional therapies are available that offer any reasonable hope of cure or significant palliation. This invention is the use of two known anti-tumor agents in combination therapy to provide a positive effect on such advanced cancers. It is also expected that the combination therapy will allow the administration of the two anti-tumor agents in quantities that will not result in intolerable side effects. Temozolomide is known for its anti-tumor effects. For example, in one study clinical responses were achieved in 17% of patients having advanced melanoma (Newlands ES, et al. Br J Cancer 65 (2) 287-2981, 1992). In another study a clinical response was achieved in 21% of patients with advanced melanoma (Journal of Clinical Oncology, Vol 13, No. 4 (April), 1995, pp 910913). However, temozolomide has dose-limiting side effects, such as hematologic toxicity, myelosuppression, anemia, leukopenia, etc. Cisplatin is known to have antitumor properties (see, for example B. Rosenberg et al. Nature 205, 698 (1965) and 222, 385 (1972). However, it too has dose-limiting side effects such as nephrotoxicity and ototoxicity. Web site: http://www.delphion.com/details?pn=US05824346__
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Combination therapy using pentafluorobenzenesulfonamides Inventor(s): Schwendner; Susan (San Bruno, CA), Timmermans; Pieter (Redwood City, CA), Walling; Jacqueline (Burlingame, CA) Assignee(s): Tularik Inc. (So. San Francisco, CA) Patent Number: 6,355,628 Date filed: July 27, 2000 Abstract: Combination therapies are provided for the treatment of proliferative disorders which use a pentafluorobenzenesulfonamide of formula I and an antineoplastic platinum coordination complex such as cisplatin. Excerpt(s): The present invention relates to combinations of pentafluorobenzenesulfonamides and cisplatin that are capable of inhibiting abnormal cell proliferation. Cancer is a generic name for a wide range of cellular malignancies characterized by unregulated growth, lack of differentiation, and the ability to invade local tissues and metastasize. These neoplastic malignancies affect, with various degrees of prevalence, every tissue and organ in the body. A multitude of therapeutic agents have been developed over the past few decades for the treatment of various types of cancer. The most commonly used types of anticancer agents include: DNA-alkylating agents (e.g., cyclophosphamide, ifosfamide), antimetabolites (e.g., methotrexate, a folate antagonist, and 5-fluorouracil, a pyrimidine antagonist), microtubule disrupters (e.g., vincristine, vinblastine, paclitaxel), DNA intercalators (e.g., doxorubicin, daunomycin, cisplatin), and hormone therapy (e.g., tamoxifen, flutamide). The ideal antineoplastic drug would kill cancer cells selectively, with a wide therapeutic index relative to its toxicity towards non-malignant cells. It would also retain its efficacy against malignant cells, even after prolonged exposure to the drug. Unfortunately, none of the current chemotherapies possess an ideal profile. Most possess very narrow therapeutic indexes and, in practically every instance, cancerous cells exposed to slightly sublethal concentrations of a chemotherapeutic agent will develop resistance to such an agent, and quite often cross-resistance to several other antineoplastic agents. The development of new anticancer agents has given rise to new treatment regimens and new combinations that are proving more effective in combating this disease. Web site: http://www.delphion.com/details?pn=US06355628__
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Diagnostic reagents for renal function disorders and method for analyzing urine samples Inventor(s): Aoyagi; Kazumasa (Ibaraki, JP), Koiso; Kenkiti (Ibaraki, JP), Nakajima; Motoo (Chiba, JP) Assignee(s): Kikkoman Corporation (Noda, JP) Patent Number: 6,569,637 Date filed: October 15, 1999 Abstract: The present invention aims at providing a reagent and a method for simply, rapidly, and accurately diagnosing renal dysfunction.According to the present invention, free ATP in a urine sample from a patient suffering from renal dysfunction is determined by a bioluminescent technique using luciferin and luciferase. By determining the value, it is possible to simply, rapidly, and accurately diagnose common renal dysfunction. Moreover, according to the present invention, it is possible
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to avoid renal dysfunction caused by side-effects of drugs, by collecting daily the urine of a patient who has been administered with carcinostatic that is toxic to kidney such as cisplatin or methotrexate, and analyzing the changes in the ATP level in the urine sample by a bioluminescent technique, thereby detecting hypersensitivity of the patient caused by such drug or by an excessive administration of such drug, or thereby determining an optimal dose (a maximum acceptable dose) of such drug. Excerpt(s): The present invention relates to a reagent for diagnosing renal dysfunction, which contains luciferin and luciferase. The present invention also relates to a method for analyzing a urine sample, which is useful to diagnose renal dysfunction and to determine an optimal dose of a nephrotoxic drug, the method including determining free adenosine 5'-triphosphate (hereinafter, referred to as "ATP") in the urine sample by a bioluminescence technique using the above-mentioned diagnostic reagent. As a conventional method for diagnosing renal dysfunction, for example, the following methods are known: a method in which urea in a blood sample is determined (JP-B-6147382); a method in which creatinine in a blood sample is determined (JP-B-60-38666); and a method in which albumin and an albumin degradation substance in a urine sample are determined (JP-A-5-302922). Although numbers of methods are known for diagnosing renal dysfunction by determining components in a urine or a blood sample, such methods are disadvantageous in that they take time to obtain the results of the determination. Web site: http://www.delphion.com/details?pn=US06569637__ •
Drug mitochondrial targeting agents Inventor(s): Steliou; Kosta (Boston University Department of Chemistry 590 Commonwealth Ave., Boston, MA 02215) Assignee(s): none reported Patent Number: 6,316,652 Date filed: June 6, 1995 Abstract: The invention relates to novel targeting drug agents that are targeted for entry into the mitochondria. More specifically, the agents are cisplatin derivatives called mitoplatins which are useful as anti-tumor agents. Mitoplatins are named for their targeting to the mitochondrial DNA via the carnitine-acylcarnitine translocase system. The invention also relates to methods of synthesizing mitoplatins, compositions of matter containing mitoplatins and methods of using the mitoplatins. Excerpt(s): The present invention relates to novel drug targeting agents. More particularly, the invention relates to drug agents having a unique targetor which affords the agents access to mitochondria via the acylcarnitine translocase system. These novel drug targeting agents are useful in the treatment of cancer, arthritis, skin, metabolic (i.e. diabetes), immunological (i.e. AIDS, tissue rejection) and neurodegenerative disorders (i.e. dementia, Alzheimer's disease). The agents also have useful diagnostic and monitoring applications. Transport of exogenous substances such as therapeutic or diagnostic agents across cell membranes into mitochondria is highly selective and tightly controlled by two separate membrane barriers. Access to mitochondria is achieved through the acylcarnitine translocase system. L-Carnitine (.gamma.-amino-(R).beta.-hydroxybutyric acid trimethylbetaine), acting in concert with mitochondrial acyltransferases, CPT.sub.o and CPT.sub.i, and an enzyme known as the carnitine acylcarnitine translocase, facilitates transport of fatty acids through the inner membrane
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of the mitochondria and into the matrix where the energy yielding fatty acid.beta.oxidation, as well as ketone body synthesis takes place. Consequently, L-camnitine is an essential natural compound and is found in both plant and animal tissues. Though there is a propensity in vertebrates for L-carnitine to concentrate in heart and muscle tissue, both of which depend heavily on fatty acid oxidation for the production of energy, carnitine also concentrates 10 to 100 fold higher in the liver, kidney, brain, testes and epididymis than in plasma. Thus, a variety of diseases can be targeted with a caritine delivery system. Web site: http://www.delphion.com/details?pn=US06316652__ •
Fine cisplatin powder and process for the production thereof Inventor(s): Ishikawa; Keizou (Saitama, JP), Iwata; Kenji (Saitama, JP), Kogawa; Osamu (Chiba, JP), Murata; Toshitaka (Saitama, JP) Assignee(s): Nippon Kayaku Kabushiki Kaisha (Tokyo, JP) Patent Number: 6,251,355 Date filed: June 10, 1999 Abstract: The present invention relates to a novel fine cisplatin powder utilized as an anticancer agent. The fine cisplatin powder obtained in the present invention does not cause secondary agglomeration, is excellent in fluidity and easily handleable in the pharmaceutical preparation step. Furthermore, the fine cisplatin powder is reduced in the content of N,N-dimethylformamide as the residual solvent, and can be dissolved rapidly in physiological saline, thus being suitable for cancer therapy particularly by intra-arterial injection. This fine powder can be produced by contriving specified means for crystallizing cisplatin from a solution thereof in N,N-dimethylformamide. Excerpt(s): The present invention relates to a fine cisplatin powder which can be used in cancer therapy particularly by hepatic intra-arterial injection etc. Cisplatin whose antitumor effect was reported in 1969 by Rosenberg (Nature, 222, 385 (1969)) is a typical drug of an antitumor platinum complex developed as an anticancer agent and has an effect on a wide range of cancers such as bladder cancer, testicular tumor, esophageal carcinoma, ovarian cancer, lung cancer etc. Cisplatin is a yellow, odorless crystalline powder and is manufactured into a pharmaceutical preparation in the dosage form of solution mainly as an injection for intravenous infusion. As cancer therapy is developed, the method of using an anticancer agent becomes diversified. It is said that hepatic carcinoma is a hardly remediable cancer, and that hepatic arterial embolization therapy, chemotherapy such as hepatic intra-arterial injection chemotherapy, general administration chemotherapy etc. plays a certain role for multidisciplinary treatment. In particular, hepatic intra-arterial injection chemotherapy which permits a drug to reach cancer tissues at high concentration is effective. Cisplatin is recognized as a highly effective anticancer agent, and is also expected to use for treatment of hepatic carcinoma. However, the solubility of cisplatin in water is as extremely low as about 1 mg/ml at room temperature, so a commercial injection thereof (0.5 mg/ml) is a dilute solution, thus disadvantageously requiring a too much volume for hepatic intra-arterial injection. Hence, a highly convenient powdered preparation capable of forming a solution at high concentration and usable in hepatic intra-arterial injection chemotherapy has been desired. Web site: http://www.delphion.com/details?pn=US06251355__
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Liposomes containing a cisplatin compound Inventor(s): Abra; Robert M. (San Francisco, CA), Reis; Karen (San Jose, CA) Assignee(s): Sequus Pharmaceuticals, Inc. (Menlo Park, CA) Patent Number: 5,945,122 Date filed: August 22, 1997 Abstract: A liposome composition containing an entrapped cisplatin compound is described. The liposomes have a surface coating of hydrophilic polymer chains on inner and outer surfaces and an entrapped cisplatin compound. The compound is entrapped with substantially greater retention in the liposomes, when compared to liposomes lacking the polymer coating. A method of preparing the composition is also described. Excerpt(s): The present invention relates to a liposomal composition containing an entrapped cisplatin compound. Freise, J., et al., Arch. Int. Pharmacodyn. 258:180-192 (1982). Gondal, J. A., et al., Eur. J. Cancer 29A (11):1536-1542 (1993). Web site: http://www.delphion.com/details?pn=US05945122__
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Method of treating neoplastic cells with prostaglandin and radiation treatment or prostaglandin and platinum-based anti-tumor agents Inventor(s): Gattoni-Celli; Sebastiano (Mt. Pleasant, SC), Jenrette, III; Joseph M. (Charleston, SC), McClay; Edward F. (Folly Beach, SC) Assignee(s): Medical University of South Carolina (Charleston, SC) Patent Number: 5,877,215 Date filed: March 20, 1996 Abstract: The invention is directed to a method of increasing ionizing radiation's cytotoxic effects on a neoplasm in a subject by increasing the neoplasm's sensitivity to ionizing radiation, comprising administering a therapeutically effective amount of prostaglandin to the subject, and subjecting the neoplasm to a therapeutically effective amount of ionizing radiation, thereby increasing the cytotoxic effects of the ionizing radiation on the neoplasm. The invention is further directed to a method of reducing the therapeutically effective amount of ionizing radiation required to treat a neoplasm in a subject, compared to treating with ionizing radiation alone, comprising administering a therapeutically effective amount of prostaglandin to the subject, thereby reducing the therapeutically effective amount of ionizing radiation required to treat the neoplasm in the subject, compared to treating with ionizing radiation alone, and subjecting the neoplasm in the subject to the reduced therapeutically effective amount of ionizing radiation. The invention is also directed to a method of treating a neoplasm in a subject, comprising administering a therapeutically effective amount of prostaglandin and administering a therapeutically effective amount of cisplatin to the subject, wherein the therapeutically effective amount of the platinum-based anti-tumor agent is less than 60 mg/meter.sup.2. Excerpt(s): This invention relates generally to a method of treating neoplastic cells with prostaglandin. More particularly, a therapeutically effective amount of ionizing radiation required to treat a neoplasm in a subject can be reduced by administering prostaglandin to the subject. In another embodiment, the present invention relates to treating a neoplasm in a subject by administering to the neoplasm a therapeutically effective amount of prostaglandin and a therapeutically effective amount of cisplatin.
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Treatment of neoplasms often requires the use of ionizing radiation to kill or halt the growth of neoplastic cells. In that respect, ionizing radiation has proven valuable as a tool for clinical diagnosis and radiotherapy. Exposing a subject to ionizing radiation, however, has the inherent risk of injuring or killing surrounding normal cells, inducing mutations, or even producing latent cancers. Any technique for treating a neoplasm in a subject which can decrease the therapeutically effective dose of ionizing radiation necessary to treat the neoplastic cells will be important in order to reduce the chances of causing damage to the subject. The present invention provides such a method of reducing the effective dose of ionizing radiation necessary to treat a neoplasm by administering to the neoplastic cells a prostaglandin. In addition, in another embodiment of the invention, the use of prostaglandin provides for a reduction in the amount of a platinum-based anti-tumor agent to treat a neoplasm. In accordance with the purpose(s) of this invention, as embodied and broadly described herein, this invention, in one aspect relates to a method of treating a neoplasm in a subject, comprising administering a therapeutically effective amount of prostaglandin to the subject, and subjecting the neoplasm to a cytotoxic amount of ionizing radiation, thereby treating the neoplasm. Web site: http://www.delphion.com/details?pn=US05877215__ •
Method of treatment or inhibition of tumors using pyridyl-substituted metaldiphosphine complexes Inventor(s): Berners-Price; Susan Jane (Paddington, AU), Bowen; Richard John (Cleveland, AU), Parsons; Peter Gordon (St. Lucia, AU) Assignee(s): Griffith University (Queensland, AU) Patent Number: 6,159,957 Date filed: August 18, 1999 Abstract: A method of treatment or inhibition of tumors involves administering a compound to a subject. The compound is one in which one or more of the eight phenyl substituents in the compound [M(dppe).sub.2 ].sup.+, in which M is selected from Au(I), Ag(I) and Cu(I), is substituted by 2, 3, or 4 pyridyl substituents. The compound has antitumor activity and an octanol/water partition coefficient between 0.01 and 25.5. The compound has selective toxicity to cancer cells, including cisplatin resistant human carcinoma cells lines. Excerpt(s): This invention relates to metal complexes of aryl phosphines and processes for their preparation. Although platinum anti-cancer drugs are currently the only metal compounds in clinical use for cancer chemotherapy, many other metal complexes have shown high antitumour activity in animal models. There is great scope for the design of metal antitumour drugs that may be less toxic and more effective than platinum complexes. Previous work contributed to the identification of certain metal disphosphine complexes as a potential new class of anti-cancer agents. In particular, the Au(I) complex [Au(dppe).sub.2 ]Cl (where dppe is 1,2-bis(diphenylphosphino)ethane) showed good antitumour activity against a range of tumour models in mice as disclosed in Berners-Price et al., 1986, Cancer Research 46 5486-5493. Structure activity relationships have been evaluated for a wide range of disphosphine ligands and their metal complexes as disclosed in Berners-Price et al., 1988, Structure Bonding (Berlin) 70 27-102. For complexes of the type [Au(R.sub.2 P(CH.sub.2).sub.n PR'.sub.2).sub.2 ]X highest activity was found where R=R'=phenyl and n=2,3 or the cis-CH.dbd.CH analogue. In general, activity was reduced, or lost altogether when the phenyl
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substituents on the phosphine were replaced by other substituents, but retained when Au(I) is substituted by Ag(I) or Cu(I). Dppe complexes of other metals (e.g. Pt(II) and Pd(II)) were found to be less active than the phosphine alone as shown in Khohkar et al., 1990, Inorg. Biochem. 39 117 and Mirabelli et al., 1987, J. Med. Chem. 30 2181. Since the tetrahedral complexes of the Group 11 metal ions have kinetically labile M-P bonds it is possible that the metal acts as a delivery system for the cytotoxic disphosphines. The mechanism of the cytotoxic activity is, however, still unknown, although the available evidence indicates that the primary cytotoxic lesion may arise from damage to nuclear chromatin. [Au(dppe).sub.2 ].sup.+ produced DNA-single strand breaks and DNAprotein crosslinks in tumour cells, with the latter being the critical lesions at low concentrations (Berners-Price et al., (1986) above). Web site: http://www.delphion.com/details?pn=US06159957__ •
Methods for identifying cisplatin resistant tumor cells Inventor(s): Yokoyama; Shiro (1-17-7, Miwamidoriyama, Machida-City, Tokyo 195, JP) Assignee(s): none reported Patent Number: 5,846,725 Date filed: May 8, 1997 Abstract: Isolated nucleic acids which can confer on a cell at least a 5-fold increase in cisplatin resistance relative to a cisplatin sensitive cell are disclosed. The nucleic acids of the invention can further confer on a cell resistance to heavy metals such as cadmium and copper. Isolated proteins encoded by the nucleic acids of the invention are also disclosed. The isolated nucleic acids and proteins of the invention are useful for conferring cisplatin resistance on a cell, for example non-malignant cells in a tumor bearing subject being treated with cisplatin. Alternatively, the cisplatin resistance of a cell can be inhibited by contacting the cell with an agent which inhibits the activity of the protein of the invention, for example to reverse the cisplatin resistance of a tumor cell. The invention also discloses methods for identifying substances which inhibit cisplatin resistance in a cell or which are chemosensitizers of cisplatin. The invention further discloses methods for identifying cisplatin resistant tumor cells using the nucleic acids and proteins of the invention. Excerpt(s): The chemotherapeutic drug cisplatin (cis-diamminedichloroplatinum or CDDP) was discovered to have cytotoxic properties in 1968 and is used extensively worldwide in the treatment of many tumors, in particular solid tumors such as ovarian cancer, testicular cancer and head and neck cancers. This platinum drug is thought to act by platination of DNA, thereby crosslinking DNA (both interstrand and intrastrand) and disrupting cellular processes. The clinical effectiveness of cisplatin is limited by the occurrence of cisplatin-resistant cancer cells. Certain tumors exhibit intrinsic or natural resistance to cisplatin and undergo no regression even upon initial chemotherapeutic treatment. Other tumors respond well to initial treatment but upon relapse exhibit reduced responsiveness to the drug. This type of resistance, which occurs after a course of therapy with cisplatin, is termed acquired resistance. The ability to prevent, overcome or reverse cisplatin resistance would be of great benefit to the treatment of malignant diseases. Attempts have been made to identify the mechanism of cisplatin resistance but this mechanism remains to be elucidated. In various studies, cisplatin resistance has been associated with reduced intracellular accumulation of the drug, increased DNA repair function and/or increased drug detoxification by intracellular thiols (for reviews of possible mechanim of cisplatin resistance see e.g. Andrews, P. A.
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and Howell, S. B. (1990) Cancer Cells 2:35-43; Kelley, S. L. and Rozencweig, M. (1989) Eur. J Clin. Oncol. 25:1135-1140; Perez, R. P. et al. (1990) Pharmacol. Ther. 48:19-27; and Timmer-Bosscha, H. et al. (1992) Br. J Cancer 66:227-238). A role for drug detoxification by intracellular thiols has been postulated due to an association of cisplatin resistance in certain cancer cell lines with increased levels of glutathione and metallothionein (see e.g. Godwin, A. K. et al. (1992) Proc. Natl. Acad. Sci. USA 89:3070-3074; and Kelley, S. L. et al. (1988) Science 241:1813-1815). Attempts have also been made to implicate particular genes with acquisition of a cisplatin resistant phenotype. For example, glutathione-Stransferase (GST) and metallothionein genes have been transfected into cell lines to try to confer cisplatin resistance on the cells. GST has been reported to confer cisplatin resistance on cells but the level of increased resistance was only in the range of 1.5 to 3.0 fold (see e.g. Miyazaki, M. et al. (1990) Biochem. Biophys. Res. Commun. 166:1358-1364; and Puchalski, R. B. et al. (1990) Proc. Natl. Acad. Sci. USA 87:2443-2447). Another study has reported that transfection of cells with a metallothionein gene can confer cisplatin resistance on cells but again the level of increased resistance was less than 5-fold (see Kelley, S. L. et al. (1988) Science 241:1813-1815) and other studies found no increase in cisplatin resistance upon transfection of cells with the metallothionein gene (see Morton, K. A. et al. (1993) J. Pharmacol. Exp. Ther. 267:697-702; and Koropatnick, J. and Pearson, J. (1993) Molec. Pharmacol. 44:44-50). In another study, cells transfected with the c-myc gene were reported to have acquired resistance to cisplatin but once again the level of increased resistance was very low (i.e., less than 3-fold). Web site: http://www.delphion.com/details?pn=US05846725__ •
Parenteral Cisplatin emulsion Inventor(s): Kocharekar; Shilpa Sudhakar (Thane, IN), Pai; Srikanth Annappa (Thane, IN), Rivankar; Sangeeta Hanurmesh (Thane, IN) Assignee(s): Vinod; Daftary Gautam (State of Maharashtra, IN) Patent Number: 6,572,884 Date filed: June 14, 2002 Abstract: A sterile pharmaceutical cisplatin composition as an oil-in-water emulsion having low toxicity for parenteral administration comprising:a) an oily phase selected from the group consisting of: vegetable oils, esters of medium or long chain fatty acids, and fractionated or modified oils;b) cisplatin incorporated in the oily phase;c) an emulsifier selected from the group consisting of: natural phosphatides; modified phosphatides, and synthetic non-ionic surfactants;d) a tonicity modifying agent selected from the group of compounds consisting of: glycerin, mannitol, and dextrose;e) a chelating agent selected from the group of compounds consisting of: edetates, and desferrioxamine mesylate; andf) water. Excerpt(s): The present invention is related to Cisplatin emulsion formulation with reduced toxicity, which is suitable for parenteral administration. Cisplatin-cis-diaminodichloroplatinum (CDDP) is a heavy metal complex containing a central atom of platinum surrounded by two chlorine atoms and two ammonium molecules in cis position. It is a potent anticancer drug used in the treatment of various solid tumors particularly of testes, ovaries and bladder. Cisplatin covalently binds to DNA bases and disrupts DNA function. Cisplatin is inactivated intracellularly and in the blood stream by sulfhydryl groups. U.S. Pat. No. 4,302,446 (1981) and U.S. Pat. No. 4,322,391 (1982) patents describe preparation of cisplatin in microcrystalline form for ready solubility. U.S. Pat. No. 4,310,515 (1982) patent describes the method for preparing sterile aqueous
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solution of cisplatin. U.S. Pat. No. 4,915,956 (1990) patent also describes similar method for preparing sterile aqueous solution of cisplatin. Web site: http://www.delphion.com/details?pn=US06572884__ •
Pharmaceutical composition comprised of cisplatin, and processes for making and using same Inventor(s): Shaw; Jiajiu (Ann Arbor, MI) Assignee(s): Unitech Pharmaceuticals, Inc. (Ann Arbor, MI) Patent Number: 6,001,817 Date filed: January 12, 1998 Abstract: A pharmaceutical composition, comprising cisplatin, a special carrier and, optionally, customary pharmaceutical excipients, is disclosed. The preparation of this pharmaceutical composition is also disclosed. The composition may be used to treat cancer and Acquired Immune Deficiency Syndrome (AIDS). Excerpt(s): Cisplatin (cis-diamminedichloroplatinum, cis-Pt(NH.sub.3).sub.2 Cl.sub.2, molecular weight 300.05) has been used as a chemotherapeutic agent for many years since the discovery of its anti-tumor activity by B. Rosenberg et al. (Nature, 1965, 205, 698;Nature, 1972, 222, 385). After so many years, cisplatin is still being widely used because of its efficacy. It has been used to treat cancer patients for head, neck, ovarian cancer, etc. However, its major drawback, the toxicity, is still a big concern. Many attempts have been made to modify the cisplatin molecule in order to reduce its toxicity; many other attempts have been made to understand the interaction between cisplatin and DNA, which is the ultimate target of cisplatin. A few attempts have also been made to modify the composition of cisplatin dosage form to reduce its toxicity or improve its efficacy. Web site: http://www.delphion.com/details?pn=US06001817__
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Photo-potentiation of cisplatin chemotherapy Inventor(s): Kane; Stefanie A. (Schwenksville, PA), Lippard; Stephen J. (Cambridge, MA) Assignee(s): Massachusetts Institute of Technology (Cambridge, MA) Patent Number: 6,030,783 Date filed: January 28, 1998 Abstract: Methods disclosed herein capitalize on the discovery that DNA Structure Specific Recognition Proteins (SSRPs) can be induced to bind covalently to genomic lesions formed by chemotherapeutic agents, particularly cisplatin-type agents, by photoirradiation with ultraviolet light. Methods and compositions based on this discovery are provided for sensitizing particular eukaryotic cells to killing by chemotherapeutic agents, particularly cisplatin-type drugs. Methods and compositions also are provided for potentiating cytotoxicity of a chemotherapeutic agent, particularly a cisplatin-type agent. Excerpt(s): The present invention relates generally to novel chemotherapeutic methods for cancer management. Cancer chemotherapy is based on the use of drugs that are
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selectively toxic (cytotoxic) to cancer cells (also referred to herein as tumorigenic cells, transformed cells or neoplastic cells). Harrison's Principles of Internal Medicine, Part 11 Hematology and Oncology, Ch. 296, 297 and 300-308 (12th ed. 1991). A preferred class of chemotherapeutic drugs inflict damage on cellular DNA. Drugs of these classes generally are referred to as genotoxic. Two widely used genotoxic anticancer drugs are cisplatin [cis-diamminedichloroplatinum(II)] and carboplatin [diaminine(1,1cyclobutane dicarboxylato)platinum(II)]. Bruhn et al. (1990), 38 Prog. Inorg. Chem. 477, Burnouf et al. (1987), 84 Proc. Natl. Acad. Sci. USA 3758, Sorenson and Eastman (1987), 48 Cancer Res. 4484 and 6703, Pinto and Lippard (1985), 82 Proc. Natl. Acad. Sci., USA 4616, Lim and Martini (1984), 38 J. Inorg. Nucl. Chem. 119, Lee and Martin (1976), 17 Inorg. Chim. Acta 105, Harder and Rosenberg (1970), 6 Int. J. Cancer 207, Howle and Gale (1970), 19 Biochem. Pharmacol 2757. Cisplatin and/or carboplatin currently are used in the treatment of selected, diverse neoplasms of epithelial and mesenchymal origin, including carcinomas and sarcomas of the respiratory, gastrointestinal and reproductive tracts, of the central nervous system, and of squamous origin in the head and neck. Harrison's Principles of Internal Medicine (12th ed. 1991) at Ch. 301. Cisplatin currently is preferred for the management of testicular carcinoma, and in many instances produces a lasting remission. Loehrer and Einhorn (1984), 100 Ann. Int. Med. 704. Susceptibility of an individual neoplasm to a desired chemotherapeutic drug or combination thereof often, however, can be accurately assessed only after a trial period of treatment. The time invested in an unsuccessful trial period poses a significant risk in the clinical management of aggressive malignancies. The rate of cellular repair of genotoxin-induced DNA damage, as well as the rate of cell growth via the cell division cycle, affects the effectiveness of genotoxin therapy. Unrepaired lesions in a cell's genome can impede DNA replication, impair the replication fidelity of newly synthesized DNA or hinder the expression of genes needed for cell survival. Thus, one determinant of a genotoxic agent's cytotoxicity (propensity for contributing to cell death) is the resistance of genomic lesions formed therefrom to cellular repair. Genotoxic agents that form persistent genomic lesions, e.g., lesions that remain in the genome at least until the cell commits to the cell cycle, generally are more effective cytotoxins than agents that form transient, easily repaired genomic lesions. Hence, genotoxic agents that form persistent genomic lesions are preferred for use as chemotherapeutic agents in the clinical management of cancer. Web site: http://www.delphion.com/details?pn=US06030783__ •
Process and composition for therapeutic cisplatin (CDDP) Inventor(s): Jones; Richard E. (Palo Alto, CA), Maskiewicz; Richard (Sunnyvale, CA), Roskos; Kathleen V. (Los Altos Hills, CA) Assignee(s): Matrix Pharmaceuticals, Inc. (Fremont, CA) Patent Number: 6,077,545 Date filed: October 30, 1995 Abstract: An improved diluent for the preparation of cisplatin suspensions from a lyophilized powder is provided. The diluent contains a pharmaceutically acceptable nonionic surfactant, which improves the accuracy and homogeneity of the therapeutic formulation. The suspension may be used directly, or may be used in preparing gel formulations for direct injection into a neoplastic lesion or surrounding tissue. Excerpt(s): The field of this invention is preparation of injectable cisplatin (cisdiamminedichloroplatinum, CDDP) compositions. Cisplafin (cis-
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diamminedichloroplatinum, CDDP) is an antineoplastic drug that has been used in cancer chemotherapy for a number of years. It is typically administered intravenously as an aqueous solution, either as a bolus injection or via infusion over a number of hours. It has been marketed both as a lyophilized powder for reconstitution into an aqueous solution, or as a ready-to-use aqueous solution. Intravenous delivery typically requires an aqueous solution, or, in some cases, a liquid emulsion or liposome system, wherein solid particulates which may occlude vessels and capillaries are absent. The concentration of CDDP in such intravenously injectable solutions is limited by its solubility in water, on the order of 1 mg/ml. Cisplatin has also been administered in various forms for locoregional delivery, such as administration to the liver via infusion into the hepatic artery. In these cases, the drug can be administered in solution or emulsion forms above (for example, see Campbell et al. (1983) J. Clin. Oncol. 1:755-762). It can also be administered along with materials intended to bring about embolization in the target organ, thus blocking blood flow through that organ, inhibiting clearance of the CDDP away from the target organ. The cisplatin in these cases is typically in solution in water, but also may be combined with other nonaqueous materials such as iodized oil (Lipiodol; for example, see Araki et al. (1989) Gastrointest. Radiol. 14:46-48 or Feun et al. (1994) Am. J. Clin. Oncol. 17:405-410) or polyvinyl alcohol particles (Mavligit et al. (1993) Cancer 72:375-380). Unfortunately, this procedure is often associated with significant toxicity and morbidity to the patient, due to the blockage of blood flow to normal parts of the liver. Web site: http://www.delphion.com/details?pn=US06077545__ •
Radioactive cisplatin in the treatment of cancer Inventor(s): Order; Stanley E. (Old Westbury, NY) Assignee(s): Molecular Radiation Management, Inc. (Garden City, NJ) Patent Number: 6,074,626 Date filed: March 19, 1999 Abstract: Background: Between 1991 and 1997 sixty-seven patients with non-resectable hepatoma were treated with hepatic artery infusions (HAI) of cisplatinum. Patients were divided into groups for analysis based on alpha-fetoprotein elevation (AFP+) or no elevation (AFP-), hepatitis B/C status, the presence or absence of extra-hepatic metastases and primary treatment at our facility or initial therapy elsewhere.Methods: Forty-four patients received an initial course of 21-24 Gy whole liver external radiation with cisplatinum 50 mg/m.sup.2 IV on days 1 and 8 of radiation. Twenty-three patients did not receive external radiation and received HAI cisplatinum only. All patients were then treated with HAI cisplatinum at 50 mg/m.sup.2 on a monthly basis. The rationale for the advantage to HAI cisplatinum was evaluated by giving a tracer dose of radioactive.sup.195m cisplatinum for quantitative determinations by the intra-arterial route in six patients.Results: A 50% overall response rate was seen, as judged by a 50% reduction in tumor diameter or a 50% reduction in AFP titer. Monthly HAI cisplatinum at 50 mg/m.sup.2 was well tolerated and could be repeated indefinitely without significant toxicity. Median survival for primarily treated non-resectable hepatomas AFP(+) and AFP(-) was 12 months and 17.5 months, respectively. Statistical analysis of all patients AFP(+) versus AFP(-) revealed a log rank statistical difference in survival of P=0.007. For patients with hepatitis B or C median survival was 10.7 months regardless of AFP status. Radioactive cisplatinum given by hepatic arterial infusion provided 3455% tumor uptake of cisplatinum.Conclusions: Intra-arterial delivery of 50 mg/m.sup.2
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cisplatinum on a monthly basis is a well-tolerated regimen for patients with nonresectable hepatoma. These data suggest a baseline chemotherapy regimen against which randomized trials could be evaluated. Further, the selective uptake of cisplatinum delivered intra-arterially suggests other selective intra-arterial protocols would be of use in regional cancers treated with cisplatinum.Keywords: Hepatoma, hepatocellular, carcinoma, cisplatin, cisplatinum,.sup.195m cisplatinum, radioisotopes, intra-arterial. Excerpt(s): Hepatocellular cancer that is non-resectable has had a median survival of six months when treated. A variety of chemotherapeutic agents have been given intravenously, with less-than-realistic results. During the course of investigations in hepatocellular cancer, I surprisingly discovered that intra-arterial cisplatin at 50 mg./m.sup.2 caused a 50% remission in 28 patients; and, recently, in 67 patients, a 50% response. Thus, 95 patients have had a 50% remission, with median survival extended one year to 46 months depending on the classification of the tumor. In addition to these findings, the median survival rate for the worst group of hepatomas (AFP+positive) was one year greater than the six months reported from the other therapeutic regimens. In order to discern why intra-arterial cisplatin was superior to intravenous, I created 195.sup.m cisplatin, and studied the same patient intravenously and intra-arterially. When the drug was given intravenously, less than five percent deposited in the tumor. When the drug was given intra-arterially, 35 to 40 percent of the drug deposited in the tumor, as witnessed by scintigraphic scans. The cisplatin that binds on the hepatoma apparently stays there for a persistent period of time and interrupts DNA metabolism. The use of intravenous cisplatin has had less than a five-percent response rate, and the arterial route is 50 percent or greater. Having studied the diagnostic distribution of 195.sup.m cisplatin, I realized that the possibility of treating cancer with a radioactive cisplatin exists. Web site: http://www.delphion.com/details?pn=US06074626__ •
Sterile aqueous parenteral formulations of cis-diammine dichloro platinum Inventor(s): Haridas; Kochat (San Antonio, TX), Hausheer; Frederick H. (San Antonio, TX), Murali; Dhanabalan (San Antonio, TX), Reddy; Dasharatha Gauravaram (San Antonio, TX), Seetharamulu; Peddaiahgari (San Antonio, TX) Assignee(s): Bionumerik Pharmaceuticals, Inc. (San Antonio, TX) Patent Number: 5,789,000 Date filed: November 14, 1994 Abstract: This invention describes a novel formulation containing both cis-diammine dichloro platinum and a water soluble disulfide, 2,2'-dithio-bis-ethane sulfonate in the same solution, wherein the presence of the disulfide and the parenteral administration of the formulation reduces the risk of cisplatin induced nephrotoxicity when treating human patients with cancer. Excerpt(s): This invention describes a novel aqueous formulation and methods of use thereof, of cis-diammine dichloro platinum and a water soluble disulfide, 2,2'-dithio-bisethane sulfonate and wherein the cis-diammine dichloro platinum and 2,2'-dithio-bisethane sulfonate are administered simultaneously to reduce the risk of cisplatin induced nephrotoxicity when treating human patients with cancer. The use of cytotoxic anticancer drugs pose an increased risk of certain untoward side effects in human subjects undergoing cancer treatment. Drug toxicity associated with the use of anticancer drugs greatly limits their clinical utility and safety in human subjects. For
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example, drug induced impairment of cellular and/or organ functions may result in organ-specific toxicities in human subjects being treated for cancer. Additionally, the drugs themselves or their metabolites may accumulate or damage certain cellular components or impair certain biochemical reactions in specific organs. The toxicities observed due to the administration of anticancer drugs are usually dose dependent (e.g., busulfan induced myelosuppression), are often related to cumulative dosages administered (e.g., BCNU induced pulmonary toxicity; anthracycline induced cardiac toxicity), and idiosyncratic drug toxicities are noted with some frequency with certain anticancer drugs (e.g., mitomycin-C induced hemolytic uremic syndrome). By impairing or damaging normal cellular function in specific organs the anticancer drug is causally connected with the drug-induced organ damage. As a result of drug induced toxicity associated with the administration of anticancer drugs to humans, clinicians attempt to prevent or reduce the risk of drug toxicity by certain pharmacologic maneuvers. Such clinical maneuvers can impose risk of additional side effects, or result in a dose reduction of the anticancer drug which in turn may adversely affect the likelihood of achieving control of the patient's tumor. If the major dose-limiting organ toxicity of a particular anticancer drug is eliminated or substantially reduced, the result is that the safety and efficacy of the primary anticancer drug is greatly increased. A significant reduction in drug toxicity in cancer treatment generally results in greater ability to administer higher doses of the drug, prevents or reduces the number of treatment delays, and increases the safety and the quality of life for patients. An example of this approach is the use of G-CSF to reduce the duration and magnitude of drug induced myelosuppression resulting from the administration of several different types of anticancer drugs. Therefore, an important area of drug research and treatment is aimed at developing new methods to prevent or reduce drug induced dose limiting toxicities in human cancer patients. Web site: http://www.delphion.com/details?pn=US05789000__ •
Therapeutic use of d-methionine to reduce the toxicity of platinum-containing antitumor compounds Inventor(s): Campbell; Kathleen C. M. (Glenarm, IL) Assignee(s): Southern Illinois University School of Medicine (Springfield, IL) Patent Number: 6,187,817 Date filed: October 2, 1997 Abstract: Methods of preventing or reducing hearing or balance loss, damage to ear cells, weight loss, gastrointestinal toxicity, neurotoxicity, alopecia, and prolonging survival in patients undergoing treatment with therapeutically effective amounts of platinum-containing chemotherapeutic agents such as cisplatin are provided. These methods comprise administering an effective amount of a methionine protective agent, such as D-methionine, prior to, simultaneously with, or subsequently to administration of the platinum-containing chemotherapeutic agent. Combinations of these time periods can also be employed. Excerpt(s): The present invention relates to the use of protective agents in cancer chemotherapy in human and animal subjects. Protective agents are compounds that prevent, reduce, or otherwise ameliorate the toxic side effects of anti-cancer chemotherapeutic compounds in normal body cells while substantially preserving the anti-tumor properties of these compounds in vivo when administered prior to, concomitantly with, or subsequently to administration of such chemotherapeutic
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compounds. More specifically, the present invention relates to the use of D-methionine and structurally related compounds as protective agents having oto-protective, weight loss-protective, gastrointestinal-protective, neuro-protective, alopecia-protective, and survival-enhancing effects in conjunction with chemotherapy employing platinumcontaining antineoplastic agents, such as cisplatin. Cisplatin (cisdiamminedichloroplatinum(II); CDDP) is a widely used antineoplastic agent. Cisplatin administration has increased both in the variety of cancer types for which it is employed and in the amount used in a given individual to achieve maximal therapeutic effect (Blumenreich et al., 1985; Forastiere et al., 1987; Gandara et al., 1989). The toxic side effects of cisplatin have long been recognized and are widely reported (Lippman et al., 1973; also see the review by Hacker, 1991). These toxicities include a variety of peripheral neuropathies, myelo-suppression, gastrointestinal toxicity, nephrotoxicity, and ototoxicity (Ozols and Young, 1985; Stewart et al., 1987; Stoter et al., 1989). Initially, the primary dose-limiting factor was nephrotoxicity, but now the routine administration of mannitol, hypertonic saline, and high fluid administration have ameliorated, but not eliminated, that side effect. However, ototoxicity remains uncontrolled (Bajorin et al., 1987; Fillastre and Raguenez-Viotte, 1989). Although nephrotoxicity can still be doselimiting, currently the primary dose-limiting factor is ototoxicity (Blumenreich et al., 1985; Forastiere et al., 1987; Berry et al., 1990). Web site: http://www.delphion.com/details?pn=US06187817__ •
Treatment of carcinomas using squalamine in combination with other anti-cancer agents Inventor(s): Williams; Jon (Robbinsville, NJ), Zasloff; Michael (Merion Station, PA) Assignee(s): Magainin Pharmaceuticals (Plymouth Meeting, PA) Patent Number: 6,147,060 Date filed: April 25, 1997 Abstract: A method for treating a tumor includes a first treatment procedure using a conventional cancer treatment technique, and a second treatment procedure which includes administering an effective amount of squalamine. The first treatment procedure may be a treatment with one or more conventional cytotoxic chemical compounds. As examples, the cytotoxic chemical compound may be a nitrosourea (such as BCNU), cyclophosphamide, adriamycin, 5-fluorouracil, paclitaxel and its derivatives, cisplatin or other platinum containing cancer treating agents. The cytotoxic chemical compound and the squalamine may be administered by any suitable route. The first treatment procedure may take place prior to the second treatment procedure, after the second treatment procedure, or the two treatment procedures may take place simultaneously. In one example, the first treatment procedure (e.g., a one time intravenous dosage of BCNU) is completed before the second treatment procedure with squalamine begins. As an alternative, the first treatment procedure may be a conventional radiation treatment regimen. Excerpt(s): U.S. patent application Nos. 08/416,883 (filed Apr. 20, 1995) and 08/478,763 (filed Jun. 7, 1995) describe the use of squalamine as an antiangiogenic agent. These U.S. patent applications are entirely incorporated herein by reference. Additional uses of squalamine (e.g., as a sodium/proton exchanger (isoform 3), or NHE3, inhibiting agent and as an agent for inhibiting the growth of endothelial cells) and squalamine synthesis techniques are disclosed in U.S. patent application No. 08/474,799 (filed Jun. 7, 1995). This U.S. patent application also is entirely incorporated herein by reference. About
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50,000 new cases of CNS (central nervous system) tumors are diagnosed each year. Of these, about 35,000 are metastatic tumors (e.g., lung, breast, melanomas) and about 15,000 are primary tumors (mostly astrocytomas). Astrocytomas, along with other malignant gliomas (i.e., cancers of the brain), are the third leading cause of death from cancer in persons between the ages of 15 and 34. Treatment options for a patient with a CNS tumor are very limited. Currently, surgery is the treatment of choice. Surgery provides a definite diagnosis, relieves the mass bulkiness of the tumor, and extends survival of the patient. The only post-surgery adjuvant treatment which is known to work on CNS tumors is radiation, and it can prolong survival. Radiation treatment, however, has many undesirable side effects. It can damage the normal tissue of the patient, including the brain tissue. Radiation also can cause the patient to be sick (e.g., nausea) and/or to temporarily lose their hair. Web site: http://www.delphion.com/details?pn=US06147060__
Patent Applications on Cisplatin As of December 2000, U.S. patent applications are open to public viewing.9 Applications are patent requests which have yet to be granted. (The process to achieve a patent can take several years.) The following patent applications have been filed since December 2000 relating to cisplatin: •
Combination chemotherapy Inventor(s): Grove, William Richard; (Whitmore Lake, MI), Klohs, Wayne Daniel; (Ann Arbor, MI), Merriman, Ronald Lynn; (Ann Arbor, MI) Correspondence: Steven R. Eck; Warner-Lambert Company; 2800 Plymouth Road; Ann Arbor; MI; 48105; US Patent Application Number: 20030086965 Date filed: October 9, 2002 Abstract: Acetyldinaline in combination with gemcitabine, a pharmaceutically acceptable salt thereof, capecitabine, or cisplatin is synergistic for treating cancer. Excerpt(s): The invention concerns a method for treating tumors utilizing a combination of known oncolytic agents. The use of the agents together provides unexpectedly greater efficacy than employing the single agents alone. Cancer chemotherapy has advanced dramatically in recent years. Many tumors can be effectively treated utilizing compounds which are either naturally occurring products or synthetic agents. Cancer chemotherapy often entails use of a combination of agents, generally as a means of providing greater therapeutic effects and reducing the toxic effects that are often encountered with the individual agents when used alone. We have now discovered a unique combination of known oncolytic agents which exhibits a dramatic synergistic effect. The combination utilizes the agent acetyldinaline, together with either gemcitabine, capecitabine, or cisplatin. The combination is especially effective in treating patients with solid tumors, especially nonsmall cell lung cancer and other advanced solid tumors. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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This has been a common practice outside the United States prior to December 2000.
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Compositions and methods for chemotherapy having reduced nephrotoxicity Inventor(s): Baliga, Radhakrishna; (Madison, MS), Shah, Sudhir V.; (Little Rock, AR) Correspondence: Gilbreth & Associates, P.C.; P.O. Box 2428; Bellaire; TX; 77402-2428; US Patent Application Number: 20020183333 Date filed: March 19, 2002 Abstract: Compositions and methods for chemotherapy are disclosed. The compositions and methods disclose herein are effective inhibitors of chemotherapy-induced nephrotoxicity, yet unexpectedly do not inhibit the antineoplastic activity of the chemotherapeutic compound. The chemotherapeutic compositions and methods of the invention comprise an inhibitor of catalytic iron. In a preferred embodiment, the inhibitor is a cytochrome P450 inhibitor and the chemotherapeutic compound is cisplatin. Excerpt(s): The present invention is directed to compositions and methods wherein said compositions and methods comprise an agent that reduces chemotherapy-induced nephrotoxicity without reducing antineoplastic activity of the chemotherapy. The present invention is also directed to compositions and methods for chemotherapy comprising an agent selected from the group consisting of iron chelators, hydroxy radical scavengers and cytochrome P450 inhibitor, wherein said agent reduces chemotherapy-induced nephrotoxicity without reducing antineoplastic activity of the chemotherapy. Cisplatin (CP) is one of the most effective chemotherapeutic agents used in the treatment of a variety of human solid tumors (Rozencweig et al., 1997, Ann.Intern.Med.86:803-812). Unfortunately the efficacy of cisplatin is limited by the concomitant cisplatin-induced nephrotoxicity that develops at the S.sub.3 segment of the proximal tubule (Balchley and Hill, 1981, Ann.Intern.Med.95:628-632). Reactive oxygen metabolites (ROMs) have been implicated as the mediators of this renal injury (Sugihara and Gemba, 1986, Jpn.J.Pharmacol.40:353-355). Catalytic iron is believed to play an important role in the generation of ROMs via the metal-catalyzed Haber-Weiss reaction, and/or in the generation of the highly reactive iron-oxygen complexes such as ferryl or perferryl ions (Halliwell and Gutteridge, 1990, Meth.Enzym.186:1-85). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Device and methods for sequential, regional delivery of multiple cytotoxic agents and directed assembly of wound repair tissues Inventor(s): Brekke, John H.; (Duluth, MN), Gubbe, John H.; (Duluth, MN) Correspondence: Alan D. Kamrath; Rider Bennett, Llp; Suite 2000; 333 South Seventh Street; Minneapolis; MN; 55402; US Patent Application Number: 20040126426 Date filed: October 21, 2003 Abstract: An implantable delivery system includes a macrostructure formed of bioresorbable material selected from a group of alphahydroxy acids and defined to include an internal architecture of intercommunicating void spaces. A first cytotoxic agent in the preferred form of cisplatin is joined to the macrostructure during formation. A microstructure in the preferred form of a blend of high molecular weight hyaluronic acid conjugated with a second cytotoxic agent in the preferred form of paclitaxel and of pure high molecular weight hyaluronic acid is invested in the void
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spaces. Thus, when implanted, the paclitaxel and cisplatin are released sequentially, each initially at high level concentrations followed by lower release. Radiotherapy can be begun after the release of the paclitaxel has been completed but while the cisplatin is being released. Excerpt(s): The present invention generally relates to devices and methods for treatment of cancer and particularly breast cancer and specifically to devices and methods for the regional delivery of multiple cytotoxic agents in a programmable, sequential manner and for the directed assembly of wound repair tissues. Every adult is at risk for breast cancer. One in nine women who live to the age of 90 will be treated for breast cancer at some time in her life, and more than 180,000 women in the United States were diagnosed with the disease in 2000. Although breast cancer is rare in men, it does occur: an estimated 1,400 cases will be diagnosed in American men in the year 2002. In 1999, approximately 43,000 women died from the disease according to the American Cancer Society. Breast cancer is the most common form of cancer in women and ranks as the second leading cause of cancer deaths among women of all ages. Breast cancer is the number one cause of cancer death for women aged 29-59. Despite the development of innovative systemic medical therapies for the treatment of breast cancer, local disease control is still a problem. This is also true for other common malignancies such as prostatic carcinoma and colon cancer. Under most current systemic therapy protocols, chemotherapeutic drugs are given to patients systemically as an adjunct to the removal of malignant tumors. Even with preoperative and postoperative radiation therapy, local recurrences often develop. Because of the toxicity of the drugs, the attainable concentration of an active drug in the tumor after systemically-administered chemotherapy is, in part, restricted by the dose-limiting systemic toxicity tolerated by the body. Pre-operative high dose chemotherapy or radiation therapy can adversely affect normal tissue healing, add morbidity and expense and may allow primary tumors that are insensitive to preoperative treatment an opportunity to extend locally, to distant sites, or both. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Medicinal compositions for concomitant use as anticancer agent Inventor(s): Kai, Junko; (Ibaraki, JP), Ozawa, Yoichi; (Ibaraki, JP), Yoshimatsu, Kentaro; (Ibaraki, JP) Correspondence: Birch Stewart Kolasch & Birch; PO Box 747; Falls Church; VA; 220400747; US Patent Application Number: 20030215523 Date filed: May 8, 2003 Abstract: The present invention provides a medicinal composition having an excellent antitumor activity. That is, it provides a medicinal composition comprising a sulfonamide compound, a sulfonate compound or a salt of them, which is represented by the following formula: 1(wherein ring A represents an aromatic ring which may have a substituent group; ring B represents a 6-membered unsaturated hydrocarbon ring which may have a substituent group etc.; ring C represents a 5-membered hetero-ring containing one or two nitrogen atoms, and the ring C may have a substituent group; W represents a single bond or --CH.dbd.CH--; X represents --NH-- etc.; and Y represents a carbon atom or a nitrogen atom; and Z represents --NH-- etc.), particularly N-(3-chloro1H-indol-7-- yl)-4-sulfamoylbenzenesulfonamide or a salt thereof, combined with at least one substance selected from (1) irinotecan hydrochloride trihydrate; (2) mitomycin
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C; (3) 5-fluorouracil; (4) cisplatin; (5) gemcitabine hydrochloride; (6) doxorubicin; (7) taxol; (8) carboplatin; (9) oxaliplatin; (10) capecitabine; and (11) a salt of the abovementioned (1) to (10). Excerpt(s): The present invention relates to a novel medicinal composition comprising a compound useful as an anticancer drug, particularly N-(3-chloro-1H-indol-7-yl)-4sulfamoylbenzenesulfonamide or a pharmacologically acceptable salt thereof, combined with another anticancer agent. As chemicals used conventionally as chemotherapeutic drugs for cancers, there are a large number of chemicals such as cyclophosphamide as an alkylating agent, methotrexate and fluorouracil as antimetabolites, doxorubicin, mitomycin and bleomycin as antibiotics, vincristine and etoposide derived from plant, and cisplatin as a metal complex, but their antitumor effects are insufficient, so there is a demand for development of new antitumor agents. exhibits an activity on various types of tumors and is very useful. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Methods of treating cancer using a combination of drugs Inventor(s): Jolivet, Jacques; (Laval, CA) Correspondence: Millen, White, Zelano & Branigan, PC; 2200 Clarendon Blvd; Suite 1400; Arlington; VA; 22201; US Patent Application Number: 20030027799 Date filed: March 28, 2002 Abstract: The present invention provides a novel method for treating a patient with cancer comprising administering to the patient a therapeutically effective amount of cisplatin and a compound having the formula I: 1wherein B is cytosine or 5fluorocytosine and R is selected from the group comprising H, monophosphate, diphosphate, triphosphate, carbonyl substituted with a C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, and 2wherein each Rc is independently selected from the group comprising H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl and a hydroxy protecting group. Excerpt(s): This application claims the benefit of U.S. Provisional Application Serial No. 60/279,770 filed Mar. 30, 2001 which is hereby incorporated in its entirety. The present invention relates to pharmaceutical combinations and to methods useful in the treatment of cancer. Particularly, the combinations of this invention relate to dioxolane nucleosides in combination with cisplatin. Cancer is the second leading cause of death in the United States. It is estimated that cancer is responsible for 30% of all deaths in the Western world. Lung, colorectal, breast and prostate cancers are the four biggest killers. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Microgranules containing cisplatin Inventor(s): Debregeas, Patrice; (Paris, FR), Leduc, Gerard; (Malesherbes, FR), Oury, Pascal; (Paris, FR), Suplie, Pascal; (Montaure, FR) Correspondence: Foley And Lardner; Suite 500; 3000 K Street NW; Washington; DC; 20007; US Patent Application Number: 20030017210 Date filed: July 25, 2002 Abstract: The invention concerns an oral formulation of cisplatin, in the form of controlled-release microgranules, and its method of formulation by grossing in an aqueous medium. The invention also concerns a pharmaceutical preparation containing controlled-release cisplatin microgranules, optionally combined with an anticancer agent, to be used in anticancer therapy. The invention further provides a use for these microgranules for making orally administered medicaments for polychemotherapy or in combination with radiotherapy. Excerpt(s): The present invention relates to a cisplatin formulation for oral administration. Cisplatin is an anticancer agent known for its effectiveness but also for its significant side effects observed when it is administered intravenously, in particular: nephrotoxicity, gastrointestinal toxicity (nausea, vomiting), neurotoxicity and moderate myelo-suppression. The nephrotoxicity induced by cisplatin can be alleviated by intravenous saline hydration and by diuresis. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Platinum complexes as antitumor agents in combination with biochemical modulation Inventor(s): Khokhar, Abdul R.; (Houston, TX), Siddik, Zahid H.; (Houston, TX) Correspondence: Fulbright & Jaworski L.L.P.; 600 Congress AVE.; Suite 2400; Austin; TX; 78701; US Patent Application Number: 20040097423 Date filed: September 5, 2003 Abstract: The present invention concerns the use of methods and compositions for the treatment of cancer and other hyperproliferative diseases. In certain embodiments, methods are described for the treatment of cancer and/or hyperproliferative diseases by administration of compositions containing at least one platinum complex alone or in combination with a modulator of glutathione. In particular, the methods may be used to treat cisplatin or carboplatin resistant tumor cells. Excerpt(s): The present invention relates generally to the field of cancer therapy. More particularly, it concerns formulations and methods for the treatment of cancer patients using compositions including specific platinum complexes and/or inhibitors of glutathione (GSH) synthesis or activity, such as L-buthionine-sulfoximine (BSO). Cisplatin is one of the most effective and broadly used anticancer drugs. Apoptosis induced by cisplatin is generally considered to be mediated by the formation of covalent DNA adducts, which block replication and transcription. Cisplatin (cisdiamminedichloroplatinum) has been used as a chemotherapeutic agent for many years. Rosenberg et al., U.S. Pat. No. 4,177,263, describes methods of treating cancer using cisplatin and cisplatin analogs. The compounds were effective for treating leukemia
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and tumors induced in mice. Cisplatin and an analog, carboplatin, are now among the most widely used anticancer drugs. Platinum-based antitumor agents (e.g., cisplatin and carboplatin) play critical roles in the treatment of several cancers. One of the major limitations to these treatments is relapse in a majority of patients, which fail subsequent treatment with platinum agents due to drug resistant tumor cells. This limitation has resulted in an effort to identify platinum analogs that are effective against resistant tumors. Indeed several such analogs (e.g., oxaliplatin and JM216) have entered clinical trials. However, little or no knowledge of the effective mode of action of these analogs is known. Although reduced drug accumulation, increased intracellular glutathione, and increased DNA adduct repair are usually identified as key mechanisms of resistance for cisplatin, satisfactory explanations for reversal of resistance by analogs have not been provided. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Polymeric micelle containing cisplatin enclosed therein and use thereof Inventor(s): Kataoka, Kazunori; (Tokyo, JP), Nishiyama, Nobuhiro; (Tokyo, JP), Okano, Teruo; (Chiba-ken, JP), Yokoyama, Masayuki; (Chiba-shi, JP) Correspondence: Wenderoth, Lind & Ponack, L.L.P.; 2033 K Street N. W.; Suite 800; Washington; DC; 20006-1021; US Patent Application Number: 20030170201 Date filed: May 5, 2003 Abstract: A complex comprising cisplatin and a poly(ethylene glycol)/poly(glutamic acid) block copolymer, wherein the cisplatin is enclosed in the copolymer through ligand displacement in which a carboxyl anion of the copolymer is replaced with a chlorine ion of the cisplatin. This complex can give a medicine reduced in toxicity and usable by a new method of administration. Excerpt(s): The present invention relates to a complex of a copolymer (hereinafter abbreviated as PEG-P(Glu)) comprising a poly(ethylene glycol) segment (hereinafter abbreviated as PEG) and a poly(.alpha.-glutamic acid) segment (hereinafter abbreviated as P(Glu)) with cisplatin and a medicine comprising the above complex as an effective ingredient. Cisplatin (cis-Diaminedichloroplatinum (II); hereinafter abbreviated as CDDP) is a very effective carcinostatic agent in a medical practice, but it is known that it has very strong side effects such as nephrotoxicity. Further, when CDDP is administered in blood, it is quickly excreted to the outside of the body by glomerular filtration, and therefore the blood half-time thereof is very short. Accordingly, a lot of pharmaceutical preparations have so far been tried to be developed by many researchers in order to extend this blood half-time of CDDP and reduce nephrotoxicity, but the existing situation is that the successful examples thereof have not yet been achieved. Thus, it is the existing situation that in general, a suitable transfusion is administered before administering a CDDP agent and that CDDP is then mixed with a large amount of a physiological salt solution or a glucose-salt solution and it is intravenously dripped in several hours. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Prevention of cisplatin induced deafness Inventor(s): Ehrsson, Hans; (Stockholm, SE), Ekborn, Andreas; (Stockholm, SE), Laurell, Goran; (Stockholm, SE), Miller, Josef; (Ann Arbor, MI) Correspondence: Medlen & Carroll, Llp; Suite 350; 101 Howard Street; San Francisco; CA; 94105; US Patent Application Number: 20030180388 Date filed: January 16, 2003 Abstract: The present invention relates to compositions and methods for the protection and restoration of hearing. In particular, the present invention relates to methods and compositions for the prevention of chemical (e.g., cisplatin) induced deafness. The present invention thus provides methods of improving the outcome of subjects treated with cisplatin. Excerpt(s): This application claims priority to U.S. provisional patent application serial No. 60/349,801, filed Jan. 17, 2002 and U.S. provisional patent application serial No. 60/351,662, filed Jan. 25, 2002. The present invention relates to compositions and methods for the protection and restoration of hearing. In particular, the present invention relates to methods and compositions for the prevention of chemical (e.g., cisplatin) induced deafness. Hearing impairment is the United State's number one disability. It has been estimated to compromise the quality of life and communication in more than 30 million Americans, and approximately 1 billion individuals worldwide. With the increase in longevity in life and the association of hearing impairment with aging, this disability is increasing in incidence and prevalence. In children, it severely affects education and future employment opportunities. In a working individual, it compromises the quality of life, job satisfaction, and productivity; and in the elderly, it leads to isolation and increased medical costs. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Remedies for cisplatin-tolerant cancer Inventor(s): Fukushima, Shoji; (Hyogo-ken, JP), Kishimoto, Shuichi; (Hyogo-ken, JP), Takeuchi, Yoshikazu; (Hyogo-ken, JP) Correspondence: Birch Stewart Kolasch & Birch; PO Box 747; Falls Church; VA; 220400747; US Patent Application Number: 20030171430 Date filed: February 11, 2003 Abstract: Preparation of a lipophilic platinum complex being dissolved or suspended in an iodized poppyseed oil fatty acid ethyl ester is useful as an agent for treatment of cisplatin-resistant cancers. Excerpt(s): The present invention relates to a method for promoting the uptake of a platinum complex into cancer cells, which comprises administering a solution or suspension of a lipophilic platinum complex in an iodized poppyseed oil fatty acid ethyl ester, and further relates to an agent for treatment of cisplatin-resistant cancer which comprises as an active ingredient a lipophilic platinum complex being dissolved or suspended in an iodized poppyseed oil fatty acid ethyl ester. Cisplatin (CDDP) is a platinum complex having a wide anticancer spectrum and potent anti-tumor activity, and has contributed to the improvement of treatment results of various cancers as a key
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medicament in combination of multiple drugs for the treatment of solid cancers. However, cisplatin shows serious side effects such as serious nephrotoxic, nausea and vomiting, and further the existence of cancers being resistant against cisplatin becomes clinical problems for the treatment of cancers. Under these circumstances, it has been reported that a number of platinum complexes having 1,2-diaminocyclohexane (DACH) and 1,2-diaminocycloheptane as ligands do not show cross-resistance to cisplatinresistant L1210 murine leukemia cells, and maintain their anti-tumor activity (cf. Jpn. J. Cancer Chemother., 10, pp 2442-2451 (1983)). However, in the research thereafter, there are cases wherein certain cisplatin resistant cancer cells shows sensitivity to platinum complexes having DACH ligand, but other cisplatin-resistant cancer cells show crossresistance to the said platinum complexes having DACH ligand, or cases wherein certain cisplatin resistant cancer cells show sensitivity to certain platinum complexes but show cross-resistance to other platinum complexes (cf. Ann. Oncol., 2, 535-540 (1991); Cancer Research, 52, 5674-5680 (1992); ibid., 53, 4913-4919 (1993), etc.). The reasons therefor have been studied, and speculated to be due to the properties of each cell or the resistance mechanism thereof, but they have not been clarified yet. The mechanism of having resistance of cancer cells to platinum complexes such as cisplatin may be, for example, decrease in the uptake of platinum into cells, increase in glutathione and metallothionein level as intracellular detoxication, increase of DNA repair ability, increase of permissibility to DNA injury, etc. (cf., Biochem. Pharmacol., 30, 2721-2723 (1981); Br. J. Cancer, 54, 239-243 (1986); Cancer Lett., 31, 163-169 (1986); Biochem. Pharmacol., 52, 1855-1865 (1996)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Therapeutic use of methionine to reduce the toxicity of platinum-containing antitumor compounds Inventor(s): Campbell, Kathleen C.M.; (Glenarm, IL) Correspondence: Senniger Powers Leavitt And Roedel; One Metropolitan Square; 16th Floor; ST Louis; MO; 63102; US Patent Application Number: 20040110719 Date filed: October 27, 2003 Abstract: Methods of preventing or reducing ototoxicity in patients undergoing treatment with therapeutically effective amounts of platinum-containing chemotherapeutic agents such as cisplatin or aminoglycoside antibiotics are provided. The methods comprise administering an effective amount of an otoprotective agent comprising methionine or a methionine-like moiety to said patient prior to, simultaneously with, or subsequently to administration of the platinum-containing chemotherapeutic agent or aminoglycoside antibiotic. Combinations of these time periods can also be employed. Excerpt(s): This patent application is a continuation of pending U.S. patent application Ser. No. 09/911,195 filed Jul. 23, 2001, which is a continuation-in-part of U.S. patent application Ser. No. 09/057,065 filed Apr. 8, 1998 (issued as U.S. Pat. No. 6,265,386), which is a continuation-in-part of U.S. patent application Ser. No. 08/942,845 filed Oct. 2, 1997 (issued as U.S. Pat. No. 6,187,817), which claims priority from U.S. Provisional Application Serial No. 60/027,750 filed Oct. 3, 1996 (now abandoned). The entire texts of U.S. patent application Ser. Nos. 09/911,195, 09/057,065, 08/942,845, and U.S. Provisional Application Serial No. 60/027,750 are hereby incorporated herein by reference. The present invention relates to the use of protective agents in cancer
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chemotherapy in human and animal subjects. Protective agents are compounds that prevent, reduce, or otherwise ameliorate the toxic side effects of anti-cancer chemotherapeutic compounds in normal body cells while substantially preserving the anti-tumor properties of these compounds in vivo when administered prior to, concomitantly with, or subsequently to administration of such chemotherapeutic compounds. More specifically, the present invention relates to the use of D-methionine and structurally related compounds as protective agents having oto-protective, weight loss-protective, gastrointestinal-protective, neuro-protective, alopecia-protective, and survival-enhancing effects in conjunction with chemotherapy employing platinumcontaining anti-neoplastic agents, such as cisplatin. The present invention also relates to the use of D-methionine and structurally related compounds as protective agents having oto-protective effects against noise-induced, loop diuretic-induced, aminoglycoside antibiotic-induced, iron chelator-induced, quinine- and quinidine-induced, and radiation-induced hearing loss, as well as protective effects in ameliorating other radiation-induced side effects such as neural damage, alopecia, gastrointestinal disorders, and reduced patient survival. Cisplatin (cis-diamminedichloroplatinum(II); CDDP) is a widely used antineoplastic agent. Cisplatin administration has increased both in the variety of cancer types for which it is employed and in the amount used in a given individual to achieve maximal therapeutic effect (Blumenreich et al., 1985; Forastiere et al., 1987; Gandara et al., 1989). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Therapy for human cancers using cisplatin and other drugs or genes encapsulated into liposomes Inventor(s): Boulikas, Teni; (Palo Alto, CA) Correspondence: Bingham, Mccutchen Llp; Three Embarcadero, Suite 1800; San Francisco; CA; 94111-4067; US Patent Application Number: 20030185879 Date filed: January 23, 2003 Abstract: A method for encapsulating cisplatin and other positively-charged drugs into liposomes having a different lipid composition between their inner and outer membrane bilayers is disclosed. The liposomes are able to reach primary tumors and their metastases after intravenous injection to animals and humans. The encapsulated cisplatin has a high therapeutic efficacy in eradicating a variety of solid human tumors including but not limited to breast carcinoma and prostate carcinoma. Combination of the encapsulated cisplatin with encapsulated doxorubicin or with other antineoplastic drugs are claimed to be of therapeutic value. Also of therapeutic value in cancer eradication are claimed to be combinations of encapsulated cisplatin with a number of anticancer genes including but not limited to p53, IL-2, IL-12, angiostatin, and oncostatin encapsulated into liposomes as well as combinations of encapsulated cisplatin with HSV-tk plus encapsulated ganciclovir. Excerpt(s): The present invention relates to liposome encapsulated drugs and delivery systems, specifically liposome encapsulated cisplatin. The drugs are useful to kill cancer cells in a variety of human malignancies after intravenous injection. Throughout this application various publications, patents and published patent specifications are referenced by author and date or by an identifying patent number. Full bibliographic citations for the publications are provided within this disclosure or immediately preceding the claims. The disclosures of these publications, patents and published
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patent specifications are hereby incorporated by reference into the present disclosure to more fully describe the state of the art to which this invention pertains. Cisdiamminedichloroplatinum(II), cis-[Pt(NH.sub.3).sub.2Cl.sub.2].- sup.2+, abbreviated cisplatin or cis-DDP, is one of the most widely used antineoplastic drugs for the treatment of testicular, ovarian carcinomas and against carcinomas of the head and neck. More than 90% of testicular cancers are cured by cisplatin. The most severe side effects are nephrotoxicity, bone marrow toxicity and gastrointestinal irritation (Oliver and Mead, 1993). Bilateral optic neuropathy was observed in a patient affected by ovarian carcinoma treated with 160 mg/m.sup.2 cisplatin and 640 mg/m.sup.2 carboplatin (Caraceni et al., 1997). Oral hexamethylmelamine treatment in a group of 61 patients with epithelial ovarian carcinoma with cis- or carboplatin resistance (relapse within 6 months after the end of that therapy) showed a 14% objective response rate (Vergote et al., 1992). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Treatment of carcinomas using squalamine in combination with other anti-cancer agents or modalities Inventor(s): Sokoloff, Mitchell H.; (Hinsdale, IL), Williams, Jon; (Robbinsville, NJ), Zasloff, Michael; (Merion Station, PA) Correspondence: Morgan, Lewis & Bockius; 1800 M Street NW; Washington; DC; 200365869; US Patent Application Number: 20010046521 Date filed: March 12, 2001 Abstract: A method for treating a tumor includes a first treatment procedure using a conventional cancer treatment technique, and a second treatment procedure which includes administering an effective amount of squalamine. Synergistically effective amounts are preferred. The first treatment procedure may be a treatment with one or more conventional cytotoxic chemical compounds. As examples, the cytotoxic chemical compound may be a nitrosourea (such as BCNU), cyclophosphamide, doxorubicin, 5fluorouracil, paclitaxel and its derivatives, cisplatin or other platinum containing cancer treating agents. Alternatively, the first treatment may be a treatment with one or more conventional anti-hormonal agents. As examples, the anti-hormonal agents may be a LHRH (luteinizing hormone releasing hormone) agonist or an anti-androgen such as flutamide, biclutamide, nilutamide, and luprolide. These conventional cancer treatments compounds and the squalamine may be administered by any suitable route. The first treatment procedure may take place prior to the second treatment procedure, after the second treatment procedure, or the two treatment procedures may take place simultaneously. As an alternative, the first treatment procedure may be a conventional radiation treatment regimen. As a further alternative the first treatment procedure may be a combination of treatment with one or more conventional cytotoxic chemical compounds and a conventional radiation treatment regimen. Excerpt(s): This application is a continuation-in-part of 09/150,724, filed Sep. 10, 1998, which is a continuation-in-part of 08/840,706, filed Apr. 25, 1997, which claims the benefit of provisional application, 60/016,387, filed Apr. 26, 1996, under 35 U.S.C.sctn. 119. All of these applications are herein incorporated by reference in their entirety. U.S. Patent Nos. 5,733,899 and 5,721,226 describe the use of squalamine as an antiangiogenic agent. These U.S. patents are entirely incorporated herein by reference. Additional uses of squalamine (e.g., as a sodium/proton exchanger (isoform 3), or NHE3, inhibiting
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agent and as an agent for inhibiting the growth of endothelial cells) and squalamine synthesis techniques are disclosed in U.S. Pat. No. 5,792,635. This U.S. patent is also entirely incorporated herein by reference. About 50,000 new cases of CNS (central nervous system) tumors are diagnosed each year. Of these, about 35,000 are metastatic tumors (e.g., lung, breast, melanomas) and about 15,000 are primary tumors (mostly astrocytomas). Astrocytomas, along with other malignant gliomas (i.e., cancers of the brain), are the third leading cause of death from cancer in persons between the ages of 15 and 34. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Use of Rad51 inhibitors for p53 gene therapy Inventor(s): Reddy, Gurucharan; (Fremont, CA), Zarling, David A.; (Menlo Park, CA) Correspondence: Flehr Hohbach Test; Albritton & Herbert Llp; Four Embarcarero Center, Suite 3400; San Francisco; CA; 94111-4187; US Patent Application Number: 20020086840 Date filed: January 26, 2001 Abstract: The present invention is directed to methods and compositions for inhibiting or reducing tumor cell proliferation in an individual in vivo. More specifically, a tumor cell is contacted, in vivo, with a Rad51 inhibitor, and a polynucleotide capable of expressing functional p53 protein. In a further embodiment of the present invention the tumor cell is exposed in vivo to radiation or chemotherapeutic agents (e.g., BCNU, CCNU, and DMZ, GB, cisplatin and the like). The Rad51 inhibitor may be selected from the group consisting of peptides, small molecules and Rad51 antisense molecules. The Rad51 antisense molecule and the p53 polynucleotide may be encoded on an expression vector under the control of one or more promoters, and the expression vector may then be incorporated into a viral genome, preferably an andeno or retro virus, which is then used to introduce the expression vector into the tumor cell. Excerpt(s): The present invention relates to therapeutic treatment of cancer using Rad51 inhibitors in combination with p53 gene therapy, and in further combination with chemo- or radiation therapy. It is now well established that a variety of cancers are caused, at least in part, by genetic abnormalities that result in either the over expression of one or more genes, or the expression of an abnormal or mutant gene or genes. For example, in many cases, the expression of oncogenes is known to result in the development of cancer. Oncogenes are genetically altered genes whose mutated expression product somehow disrupts normal cellular function or control (Spandidos et al., J. Pathol., 157:1-10 (1989)). Most oncogenes studied to date have been found to be activated as the result of a mutation, often a point mutation, in the expressed protein product. This altered expression product exhibits an abnormal biological funtion that takes part in the neoplastic process (Travali et al., FASEB, 4:3209-3214 (1990)). The underlying mutations can arise by various means, such as by chemical mutagenesis or ionizing radiation. A number of oncogenes and oncogene families, including ras, myc, neu, raf, erb, src, fms, jun and abl have now been identified and characterized to varying degrees (Travali et al., 1990; Bishop, Science, 235:305-311 (1987)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Keeping Current In order to stay informed about patents and patent applications dealing with cisplatin, you can access the U.S. Patent Office archive via the Internet at the following Web address: http://www.uspto.gov/patft/index.html. You will see two broad options: (1) Issued Patent, and (2) Published Applications. To see a list of issued patents, perform the following steps: Under “Issued Patents,” click “Quick Search.” Then, type “cisplatin” (or synonyms) into the “Term 1” box. After clicking on the search button, scroll down to see the various patents which have been granted to date on cisplatin. You can also use this procedure to view pending patent applications concerning cisplatin. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.
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CHAPTER 6. BOOKS ON CISPLATIN Overview This chapter provides bibliographic book references relating to cisplatin. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on cisplatin include the Combined Health Information Database and the National Library of Medicine. Your local medical library also may have these titles available for loan.
Book Summaries: Federal Agencies The Combined Health Information Database collects various book abstracts from a variety of healthcare institutions and federal agencies. To access these summaries, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. You will need to use the “Detailed Search” option. To find book summaries, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer. For the format option, select “Monograph/Book.” Now type “cisplatin” (or synonyms) into the “For these words:” box. You should check back periodically with this database which is updated every three months. The following is a typical result when searching for books on cisplatin: •
Cochlear Pharmacology and Noise Trauma: Proceedings of the Joint Symposium Organised by the European Commission Concerted Action Protection Against Noise and the Novartis Foundation Source: London, England: NRN Publications. 1999. 206 p. Contact: Available from NRN Publications. Institute of Laryngology and Otology, 330 Gray's Inn Road, London, WC1X 8EE, United Kingdom. 440 207 915 1590. PRICE: Contact publisher for current price. ISBN: 190174700x. Summary: This book reprints the Proceedings of the Joint Symposium on Cochlear Pharmacology and Noise Trauma, organized by the European Commission Concerted Action Protection Against Noise and the Novartis Foundation, held in London, England in May 1998. Excessive exposure to noise results in either direct mechanical damage to the sensitive cochlear structures or from metabolic overload due to overstimulation. The probability of acquiring a hearing impairment increases if noise exposure is combined
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with other factors such as chemicals, extreme temperatures, and vibration. The book includes 16 chapters that cover inner ear pharmacology and clinical implications; immunocytochemical clues to the handling of excitatory neurotransmitters in the cochlea; GABA, dopamine, and serotonin in cochlear innervation, specifically models of protection against neurotoxicity; oral magnesium used to reduce noise induced temporary and permanent hearing loss; medical treatment for acoustic trauma; strategies for preventing hearing loss; intervention possibilities for noise induced hearing loss; strategies for protection of the inner ear from noise induced hearing loss (NIHL); toluene and styrene induced hearing losses; mechanisms of ototoxicity by chemical contaminants; therapeutic strategies for improving cochlear blood flow; peripheral and central effects of noise exposure in rats as determined by electrophysiological methods; noise induced calcium increases and the outer hair cell; protection against cisplatin ototoxicity by melanocortins; and thoughts on the type of patients who could benefit from in situ pharmacology. Each chapter concludes with a reference list and with a brief reprint of the discussion that happened after each presentation. A subject index concludes the volume.
Book Summaries: Online Booksellers Commercial Internet-based booksellers, such as Amazon.com and Barnes&Noble.com, offer summaries which have been supplied by each title’s publisher. Some summaries also include customer reviews. Your local bookseller may have access to in-house and commercial databases that index all published books (e.g. Books in Print). IMPORTANT NOTE: Online booksellers typically produce search results for medical and non-medical books. When searching for “cisplatin” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “cisplatin” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “cisplatin” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •
The Mechanism of Cisplatin Resistance and Its Circumvention by Yoshihiro Kikuchi; ISBN: 1560725486; http://www.amazon.com/exec/obidos/ASIN/1560725486/icongroupinterna
Chapters on Cisplatin In order to find chapters that specifically relate to cisplatin, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and cisplatin using the “Detailed Search” option. Go to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find book chapters, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Book Chapter.” Type “cisplatin” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on cisplatin: •
Drug Dosing and Toxicities in Renal Failure Source: in Mandal, A.K. and Nahman, N.S., Jr., eds. Kidney Disease in Primary Care. Baltimore, MD: Williams and Wilkins. 1998. p. 255-265.
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Contact: Available from Williams and Wilkins. 351 West Camden Street, Baltimore, MD 21201-2436. (800) 638-0672 or (410) 528-4223. Fax (800) 447-8438 or (410) 528-8550. E-mail:
[email protected]. PRICE: $39.95. ISBN: 0683300571. Summary: This chapter on drug dosing and toxicities in renal failure is from a textbook that provides primary care physicians with practical approaches to common clinical problems of kidney diseases. Changes in drug absorption, distribution, metabolism, and excretion must be considered in the therapeutic management of patients with impaired renal function or End Stage Renal Disease. The authors give general guidelines for the appropriate dosage adjustment of medications in patients with impaired renal function. Topics include the estimation of glomerular filtration rate (GFR), pharmacokinetics and pharmacodynamics (bioavailability, elimination coefficient and half-life, protein binding, volume of distribution), metabolism, and drug-induced nephrotoxicity (aminoglycosides, ACE inhibitors, amphotericin B, nonsteroidal anti-inflammatory agents, cisplatin, cyclosporine, radiographic contrast media, and nephrolithiasis or kidney stones). The authors note that gastrointestinal symptoms are common in renal patients and may prevent or delay oral absorption of drugs. Gastroparesis is especially common in renal patients with diabetes and may cause a delay in absorption of many drugs. 6 tables. 8 references.
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CHAPTER 7. PERIODICALS AND NEWS ON CISPLATIN Overview In this chapter, we suggest a number of news sources and present various periodicals that cover cisplatin.
News Services and Press Releases One of the simplest ways of tracking press releases on cisplatin is to search the news wires. In the following sample of sources, we will briefly describe how to access each service. These services only post recent news intended for public viewing. PR Newswire To access the PR Newswire archive, simply go to http://www.prnewswire.com/. Select your country. Type “cisplatin” (or synonyms) into the search box. You will automatically receive information on relevant news releases posted within the last 30 days. The search results are shown by order of relevance. Reuters Health The Reuters’ Medical News and Health eLine databases can be very useful in exploring news archives relating to cisplatin. While some of the listed articles are free to view, others are available for purchase for a nominal fee. To access this archive, go to http://www.reutershealth.com/en/index.html and search by “cisplatin” (or synonyms). The following was recently listed in this archive for cisplatin: •
Paclitaxel and cisplatin combination helpful in esophageal cancer Source: Reuters Industry Breifing Date: January 22, 2004
•
Radiotherapy plus cisplatin preserves organ in advanced laryngeal cancer Source: Reuters Medical News Date: November 26, 2003
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•
Pemetrexed plus cisplatin "makes a difference" in mesothelioma survival Source: Reuters Industry Breifing Date: July 21, 2003
•
Demethylation of ovarian cancer gene leads to cisplatin resistance Source: Reuters Medical News Date: April 08, 2003
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Dose-dense cisplatin plus paclitaxel effective in advanced ovarian cancer Source: Reuters Industry Breifing Date: November 27, 2002
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Zeltia's Yondelis may increase sensitivity to cisplatin -- study Source: Reuters Industry Breifing Date: November 20, 2002
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Temozolomide plus cisplatin "interesting" for recurrent glioma Source: Reuters Industry Breifing Date: October 21, 2002
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Gemcitabine/epirubicin can be good alternative to cisplatin for urothelial cancers Source: Reuters Industry Breifing Date: October 14, 2002
•
Targeted liposomal cisplatin promising in model of disseminated gastric cancer Source: Reuters Industry Breifing Date: May 27, 2002
•
Aspirin use may protect against cisplatin toxicity Source: Reuters Medical News Date: May 24, 2002 The NIH
Within MEDLINEplus, the NIH has made an agreement with the New York Times Syndicate, the AP News Service, and Reuters to deliver news that can be browsed by the public. Search news releases at http://www.nlm.nih.gov/medlineplus/alphanews_a.html. MEDLINEplus allows you to browse across an alphabetical index. Or you can search by date at the following Web page: http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within its search engine. Business Wire Business Wire is similar to PR Newswire. To access this archive, simply go to http://www.businesswire.com/. You can scan the news by industry category or company name. Market Wire Market Wire is more focused on technology than the other wires. To browse the latest press releases by topic, such as alternative medicine, biotechnology, fitness, healthcare, legal, nutrition, and pharmaceuticals, access Market Wire’s Medical/Health channel at http://www.marketwire.com/mw/release_index?channel=MedicalHealth. Or simply go to
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Market Wire’s home page at http://www.marketwire.com/mw/home, type “cisplatin” (or synonyms) into the search box, and click on “Search News.” As this service is technology oriented, you may wish to use it when searching for press releases covering diagnostic procedures or tests. Search Engines Medical news is also available in the news sections of commercial Internet search engines. See the health news page at Yahoo (http://dir.yahoo.com/Health/News_and_Media/), or you can use this Web site’s general news search page at http://news.yahoo.com/. Type in “cisplatin” (or synonyms). If you know the name of a company that is relevant to cisplatin, you can go to any stock trading Web site (such as http://www.etrade.com/) and search for the company name there. News items across various news sources are reported on indicated hyperlinks. Google offers a similar service at http://news.google.com/. BBC Covering news from a more European perspective, the British Broadcasting Corporation (BBC) allows the public free access to their news archive located at http://www.bbc.co.uk/. Search by “cisplatin” (or synonyms).
Academic Periodicals covering Cisplatin Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to cisplatin. In addition to these sources, you can search for articles covering cisplatin that have been published by any of the periodicals listed in previous chapters. To find the latest studies published, go to http://www.ncbi.nlm.nih.gov/pubmed, type the name of the periodical into the search box, and click “Go.” If you want complete details about the historical contents of a journal, you can also visit the following Web site: http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi. Here, type in the name of the journal or its abbreviation, and you will receive an index of published articles. At http://locatorplus.gov/, you can retrieve more indexing information on medical periodicals (e.g. the name of the publisher). Select the button “Search LOCATORplus.” Then type in the name of the journal and select the advanced search option “Journal Title Search.”
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CHAPTER 8. RESEARCHING MEDICATIONS Overview While a number of hard copy or CD-ROM resources are available for researching medications, a more flexible method is to use Internet-based databases. Broadly speaking, there are two sources of information on approved medications: public sources and private sources. We will emphasize free-to-use public sources.
U.S. Pharmacopeia Because of historical investments by various organizations and the emergence of the Internet, it has become rather simple to learn about the medications recommended for cisplatin. One such source is the United States Pharmacopeia. In 1820, eleven physicians met in Washington, D.C. to establish the first compendium of standard drugs for the United States. They called this compendium the U.S. Pharmacopeia (USP). Today, the USP is a nonprofit organization consisting of 800 volunteer scientists, eleven elected officials, and 400 representatives of state associations and colleges of medicine and pharmacy. The USP is located in Rockville, Maryland, and its home page is located at http://www.usp.org/. The USP currently provides standards for over 3,700 medications. The resulting USP DI Advice for the Patient can be accessed through the National Library of Medicine of the National Institutes of Health. The database is partially derived from lists of federally approved medications in the Food and Drug Administration’s (FDA) Drug Approvals database, located at http://www.fda.gov/cder/da/da.htm. While the FDA database is rather large and difficult to navigate, the Phamacopeia is both user-friendly and free to use. It covers more than 9,000 prescription and over-the-counter medications. To access this database, simply type the following hyperlink into your Web browser: http://www.nlm.nih.gov/medlineplus/druginformation.html. To view examples of a given medication (brand names, category, description, preparation, proper use, precautions, side effects, etc.), simply follow the hyperlinks indicated within the United States Pharmacopeia (USP). Below, we have compiled a list of medications associated with cisplatin. If you would like more information on a particular medication, the provided hyperlinks will direct you to ample documentation (e.g. typical dosage, side effects, drug-interaction risks, etc.). The
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following drugs have been mentioned in the Pharmacopeia and other sources as being potentially applicable to cisplatin: Cisplatin •
Systemic - U.S. Brands: Platinol; Platinol-AQ http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202143.html
Sodium Thiosulfate •
Systemic - U.S. Brands: Cyanide Antidote Package http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202690.html
Commercial Databases In addition to the medications listed in the USP above, a number of commercial sites are available by subscription to physicians and their institutions. Or, you may be able to access these sources from your local medical library.
Mosby’s Drug Consult Mosby’s Drug Consult database (also available on CD-ROM and book format) covers 45,000 drug products including generics and international brands. It provides prescribing information, drug interactions, and patient information. Subscription information is available at the following hyperlink: http://www.mosbysdrugconsult.com/. PDRhealth The PDRhealth database is a free-to-use, drug information search engine that has been written for the public in layman’s terms. It contains FDA-approved drug information adapted from the Physicians’ Desk Reference (PDR) database. PDRhealth can be searched by brand name, generic name, or indication. It features multiple drug interactions reports. Search PDRhealth at http://www.pdrhealth.com/drug_info/index.html. Other Web Sites Drugs.com (www.drugs.com) reproduces the information in the Pharmacopeia as well as commercial information. You may also want to consider the Web site of the Medical Letter, Inc. (http://www.medletter.com/) which allows users to download articles on various drugs and therapeutics for a nominal fee.
Researching Orphan Drugs Although the list of orphan drugs is revised on a daily basis, you can quickly research orphan drugs that might be applicable to cisplatin by using the database managed by the National Organization for Rare Disorders, Inc. (NORD), at http://www.rarediseases.org/. Scroll down the page, and on the left toolbar, click on “Orphan Drug Designation Database.”
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On this page (http://www.rarediseases.org/search/noddsearch.html), type “cisplatin” (or synonyms) into the search box, and click “Submit Query.” When you receive your results, note that not all of the drugs may be relevant, as some may have been withdrawn from orphan status. Write down or print out the name of each drug and the relevant contact information. From there, visit the Pharmacopeia Web site and type the name of each orphan drug into the search box at http://www.nlm.nih.gov/medlineplus/druginformation.html. You may need to contact the sponsor or NORD for further information. NORD conducts “early access programs for investigational new drugs (IND) under the Food and Drug Administration’s (FDA’s) approval ‘Treatment INDs’ programs which allow for a limited number of individuals to receive investigational drugs before FDA marketing approval.” If the orphan product about which you are seeking information is approved for marketing, information on side effects can be found on the product’s label. If the product is not approved, you may need to contact the sponsor. The following is a list of orphan drugs currently listed in the NORD Orphan Drug Designation Database for cisplatin: •
Amifostine (trade name: Ethyol) http://www.rarediseases.org/nord/search/nodd_full?code=530
•
Amifostine (trade name: Ethyol) http://www.rarediseases.org/nord/search/nodd_full?code=533
•
Amifostine (trade name: Ethyol) http://www.rarediseases.org/nord/search/nodd_full?code=950
If you have any questions about a medical treatment, the FDA may have an office near you. Look for their number in the blue pages of the phone book. You can also contact the FDA through its toll-free number, 1-888-INFO-FDA (1-888-463-6332), or on the World Wide Web at www.fda.gov.
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APPENDICES
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APPENDIX A. PHYSICIAN RESOURCES Overview In this chapter, we focus on databases and Internet-based guidelines and information resources created or written for a professional audience.
NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute10: •
Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm
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National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/news/facts/
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National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html
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National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancerinfo/list.aspx?viewid=5f35036e-5497-4d86-8c2c714a9f7c8d25
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National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/order/index.htm
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National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm
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National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375
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National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/health/
10
These publications are typically written by one or more of the various NIH Institutes.
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•
National Institute on Alcohol Abuse and Alcoholism (NIAAA); guidelines available at http://www.niaaa.nih.gov/publications/publications.htm
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National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/
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National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm
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National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm
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National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/
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National Institute of Dental and Craniofacial Research (NIDCR); guidelines available at http://www.nidr.nih.gov/health/
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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); guidelines available at http://www.niddk.nih.gov/health/health.htm
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National Institute on Drug Abuse (NIDA); guidelines available at http://www.nida.nih.gov/DrugAbuse.html
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National Institute of Environmental Health Sciences (NIEHS); environmental health information available at http://www.niehs.nih.gov/external/facts.htm
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National Institute of Mental Health (NIMH); guidelines available at http://www.nimh.nih.gov/practitioners/index.cfm
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National Institute of Neurological Disorders and Stroke (NINDS); neurological disorder information pages available at http://www.ninds.nih.gov/health_and_medical/disorder_index.htm
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National Institute of Nursing Research (NINR); publications on selected illnesses at http://www.nih.gov/ninr/news-info/publications.html
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National Institute of Biomedical Imaging and Bioengineering; general information at http://grants.nih.gov/grants/becon/becon_info.htm
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Center for Information Technology (CIT); referrals to other agencies based on keyword searches available at http://kb.nih.gov/www_query_main.asp
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National Center for Complementary and Alternative Medicine (NCCAM); health information available at http://nccam.nih.gov/health/
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National Center for Research Resources (NCRR); various information directories available at http://www.ncrr.nih.gov/publications.asp
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Office of Rare Diseases; various fact sheets available at http://rarediseases.info.nih.gov/html/resources/rep_pubs.html
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Centers for Disease Control and Prevention; various fact sheets on infectious diseases available at http://www.cdc.gov/publications.htm
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NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.11 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:12 •
Bioethics: Access to published literature on the ethical, legal, and public policy issues surrounding healthcare and biomedical research. This information is provided in conjunction with the Kennedy Institute of Ethics located at Georgetown University, Washington, D.C.: http://www.nlm.nih.gov/databases/databases_bioethics.html
•
HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html
•
NLM Online Exhibitions: Describes “Exhibitions in the History of Medicine”: http://www.nlm.nih.gov/exhibition/exhibition.html. Additional resources for historical scholarship in medicine: http://www.nlm.nih.gov/hmd/hmd.html
•
Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/
•
Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html
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Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html
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Profiles in Science: Offering the archival collections of prominent twentieth-century biomedical scientists to the public through modern digital technology: http://www.profiles.nlm.nih.gov/
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Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html
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Clinical Alerts: Reports the release of findings from the NIH-funded clinical trials where such release could significantly affect morbidity and mortality: http://www.nlm.nih.gov/databases/alerts/clinical_alerts.html
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Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html
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MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html
11
Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html). 12 See http://www.nlm.nih.gov/databases/databases.html.
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•
Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html
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Visible Human Interface: Anatomically detailed, three-dimensional representations of normal male and female human bodies: http://www.nlm.nih.gov/research/visible/visible_human.html
The NLM Gateway13 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing one-stop searching for many of NLM’s information resources or databases.14 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “cisplatin” (or synonyms) into the search box and click “Search.” The results will be presented in a tabular form, indicating the number of references in each database category. Results Summary Category Journal Articles Books / Periodicals / Audio Visual Consumer Health Meeting Abstracts Other Collections Total
Items Found 33015 31 1394 26 68 34534
HSTAT15 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.16 These documents include clinical practice guidelines, quickreference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ’s Put Prevention Into Practice.17 Simply search by “cisplatin” (or synonyms) at the following Web site: http://text.nlm.nih.gov.
13
Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.
14
The NLM Gateway is currently being developed by the Lister Hill National Center for Biomedical Communications (LHNCBC) at the National Library of Medicine (NLM) of the National Institutes of Health (NIH). 15 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 16 17
The HSTAT URL is http://hstat.nlm.nih.gov/.
Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration's Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force's Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community Services’ Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations.
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Coffee Break: Tutorials for Biologists18 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.19 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.20 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.
Other Commercial Databases In addition to resources maintained by official agencies, other databases exist that are commercial ventures addressing medical professionals. Here are some examples that may interest you: •
CliniWeb International: Index and table of contents to selected clinical information on the Internet; see http://www.ohsu.edu/cliniweb/.
•
Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.
18 Adapted 19
from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html.
The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 20 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process.
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APPENDIX B. PATIENT RESOURCES Overview Official agencies, as well as federally funded institutions supported by national grants, frequently publish a variety of guidelines written with the patient in mind. These are typically called “Fact Sheets” or “Guidelines.” They can take the form of a brochure, information kit, pamphlet, or flyer. Often they are only a few pages in length. Since new guidelines on cisplatin can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internet-based services that post them.
Patient Guideline Sources The remainder of this chapter directs you to sources which either publish or can help you find additional guidelines on topics related to cisplatin. Due to space limitations, these sources are listed in a concise manner. Do not hesitate to consult the following sources by either using the Internet hyperlink provided, or, in cases where the contact information is provided, contacting the publisher or author directly. The National Institutes of Health The NIH gateway to patients is located at http://health.nih.gov/. From this site, you can search across various sources and institutes, a number of which are summarized below. Topic Pages: MEDLINEplus The National Library of Medicine has created a vast and patient-oriented healthcare information portal called MEDLINEplus. Within this Internet-based system are “health topic pages” which list links to available materials relevant to cisplatin. To access this system, log on to http://www.nlm.nih.gov/medlineplus/healthtopics.html. From there you can either search using the alphabetical index or browse by broad topic areas. Recently, MEDLINEplus listed the following when searched for “cisplatin”:
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Anal Cancer http://www.nlm.nih.gov/medlineplus/analcancer.html Bladder Cancer http://www.nlm.nih.gov/medlineplus/bladdercancer.html Head and Neck Cancer http://www.nlm.nih.gov/medlineplus/headandneckcancer.html Lung Cancer http://www.nlm.nih.gov/medlineplus/lungcancer.html Ovarian Cancer http://www.nlm.nih.gov/medlineplus/ovariancancer.html Smallpox http://www.nlm.nih.gov/medlineplus/smallpox.html You may also choose to use the search utility provided by MEDLINEplus at the following Web address: http://www.nlm.nih.gov/medlineplus/. Simply type a keyword into the search box and click “Search.” This utility is similar to the NIH search utility, with the exception that it only includes materials that are linked within the MEDLINEplus system (mostly patient-oriented information). It also has the disadvantage of generating unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search. The NIH Search Utility The NIH search utility allows you to search for documents on over 100 selected Web sites that comprise the NIH-WEB-SPACE. Each of these servers is “crawled” and indexed on an ongoing basis. Your search will produce a list of various documents, all of which will relate in some way to cisplatin. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html. Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •
AOL: http://search.aol.com/cat.adp?id=168&layer=&from=subcats
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Family Village: http://www.familyvillage.wisc.edu/specific.htm
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Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/
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Med Help International: http://www.medhelp.org/HealthTopics/A.html
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Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/
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Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/
Patient Resources
•
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WebMDHealth: http://my.webmd.com/health_topics
Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to cisplatin. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with cisplatin. The National Health Information Center (NHIC) The National Health Information Center (NHIC) offers a free referral service to help people find organizations that provide information about cisplatin. For more information, see the NHIC’s Web site at http://www.health.gov/NHIC/ or contact an information specialist by calling 1-800-336-4797. Directory of Health Organizations The Directory of Health Organizations, provided by the National Library of Medicine Specialized Information Services, is a comprehensive source of information on associations. The Directory of Health Organizations database can be accessed via the Internet at http://www.sis.nlm.nih.gov/Dir/DirMain.html. It is composed of two parts: DIRLINE and Health Hotlines. The DIRLINE database comprises some 10,000 records of organizations, research centers, and government institutes and associations that primarily focus on health and biomedicine. To access DIRLINE directly, go to the following Web site: http://dirline.nlm.nih.gov/. Simply type in “cisplatin” (or a synonym), and you will receive information on all relevant organizations listed in the database. Health Hotlines directs you to toll-free numbers to over 300 organizations. You can access this database directly at http://www.sis.nlm.nih.gov/hotlines/. On this page, you are given the option to search by keyword or by browsing the subject list. When you have received your search results, click on the name of the organization for its description and contact information. The Combined Health Information Database Another comprehensive source of information on healthcare associations is the Combined Health Information Database. Using the “Detailed Search” option, you will need to limit your search to “Organizations” and “cisplatin”. Type the following hyperlink into your Web browser: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For publication date, select “All Years.” Then, select your preferred language and the format option “Organization Resource Sheet.” Type “cisplatin” (or synonyms) into the “For these words:” box. You should check back periodically with this database since it is updated every three months.
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The National Organization for Rare Disorders, Inc. The National Organization for Rare Disorders, Inc. has prepared a Web site that provides, at no charge, lists of associations organized by health topic. You can access this database at the following Web site: http://www.rarediseases.org/search/orgsearch.html. Type “cisplatin” (or a synonym) into the search box, and click “Submit Query.”
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APPENDIX C. FINDING MEDICAL LIBRARIES Overview In this Appendix, we show you how to quickly find a medical library in your area.
Preparation Your local public library and medical libraries have interlibrary loan programs with the National Library of Medicine (NLM), one of the largest medical collections in the world. According to the NLM, most of the literature in the general and historical collections of the National Library of Medicine is available on interlibrary loan to any library. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.21
Finding a Local Medical Library The quickest method to locate medical libraries is to use the Internet-based directory published by the National Network of Libraries of Medicine (NN/LM). This network includes 4626 members and affiliates that provide many services to librarians, health professionals, and the public. To find a library in your area, simply visit http://nnlm.gov/members/adv.html or call 1-800-338-7657.
Medical Libraries in the U.S. and Canada In addition to the NN/LM, the National Library of Medicine (NLM) lists a number of libraries with reference facilities that are open to the public. The following is the NLM’s list and includes hyperlinks to each library’s Web site. These Web pages can provide information on hours of operation and other restrictions. The list below is a small sample of
21
Adapted from the NLM: http://www.nlm.nih.gov/psd/cas/interlibrary.html.
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libraries recommended by the National Library of Medicine (sorted alphabetically by name of the U.S. state or Canadian province where the library is located)22: •
Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/
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Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)
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Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm
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California: Kris Kelly Health Information Center (St. Joseph Health System, Humboldt), http://www.humboldt1.com/~kkhic/index.html
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California: Community Health Library of Los Gatos, http://www.healthlib.org/orgresources.html
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California: Consumer Health Program and Services (CHIPS) (County of Los Angeles Public Library, Los Angeles County Harbor-UCLA Medical Center Library) - Carson, CA, http://www.colapublib.org/services/chips.html
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California: Gateway Health Library (Sutter Gould Medical Foundation)
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California: Health Library (Stanford University Medical Center), http://wwwmed.stanford.edu/healthlibrary/
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California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp
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California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html
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California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/
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California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/
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California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/
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California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html
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California: Washington Community Health Resource Library (Fremont), http://www.healthlibrary.org/
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Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.saintjosephdenver.org/yourhealth/libraries/
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Connecticut: Hartford Hospital Health Science Libraries (Hartford Hospital), http://www.harthosp.org/library/
•
Connecticut: Healthnet: Connecticut Consumer Health Information Center (University of Connecticut Health Center, Lyman Maynard Stowe Library), http://library.uchc.edu/departm/hnet/
22
Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.
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•
Connecticut: Waterbury Hospital Health Center Library (Waterbury Hospital, Waterbury), http://www.waterburyhospital.com/library/consumer.shtml
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Delaware: Consumer Health Library (Christiana Care Health System, Eugene du Pont Preventive Medicine & Rehabilitation Institute, Wilmington), http://www.christianacare.org/health_guide/health_guide_pmri_health_info.cfm
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Delaware: Lewis B. Flinn Library (Delaware Academy of Medicine, Wilmington), http://www.delamed.org/chls.html
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Georgia: Family Resource Library (Medical College of Georgia, Augusta), http://cmc.mcg.edu/kids_families/fam_resources/fam_res_lib/frl.htm
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Georgia: Health Resource Center (Medical Center of Central Georgia, Macon), http://www.mccg.org/hrc/hrchome.asp
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Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library, Honolulu), http://hml.org/CHIS/
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Idaho: DeArmond Consumer Health Library (Kootenai Medical Center, Coeur d’Alene), http://www.nicon.org/DeArmond/index.htm
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Illinois: Health Learning Center of Northwestern Memorial Hospital (Chicago), http://www.nmh.org/health_info/hlc.html
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Illinois: Medical Library (OSF Saint Francis Medical Center, Peoria), http://www.osfsaintfrancis.org/general/library/
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Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital, Lexington), http://www.centralbap.com/education/community/library.cfm
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Kentucky: University of Kentucky - Health Information Library (Chandler Medical Center, Lexington), http://www.mc.uky.edu/PatientEd/
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Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation, New Orleans), http://www.ochsner.org/library/
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Louisiana: Louisiana State University Health Sciences Center Medical LibraryShreveport, http://lib-sh.lsuhsc.edu/
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Maine: Franklin Memorial Hospital Medical Library (Franklin Memorial Hospital, Farmington), http://www.fchn.org/fmh/lib.htm
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Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center, Lewiston), http://www.cmmc.org/library/library.html
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Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm
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Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/
•
Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/
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Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10
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Maine: Stephens Memorial Hospital’s Health Information Library (Western Maine Health, Norway), http://www.wmhcc.org/Library/
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•
Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html
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Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp
•
Maryland: Health Information Center at the Wheaton Regional Library (Montgomery County, Dept. of Public Libraries, Wheaton Regional Library), http://www.mont.lib.md.us/healthinfo/hic.asp
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Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/
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Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html
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Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm
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Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp
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Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/
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Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html
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Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/
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Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm
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Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/
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Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html
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Michigan: Patient Education Resouce Center - University of Michigan Cancer Center (University of Michigan Comprehensive Cancer Center, Ann Arbor), http://www.cancer.med.umich.edu/learn/leares.htm
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Michigan: Sladen Library & Center for Health Information Resources - Consumer Health Information (Detroit), http://www.henryford.com/body.cfm?id=39330
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Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center, Missoula)
•
National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html
•
National: National Network of Libraries of Medicine (National Library of Medicine) provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/
•
National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/
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•
Nevada: Health Science Library, West Charleston Library (Las Vegas-Clark County Library District, Las Vegas), http://www.lvccld.org/special_collections/medical/index.htm
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New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/
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New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm
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New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm
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New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/
•
New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html
•
New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/
•
New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html
•
New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/
•
Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm
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Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp
•
Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/
•
Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/
•
Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml
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Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html
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Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html
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Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml
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Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp
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Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm
•
Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/
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South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp
•
Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/
•
Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/
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Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72
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ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: •
ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html
•
MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp
•
Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/
•
Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html
•
On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/
•
Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp
•
Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/nichsr/ta101/ta10108.htm
Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a).
Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •
Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical
•
MEL-Michigan Electronic Library List of Online Health and Medical Dictionaries (Michigan Electronic Library): http://mel.lib.mi.us/health/health-dictionaries.html
•
Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/
•
Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine
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CISPLATIN DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 6-Aminonicotinamide: A vitamin antagonist which has teratogenic effects. [NIH] Abdomen: That portion of the body that lies between the thorax and the pelvis. [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Ablation: The removal of an organ by surgery. [NIH] Acatalasia: A rare autosomal recessive disorder resulting from the absence of catalase activity. Though usually asymptomatic, a syndrome of oral ulcerations and gangrene may be present. [NIH] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Acoustic: Having to do with sound or hearing. [NIH] Acuity: Clarity or clearness, especially of the vision. [EU] Acute leukemia: A rapidly progressing cancer of the blood-forming tissue (bone marrow). [NIH]
Acute lymphoblastic leukemia: ALL. A quickly progressing disease in which too many immature white blood cells called lymphoblasts are found in the blood and bone marrow. Also called acute lymphocytic leukemia. [NIH] Acute lymphocytic leukemia: ALL. A quickly progressing disease in which too many immature white blood cells called lymphoblasts are found in the blood and bone marrow. Also called acute lymphoblastic leukemia. [NIH] Acute myeloid leukemia: AML. A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myelogenous leukemia or acute nonlymphocytic leukemia. [NIH] Acute renal: A condition in which the kidneys suddenly stop working. In most cases, kidneys can recover from almost complete loss of function. [NIH] Acyl: Chemical signal used by bacteria to communicate. [NIH] Acyltransferases: Enzymes from the transferase class that catalyze the transfer of acyl groups from donor to acceptor, forming either esters or amides. (From Enzyme Nomenclature 1992) EC 2.3. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it
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enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU] Adduct: Complex formed when a carcinogen combines with DNA or a protein. [NIH] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] Adenocarcinoma: A malignant epithelial tumor with a glandular organization. [NIH] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH] Adenovirus: A group of viruses that cause respiratory tract and eye infections. Adenoviruses used in gene therapy are altered to carry a specific tumor-fighting gene. [NIH] Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [NIH] Adjuvant: A substance which aids another, such as an auxiliary remedy; in immunology, nonspecific stimulator (e.g., BCG vaccine) of the immune response. [EU] Adrenal Medulla: The inner part of the adrenal gland; it synthesizes, stores and releases catecholamines. [NIH] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adverse Effect: An unwanted side effect of treatment. [NIH] Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH] Aerosol: A solution of a drug which can be atomized into a fine mist for inhalation therapy. [EU]
Afferent: Concerned with the transmission of neural impulse toward the central part of the nervous system. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Aggressiveness: The quality of being aggressive (= characterized by aggression; militant; enterprising; spreading with vigour; chemically active; variable and adaptable). [EU] Agonist: In anatomy, a prime mover. In pharmacology, a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring substances. [EU]
Dictionary 211
Albumin: 1. Any protein that is soluble in water and moderately concentrated salt solutions and is coagulable by heat. 2. Serum albumin; the major plasma protein (approximately 60 per cent of the total), which is responsible for much of the plasma colloidal osmotic pressure and serves as a transport protein carrying large organic anions, such as fatty acids, bilirubin, and many drugs, and also carrying certain hormones, such as cortisol and thyroxine, when their specific binding globulins are saturated. Albumin is synthesized in the liver. Low serum levels occur in protein malnutrition, active inflammation and serious hepatic and renal disease. [EU] Alertness: A state of readiness to detect and respond to certain specified small changes occurring at random intervals in the environment. [NIH] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alimentary: Pertaining to food or nutritive material, or to the organs of digestion. [EU] Alkaline: Having the reactions of an alkali. [EU] Alkalinization: The process by which a substance becomes an alkali. An alkali is the opposite of an acid. [NIH] Alkaloid: A member of a large group of chemicals that are made by plants and have nitrogen in them. Some alkaloids have been shown to work against cancer. [NIH] Alkylating Agents: Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as antineoplastic agents, but most are very toxic, with carcinogenic, mutagenic, teratogenic, and immunosuppressant actions. They have also been used as components in poison gases. [NIH]
Alkylation: The covalent bonding of an alkyl group to an organic compound. It can occur by a simple addition reaction or by substitution of another functional group. [NIH] Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (allergy). [EU] Allogeneic: Taken from different individuals of the same species. [NIH] Alopecia: Absence of hair from areas where it is normally present. [NIH] Alpha Particles: Positively charged particles composed of two protons and two neutrons, i.e., helium nuclei, emitted during disintegration of very heavy isotopes; a beam of alpha particles or an alpha ray has very strong ionizing power, but weak penetrability. [NIH] Alpha-fetoprotein: AFP. A protein normally produced by a developing fetus. AFP levels are usually undetectable in the blood of healthy nonpregnant adults. An elevated level of AFP suggests the presence of either a primary liver cancer or germ cell tumor. [NIH] Alternative medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used instead of standard treatments. Alternative medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Ameliorated: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Ameliorating: A changeable condition which prevents the consequence of a failure or
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accident from becoming as bad as it otherwise would. [NIH] Amenorrhea: Absence of menstruation. [NIH] Amifostine: A phosphorothioate proposed as a radiation-protective agent. It causes splenic vasodilation and may block autonomic ganglia. [NIH] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Aminocamptothecin: An anticancer drug that belongs to the family of drugs called topoisomerase inhibitors. [NIH] Ammonia: A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. [NIH] Ampicillin: Semi-synthetic derivative of penicillin that functions as an orally active broadspectrum antibiotic. [NIH] Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [NIH] Ampulla: A sac-like enlargement of a canal or duct. [NIH] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Analgesic: An agent that alleviates pain without causing loss of consciousness. [EU] Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Anaphylatoxins: The family of peptides C3a, C4a, C5a, and C5a des-arginine produced in the serum during complement activation. They produce smooth muscle contraction, mast cell histamine release, affect platelet aggregation, and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from strongest to weakest is C5a, C3a, C4a, and C5a des-arginine. The latter is the so-called "classical" anaphylatoxin but shows no spasmogenic activity though it contains some chemotactic ability. [NIH] Anaplasia: Loss of structural differentiation and useful function of neoplastic cells. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Anemic: Hypoxia due to reduction of the oxygen-carrying capacity of the blood as a result of a decrease in the total hemoglobin or an alteration of the hemoglobin constituents. [NIH] Anesthetics: Agents that are capable of inducing a total or partial loss of sensation, especially tactile sensation and pain. They may act to induce general anesthesia, in which an unconscious state is achieved, or may act locally to induce numbness or lack of sensation at a targeted site. [NIH]
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Angiogenesis inhibitor: A substance that may prevent the formation of blood vessels. In anticancer therapy, an angiogenesis inhibitor prevents the growth of blood vessels from surrounding tissue to a solid tumor. [NIH] Animal model: An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Anions: Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. [NIH] Annealing: The spontaneous alignment of two single DNA strands to form a double helix. [NIH]
Anorexia: Lack or loss of appetite for food. Appetite is psychologic, dependent on memory and associations. Anorexia can be brought about by unattractive food, surroundings, or company. [NIH] Anorexia Nervosa: The chief symptoms are inability to eat, weight loss, and amenorrhea. [NIH]
Ansa: A turn or bend in a thread or line; a bend in a wire; one of the patterns formed by the dermal ridges on the finger tips. [NIH] Antagonism: Interference with, or inhibition of, the growth of a living organism by another living organism, due either to creation of unfavorable conditions (e. g. exhaustion of food supplies) or to production of a specific antibiotic substance (e. g. penicillin). [NIH] Anthracycline: A member of a family of anticancer drugs that are also antibiotics. [NIH] Antiandrogens: Drugs used to block the production or interfere with the action of male sex hormones. [NIH] Antiangiogenic: Having to do with reducing the growth of new blood vessels. [NIH] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]
Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Antidote: A remedy for counteracting a poison. [EU] Antiemetic: An agent that prevents or alleviates nausea and vomiting. Also antinauseant. [EU]
Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the
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antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Antigen-Antibody Complex: The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes immune complex diseases. [NIH] Anti-infective: An agent that so acts. [EU] Anti-inflammatory: Having to do with reducing inflammation. [NIH] Anti-Inflammatory Agents: Substances that reduce or suppress inflammation. [NIH] Antimetabolite: A chemical that is very similar to one required in a normal biochemical reaction in cells. Antimetabolites can stop or slow down the reaction. [NIH] Antimitotic: Inhibiting or preventing mitosis. [EU] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] Antineoplastic Agents: Substances that inhibit or prevent the proliferation of neoplasms. [NIH]
Antioxidant: A substance that prevents damage caused by free radicals. Free radicals are highly reactive chemicals that often contain oxygen. They are produced when molecules are split to give products that have unpaired electrons. This process is called oxidation. [NIH] Antiproliferative: Counteracting a process of proliferation. [EU] Antipyretic: An agent that relieves or reduces fever. Called also antifebrile, antithermic and febrifuge. [EU] Antitumour: Counteracting tumour formation. [EU] Antiviral: Destroying viruses or suppressing their replication. [EU] Anus: The opening of the rectum to the outside of the body. [NIH] Anxiolytic: An anxiolytic or antianxiety agent. [EU] Aponeurosis: Tendinous expansion consisting of a fibrous or membranous sheath which serves as a fascia to enclose or bind a group of muscles. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH] Aqueous: Having to do with water. [NIH] Arachidonic Acid: An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU] Arterial embolization: The blocking of an artery by a clot of foreign material. This can be done as treatment to block the flow of blood to a tumor. [NIH]
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Arteries: The vessels carrying blood away from the heart. [NIH] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Asbestos: Fibrous incombustible mineral composed of magnesium and calcium silicates with or without other elements. It is relatively inert chemically and used in thermal insulation and fireproofing. Inhalation of dust causes asbestosis and later lung and gastrointestinal neoplasms. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Astrocytes: The largest and most numerous neuroglial cells in the brain and spinal cord. Astrocytes (from "star" cells) are irregularly shaped with many long processes, including those with "end feet" which form the glial (limiting) membrane and directly and indirectly contribute to the blood brain barrier. They regulate the extracellular ionic and chemical environment, and "reactive astrocytes" (along with microglia) respond to injury. Astrocytes have high- affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitter, but their role in signaling (as in many other functions) is not well understood. [NIH] Astrocytoma: A tumor that begins in the brain or spinal cord in small, star-shaped cells called astrocytes. [NIH] Asymptomatic: Having no signs or symptoms of disease. [NIH] Ataxia: Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharnyx, larnyx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. [NIH] Atony: Lack of normal tone or strength. [EU] ATP: ATP an abbreviation for adenosine triphosphate, a compound which serves as a carrier of energy for cells. [NIH] Attenuation: Reduction of transmitted sound energy or its electrical equivalent. [NIH] Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to strains of unusual type. [EU] Audiology: The study of hearing and hearing impairment. [NIH] Audiometry: The testing of the acuity of the sense of hearing to determine the thresholds of the lowest intensity levels at which an individual can hear a set of tones. The frequencies between 125 and 8000 Hz are used to test air conduction thresholds, and the frequencies between 250 and 4000 Hz are used to test bone conduction thresholds. [NIH] Auditory: Pertaining to the sense of hearing. [EU] Autologous: Taken from an individual's own tissues, cells, or DNA. [NIH] Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body. [NIH] Babesiosis: A group of tick-borne diseases of mammals including zoonoses in humans. They are caused by protozoans of the genus babesia, which parasitize erythrocytes, producing hemolysis. In the U.S., the organism's natural host is mice and transmission is by the deer tick ixodes scapularis. [NIH]
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Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bactericidal: Substance lethal to bacteria; substance capable of killing bacteria. [NIH] Bacterium: Microscopic organism which may have a spherical, rod-like, or spiral unicellular or non-cellular body. Bacteria usually reproduce through asexual processes. [NIH] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH] Basal Ganglia Diseases: Diseases of the basal ganglia including the putamen; globus pallidus; claustrum; amygdala; and caudate nucleus. Dyskinesias (most notably involuntary movements and alterations of the rate of movement) represent the primary clinical manifestations of these disorders. Common etiologies include cerebrovascular disease; neurodegenerative diseases; and craniocerebral trauma. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] Basophils: Granular leukocytes characterized by a relatively pale-staining, lobate nucleus and cytoplasm containing coarse dark-staining granules of variable size and stainable by basic dyes. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]
Benzo(a)pyrene: A potent mutagen and carcinogen. It is a public health concern because of its possible effects on industrial workers, as an environmental pollutant, an as a component of tobacco smoke. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile Acids: Acids made by the liver that work with bile to break down fats. [NIH] Bile duct: A tube through which bile passes in and out of the liver. [NIH] Biliary: Having to do with the liver, bile ducts, and/or gallbladder. [NIH] Biliary Tract: The gallbladder and its ducts. [NIH] Bilirubin: A bile pigment that is a degradation product of heme. [NIH] Binding agent: A substance that makes a loose mixture stick together. For example, binding agents can be used to make solid pills from loose powders. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biochemical reactions: In living cells, chemical reactions that help sustain life and allow cells to grow. [NIH] Biogenesis: The origin of life. It includes studies of the potential basis for life in organic compounds but excludes studies of the development of altered forms of life through mutation and natural selection, which is evolution. [NIH] Biological response modifier: BRM. A substance that stimulates the body's response to
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infection and disease. [NIH] Biological therapy: Treatment to stimulate or restore the ability of the immune system to fight infection and disease. Also used to lessen side effects that may be caused by some cancer treatments. Also known as immunotherapy, biotherapy, or biological response modifier (BRM) therapy. [NIH] Bioluminescence: The emission of light by living organisms such as the firefly, certain mollusks, beetles, fish, bacteria, fungi and protozoa. [NIH] Biomarkers: Substances sometimes found in an increased amount in the blood, other body fluids, or tissues and that may suggest the presence of some types of cancer. Biomarkers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and GI tract cancers), and PSA (prostate cancer). Also called tumor markers. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biopsy specimen: Tissue removed from the body and examined under a microscope to determine whether disease is present. [NIH] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] Bivalent: Pertaining to a group of 2 homologous or partly homologous chromosomes during the zygotene stage of prophase to the first metaphase in meiosis. [NIH] Bladder: The organ that stores urine. [NIH] Bleomycin: A complex of related glycopeptide antibiotics from Streptomyces verticillus consisting of bleomycin A2 and B2. It inhibits DNA metabolism and is used as an antineoplastic, especially for solid tumors. [NIH] Bloating: Fullness or swelling in the abdomen that often occurs after meals. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood Glucose: Glucose in blood. [NIH] Blood Platelets: Non-nucleated disk-shaped cells formed in the megakaryocyte and found in the blood of all mammals. They are mainly involved in blood coagulation. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]
Blotting, Western: Identification of proteins or peptides that have been electrophoretically separated by blotting and transferred to strips of nitrocellulose paper. The blots are then detected by radiolabeled antibody probes. [NIH]
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Body Fluids: Liquid components of living organisms. [NIH] Bolus: A single dose of drug usually injected into a blood vessel over a short period of time. Also called bolus infusion. [NIH] Bolus infusion: A single dose of drug usually injected into a blood vessel over a short period of time. Also called bolus. [NIH] Bolus injection: The injection of a drug (or drugs) in a high quantity (called a bolus) at once, the opposite of gradual administration (as in intravenous infusion). [EU] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bone scan: A technique to create images of bones on a computer screen or on film. A small amount of radioactive material is injected into a blood vessel and travels through the bloodstream; it collects in the bones and is detected by a scanner. [NIH] Bowel: The long tube-shaped organ in the abdomen that completes the process of digestion. There is both a small and a large bowel. Also called the intestine. [NIH] Brachytherapy: A collective term for interstitial, intracavity, and surface radiotherapy. It uses small sealed or partly-sealed sources that may be placed on or near the body surface or within a natural body cavity or implanted directly into the tissues. [NIH] Bradykinin: A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. [NIH] Brain metastases: Cancer that has spread from the original (primary) tumor to the brain. [NIH]
Breast Neoplasms: Tumors or cancer of the breast. [NIH] Broad-spectrum: Effective against a wide range of microorganisms; said of an antibiotic. [EU] Bronchi: The larger air passages of the lungs arising from the terminal bifurcation of the trachea. [NIH] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Buccal mucosa: The inner lining of the cheeks and lips. [NIH] Busulfan: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH]
Bypass: A surgical procedure in which the doctor creates a new pathway for the flow of body fluids. [NIH] Cadmium: An element with atomic symbol Cd, atomic number 48, and atomic weight 114. It is a metal and ingestion will lead to cadmium poisoning. [NIH] Cadmium Poisoning: Poisoning occurring after exposure to cadmium compounds or fumes. It may cause gastrointestinal syndromes, anemia, or pneumonitis. [NIH] Caffeine: A methylxanthine naturally occurring in some beverages and also used as a pharmacological agent. Caffeine's most notable pharmacological effect is as a central nervous system stimulant, increasing alertness and producing agitation. It also relaxes
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smooth muscle, stimulates cardiac muscle, stimulates diuresis, and appears to be useful in the treatment of some types of headache. Several cellular actions of caffeine have been observed, but it is not entirely clear how each contributes to its pharmacological profile. Among the most important are inhibition of cyclic nucleotide phosphodiesterases, antagonism of adenosine receptors, and modulation of intracellular calcium handling. [NIH] Calcifediol: The major circulating metabolite of vitamin D3 produced in the liver and the best indicator of the body's vitamin D stores. It is effective in the treatment of rickets and osteomalacia, both in azotemic and non-azotemic patients. Calcifediol also has mineralizing properties. [NIH] Calcitriol: The physiologically active form of vitamin D. It is formed primarily in the kidney by enzymatic hydroxylation of 25-hydroxycholecalciferol (calcifediol). Its production is stimulated by low blood calcium levels and parathyroid hormone. Calcitriol increases intestinal absorption of calcium and phosphorus, and in concert with parathyroid hormone increases bone resorption. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Camptothecin: An alkaloid isolated from the stem wood of the Chinese tree, Camptotheca acuminata. This compound selectively inhibits the nuclear enzyme DNA topoisomerase. Several semisynthetic analogs of camptothecin have demonstrated antitumor activity. [NIH] Capecitabine: An anticancer drug that belongs to the family of drugs called antimetabolites. [NIH]
Capillary: Any one of the minute vessels that connect the arterioles and venules, forming a network in nearly all parts of the body. Their walls act as semipermeable membranes for the interchange of various substances, including fluids, between the blood and tissue fluid; called also vas capillare. [EU] Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] Carboplatin: An organoplatinum compound that possesses antineoplastic activity. [NIH] Carcinogen: Any substance that causes cancer. [NIH] Carcinogenesis: The process by which normal cells are transformed into cancer cells. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinoid: A type of tumor usually found in the gastrointestinal system (most often in the appendix), and sometimes in the lungs or other sites. Carcinoid tumors are usually benign. [NIH]
Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]
Carcinostatic: Pertaining to slowing or stopping the growth of cancer. [NIH] Cardiac: Having to do with the heart. [NIH] Cardiotoxicity: Toxicity that affects the heart. [NIH]
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Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [NIH] Carmustine: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH]
Carnitine: Constituent of striated muscle and liver. It is used therapeutically to stimulate gastric and pancreatic secretions and in the treatment of hyperlipoproteinemias. [NIH] Carotene: The general name for a group of pigments found in green, yellow, and leafy vegetables, and yellow fruits. The pigments are fat-soluble, unsaturated aliphatic hydrocarbons functioning as provitamins and are converted to vitamin A through enzymatic processes in the intestinal wall. [NIH] Case report: A detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports also contain some demographic information about the patient (for example, age, gender, ethnic origin). [NIH] Case series: A group or series of case reports involving patients who were given similar treatment. Reports of case series usually contain detailed information about the individual patients. This includes demographic information (for example, age, gender, ethnic origin) and information on diagnosis, treatment, response to treatment, and follow-up after treatment. [NIH] Caspase: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH] Catalase: An oxidoreductase that catalyzes the conversion of hydrogen peroxide to water and oxygen. It is present in many animal cells. A deficiency of this enzyme results in acatalasia. EC 1.11.1.6. [NIH] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [NIH] Catheter: A flexible tube used to deliver fluids into or withdraw fluids from the body. [NIH] Catheterization: Use or insertion of a tubular device into a duct, blood vessel, hollow organ, or body cavity for injecting or withdrawing fluids for diagnostic or therapeutic purposes. It differs from intubation in that the tube here is used to restore or maintain patency in obstructions. [NIH] Cations: Postively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis. [NIH] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] Celecoxib: A drug that reduces pain. Celecoxib belongs to the family of drugs called nonsteroidal anti-inflammatory agents. It is being studied for cancer prevention. [NIH] Celiac Artery: The arterial trunk that arises from the abdominal aorta and after a short course divides into the left gastric, common hepatic and splenic arteries. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Count: A count of the number of cells of a specific kind, usually measured per unit volume of sample. [NIH] Cell Cycle: The complex series of phenomena, occurring between the end of one cell
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division and the end of the next, by which cellular material is divided between daughter cells. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell Division: The fission of a cell. [NIH] Cell membrane: Cell membrane = plasma membrane. The structure enveloping a cell, enclosing the cytoplasm, and forming a selective permeability barrier; it consists of lipids, proteins, and some carbohydrates, the lipids thought to form a bilayer in which integral proteins are embedded to varying degrees. [EU] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Respiration: The metabolic process of all living cells (animal and plant) in which oxygen is used to provide a source of energy for the cell. [NIH] Cell Size: The physical dimensions of a cell. It refers mainly to changes in dimensions correlated with physiological or pathological changes in cells. [NIH] Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Ceramide: A type of fat produced in the body. It may cause some types of cells to die, and is being studied in cancer treatment. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Cortex: The thin layer of gray matter on the surface of the cerebral hemisphere that develops from the telencephalon and folds into gyri. It reaches its highest development in man and is responsible for intellectual faculties and higher mental functions. [NIH] Cerebral hemispheres: The two halves of the cerebrum, the part of the brain that controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. The right hemisphere controls muscle movement on the left side of the body, and the left hemisphere controls muscle movement on the right side of the body. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cervical: Relating to the neck, or to the neck of any organ or structure. Cervical lymph nodes are located in the neck; cervical cancer refers to cancer of the uterine cervix, which is the lower, narrow end (the "neck") of the uterus. [NIH] Cervix: The lower, narrow end of the uterus that forms a canal between the uterus and vagina. [NIH] Character: In current usage, approximately equivalent to personality. The sum of the relatively fixed personality traits and habitual modes of response of an individual. [NIH] Chemoembolization: A procedure in which the blood supply to the tumor is blocked surgically or mechanically, and anticancer drugs are administered directly into the tumor. This permits a higher concentration of drug to be in contact with the tumor for a longer period of time. [NIH]
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Chemopreventive: Natural or synthetic compound used to intervene in the early precancerous stages of carcinogenesis. [NIH] Chemotactic Factors: Chemical substances that attract or repel cells or organisms. The concept denotes especially those factors released as a result of tissue injury, invasion, or immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [NIH] Chemotherapeutic agent: A drug used to treat cancer. [NIH] Chemotherapy: Treatment with anticancer drugs. [NIH] Chlorine: A greenish-yellow, diatomic gas that is a member of the halogen family of elements. It has the atomic symbol Cl, atomic number 17, and atomic weight 70.906. It is a powerful irritant that can cause fatal pulmonary edema. Chlorine is used in manufacturing, as a reagent in synthetic chemistry, for water purification, and in the production of chlorinated lime, which is used in fabric bleaching. [NIH] Chlorophyll: Porphyrin derivatives containing magnesium that act to convert light energy in photosynthetic organisms. [NIH] Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Choriocarcinoma: A malignant tumor of trophoblastic epithelium characterized by secretion of large amounts of chorionic gonadotropin. It usually originates from chorionic products of conception (i.e., hydatidiform mole, normal pregnancy, or following abortion), but can originate in a teratoma of the testis, mediastinum, or pineal gland. [NIH] Choroid: The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. [NIH] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [NIH] Chronic renal: Slow and progressive loss of kidney function over several years, often resulting in end-stage renal disease. People with end-stage renal disease need dialysis or transplantation to replace the work of the kidneys. [NIH] Chronotherapy: The adaptation of the administration of drugs to circadian rhythms. The concept is based on the response of biological functions to time-related events, such as the low point in epinephrine levels between 10 p.m. and 4 a.m. or the elevated histamine levels between midnight and 4 a.m. The treatment is aimed at supporting normal rhythms or modifying therapy based on known variations in body rhythms. While chronotherapy is commonly used in cancer chemotherapy, it is not restricted to cancer therapy or to chemotherapy. [NIH] Cinchona: A genus of rubiaceous South American trees that yields the toxic cinchona alkaloids from their bark; quinine, quinidine, chinconine, cinchonidine and others are used to treat malaria and cardiac arrhythmias. [NIH] Circadian: Repeated more or less daily, i. e. on a 23- to 25-hour cycle. [NIH] Circadian Rhythm: The regular recurrence, in cycles of about 24 hours, of biological processes or activities, such as sensitivity to drugs and stimuli, hormone secretion, sleeping,
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feeding, etc. This rhythm seems to be set by a 'biological clock' which seems to be set by recurring daylight and darkness. [NIH] CIS: Cancer Information Service. The CIS is the National Cancer Institute's link to the public, interpreting and explaining research findings in a clear and understandable manner, and providing personalized responses to specific questions about cancer. Access the CIS by calling 1-800-4-CANCER, or by using the Web site at http://cis.nci.nih.gov. [NIH] Clamp: A u-shaped steel rod used with a pin or wire for skeletal traction in the treatment of certain fractures. [NIH] Cleave: A double-stranded cut in DNA with a restriction endonuclease. [NIH] Clinical Protocols: Precise and detailed plans for the study of a medical or biomedical problem and/or plans for a regimen of therapy. [NIH] Clinical study: A research study in which patients receive treatment in a clinic or other medical facility. Reports of clinical studies can contain results for single patients (case reports) or many patients (case series or clinical trials). [NIH] Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Cochlea: The part of the internal ear that is concerned with hearing. It forms the anterior part of the labyrinth, is conical, and is placed almost horizontally anterior to the vestibule. [NIH]
Cochlear: Of or pertaining to the cochlea. [EU] Cochlear Duct: Spiral tube in the bony canal of the cochlea, lying on its outer wall between the scala vestibuli and scala tympani. [NIH] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Colloidal: Of the nature of a colloid. [EU] Colon: The long, coiled, tubelike organ that removes water from digested food. The remaining material, solid waste called stool, moves through the colon to the rectum and leaves the body through the anus. [NIH] Colony-Stimulating Factors: Glycoproteins found in a subfraction of normal mammalian plasma and urine. They stimulate the proliferation of bone marrow cells in agar cultures and the formation of colonies of granulocytes and/or macrophages. The factors include interleukin-3 (IL-3), granulocyte colony-stimulating factor (G-CSF), macrophage colonystimulating factor (M-CSF), and granulocyte-macrophage colony-stimulating factor (GMCSF). [NIH] Colorectal: Having to do with the colon or the rectum. [NIH]
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Colorectal Cancer: Cancer that occurs in the colon (large intestine) or the rectum (the end of the large intestine). A number of digestive diseases may increase a person's risk of colorectal cancer, including polyposis and Zollinger-Ellison Syndrome. [NIH] Combination chemotherapy: Treatment using more than one anticancer drug. [NIH] Combination Therapy: Association of 3 drugs to treat AIDS (AZT + DDC or DDI + protease inhibitor). [NIH] Combinatorial: A cut-and-paste process that churns out thousands of potentially valuable compounds at once. [NIH] Combined Modality Therapy: The treatment of a disease or condition by several different means simultaneously or sequentially. Chemoimmunotherapy, radioimmunotherapy, chemoradiotherapy, cryochemotherapy, and salvage therapy are seen most frequently, but their combinations with each other and surgery are also used. [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Complementary and alternative medicine: CAM. Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices are not considered standard medical approaches. CAM includes dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementary medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used to enhance or complement the standard treatments. Complementary medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementation: The production of a wild-type phenotype when two different mutations are combined in a diploid or a heterokaryon and tested in trans-configuration. [NIH] Complete remission: The disappearance of all signs of cancer. Also called a complete response. [NIH]
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Complete response: The disappearance of all signs of cancer in response to treatment. This does not always mean the cancer has been cured. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Computed tomography: CT scan. A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized tomography and computerized axial tomography (CAT) scan. [NIH] Computerized axial tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called CAT scan, computed tomography (CT scan), or computerized tomography. [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Concomitant: Accompanying; accessory; joined with another. [EU] Conduction: The transfer of sound waves, heat, nervous impulses, or electricity. [EU] Cones: One type of specialized light-sensitive cells (photoreceptors) in the retina that provide sharp central vision and color vision. [NIH] Congenita: Displacement, subluxation, or malposition of the crystalline lens. [NIH] Conjugated: Acting or operating as if joined; simultaneous. [EU] Conjunctivitis: Inflammation of the conjunctiva, generally consisting of conjunctival hyperaemia associated with a discharge. [EU] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Consolidation: The healing process of a bone fracture. [NIH] Consolidation therapy: Chemotherapy treatments given after induction chemotherapy to further reduce the number of cancer cells. [NIH] Continuous infusion: The administration of a fluid into a blood vessel, usually over a prolonged period of time. [NIH] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Contralateral: Having to do with the opposite side of the body. [NIH] Contrast Media: Substances used in radiography that allow visualization of certain tissues. [NIH]
Control group: In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works. [NIH] Conventional treatment: A currently accepted and widely used treatment for a certain type of disease, based on the results of past research. Also called conventional therapy. [NIH]
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Cooperative group: A group of physicians, hospitals, or both formed to treat a large number of persons in the same way so that new treatment can be evaluated quickly. Clinical trials of new cancer treatments often require many more people than a single physician or hospital can care for. [NIH] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Cortical: Pertaining to or of the nature of a cortex or bark. [EU] Corticosteroids: Hormones that have antitumor activity in lymphomas and lymphoid leukemias; in addition, corticosteroids (steroids) may be used for hormone replacement and for the management of some of the complications of cancer and its treatment. [NIH] Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [NIH] Cortisone: A natural steroid hormone produced in the adrenal gland. It can also be made in the laboratory. Cortisone reduces swelling and can suppress immune responses. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Creatinine: A compound that is excreted from the body in urine. Creatinine levels are measured to monitor kidney function. [NIH] Crossing-over: The exchange of corresponding segments between chromatids of homologous chromosomes during meiosia, forming a chiasma. [NIH] Cultured cells: Animal or human cells that are grown in the laboratory. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cyclin: Molecule that regulates the cell cycle. [NIH] Cyclophosphamide: Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active aldophosphamide. It is used in the treatment of lymphomas, leukemias, etc. Its side effect, alopecia, has been made use of in defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. [NIH] Cyclosporine: A drug used to help reduce the risk of rejection of organ and bone marrow transplants by the body. It is also used in clinical trials to make cancer cells more sensitive to anticancer drugs. [NIH] Cyproterone: An anti-androgen that, in the form of its acetate, also has progestational properties. It is used in the treatment of hypersexuality in males, as a palliative in prostatic carcinoma, and, in combination with estrogen, for the therapy of severe acne and hirsutism
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in females. [NIH] Cystectomy: Used for excision of the urinary bladder. [NIH] Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH] Cysteinyl: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH] Cystine: A covalently linked dimeric nonessential amino acid formed by the oxidation of cysteine. Two molecules of cysteine are joined together by a disulfide bridge to form cystine. [NIH]
Cytarabine: An anticancer drug that belongs to the family of drugs called antimetabolites. [NIH]
Cytochrome: Any electron transfer hemoprotein having a mode of action in which the transfer of a single electron is effected by a reversible valence change of the central iron atom of the heme prosthetic group between the +2 and +3 oxidation states; classified as cytochromes a in which the heme contains a formyl side chain, cytochromes b, which contain protoheme or a closely similar heme that is not covalently bound to the protein, cytochromes c in which protoheme or other heme is covalently bound to the protein, and cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, . New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [EU] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytomegalovirus: A genus of the family Herpesviridae, subfamily Betaherpesvirinae, infecting the salivary glands, liver, spleen, lungs, eyes, and other organs, in which they produce characteristically enlarged cells with intranuclear inclusions. Infection with Cytomegalovirus is also seen as an opportunistic infection in AIDS. [NIH] Cytomegalovirus Infections: Infection with Cytomegalovirus, characterized by enlarged cells bearing intranuclear inclusions. Infection may be in almost any organ, but the salivary glands are the most common site in children, as are the lungs in adults. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Cytosine: A pyrimidine base that is a fundamental unit of nucleic acids. [NIH] Cytostatic: An agent that suppresses cell growth and multiplication. [EU] Cytotoxic: Cell-killing. [NIH] Cytotoxic chemotherapy: Anticancer drugs that kill cells, especially cancer cells. [NIH] Cytotoxicity: Quality of being capable of producing a specific toxic action upon cells of special organs. [NIH] Cytotoxins: Substances elaborated by microorganisms, plants or animals that are specifically toxic to individual cells; they may be involved in immunity or may be contained in venoms. [NIH]
Daunorubicin: Very toxic anthracycline aminoglycoside antibiotic isolated from Streptomyces peucetius and others, used in treatment of leukemias and other neoplasms. [NIH]
Deamination: The removal of an amino group (NH2) from a chemical compound. [NIH]
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Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Dehydration: The condition that results from excessive loss of body water. [NIH] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Dementia: An acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. The dysfunction is multifaceted and involves memory, behavior, personality, judgment, attention, spatial relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness. [NIH] Denaturation: Rupture of the hydrogen bonds by heating a DNA solution and then cooling it rapidly causes the two complementary strands to separate. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Deoxyglucose: 2-Deoxy-D-arabino-hexose. An antimetabolite of glucose with antiviral activity. [NIH] Depolarization: The process or act of neutralizing polarity. In neurophysiology, the reversal of the resting potential in excitable cell membranes when stimulated, i.e., the tendency of the cell membrane potential to become positive with respect to the potential outside the cell. [EU] Depressive Disorder: An affective disorder manifested by either a dysphoric mood or loss of interest or pleasure in usual activities. The mood disturbance is prominent and relatively persistent. [NIH] Desensitization: The prevention or reduction of immediate hypersensitivity reactions by administration of graded doses of allergen; called also hyposensitization and immunotherapy. [EU] Detoxification: Treatment designed to free an addict from his drug habit. [EU] Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton in the nucleus. [NIH] Dexamethasone: (11 beta,16 alpha)-9-Fluoro-11,17,21-trihydroxy-16-methylpregna-1,4diene-3,20-dione. An anti-inflammatory glucocorticoid used either in the free alcohol or esterified form in treatment of conditions that respond generally to cortisone. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Dialyzer: A part of the hemodialysis machine. (See hemodialysis under dialysis.) The dialyzer has two sections separated by a membrane. One section holds dialysate. The other holds the patient's blood. [NIH] Diaphragm: The musculofibrous partition that separates the thoracic cavity from the abdominal cavity. Contraction of the diaphragm increases the volume of the thoracic cavity aiding inspiration. [NIH] Diethylcarbamazine: An anthelmintic used primarily as the citrate in the treatment of filariasis, particularly infestations with Wucheria bancrofti or Loa loa. [NIH] Diffusion: The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space; a major mechanism of biological transport. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH]
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Digestive system: The organs that take in food and turn it into products that the body can use to stay healthy. Waste products the body cannot use leave the body through bowel movements. The digestive system includes the salivary glands, mouth, esophagus, stomach, liver, pancreas, gallbladder, small and large intestines, and rectum. [NIH] Digestive tract: The organs through which food passes when food is eaten. These organs are the mouth, esophagus, stomach, small and large intestines, and rectum. [NIH] Dihydrotestosterone: Anabolic agent. [NIH] Dihydroxy: AMPA/Kainate antagonist. [NIH] Diploid: Having two sets of chromosomes. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Discrimination: The act of qualitative and/or quantitative differentiation between two or more stimuli. [NIH] Disinfectant: An agent that disinfects; applied particularly to agents used on inanimate objects. [EU] Dissociation: 1. The act of separating or state of being separated. 2. The separation of a molecule into two or more fragments (atoms, molecules, ions, or free radicals) produced by the absorption of light or thermal energy or by solvation. 3. In psychology, a defense mechanism in which a group of mental processes are segregated from the rest of a person's mental activity in order to avoid emotional distress, as in the dissociative disorders (q.v.), or in which an idea or object is segregated from its emotional significance; in the first sense it is roughly equivalent to splitting, in the second, to isolation. 4. A defect of mental integration in which one or more groups of mental processes become separated off from normal consciousness and, thus separated, function as a unitary whole. [EU] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU] Diuresis: Increased excretion of urine. [EU] Diuretic: A drug that increases the production of urine. [NIH] DNA Topoisomerase: An enzyme catalyzing ATP-independent breakage of single-stranded DNA, followed by passage and rejoining of another single-stranded DNA. This enzyme class brings about the conversion of one topological isomer of DNA into another, e.g., the relaxation of superhelical turns in DNA, the interconversion of simple and knotted rings of single-stranded DNA, and the intertwisting of single-stranded rings of complementary sequences. (From Enzyme Nomenclature, 1992) EC 5.99.1.2. [NIH] Docetaxel: An anticancer drug that belongs to the family of drugs called mitotic inhibitors. [NIH]
Dopamine: An endogenous catecholamine and prominent neurotransmitter in several systems of the brain. In the synthesis of catecholamines from tyrosine, it is the immediate precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of dopaminergic receptor subtypes mediate its action. Dopamine is used pharmacologically for its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH] Dorsal: 1. Pertaining to the back or to any dorsum. 2. Denoting a position more toward the back surface than some other object of reference; same as posterior in human anatomy; superior in the anatomy of quadrupeds. [EU] Dorsum: A plate of bone which forms the posterior boundary of the sella turcica. [NIH]
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Dose-dependent: Refers to the effects of treatment with a drug. If the effects change when the dose of the drug is changed, the effects are said to be dose dependent. [NIH] Dose-limiting: Describes side effects of a drug or other treatment that are serious enough to prevent an increase in dose or level of that treatment. [NIH] Dosimetry: All the methods either of measuring directly, or of measuring indirectly and computing, absorbed dose, absorbed dose rate, exposure, exposure rate, dose equivalent, and the science associated with these methods. [NIH] Double-blind: Pertaining to a clinical trial or other experiment in which neither the subject nor the person administering treatment knows which treatment any particular subject is receiving. [EU] Doxorubicin: Antineoplastic antibiotic obtained from Streptomyces peucetics. It is a hydroxy derivative of daunorubicin and is used in treatment of both leukemia and solid tumors. [NIH] DPPE: Belongs to a group of antihormone drugs. [NIH] Drive: A state of internal activity of an organism that is a necessary condition before a given stimulus will elicit a class of responses; e.g., a certain level of hunger (drive) must be present before food will elicit an eating response. [NIH] Drug Delivery Systems: Systems of administering drugs through controlled delivery so that an optimum amount reaches the target site. Drug delivery systems encompass the carrier, route, and target. [NIH] Drug Design: The molecular designing of drugs for specific purposes (such as DNAbinding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include pharmacokinetics, dosage analysis, or drug administration analysis. [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] Drug Resistance: Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from drug tolerance which is the progressive diminution of the susceptibility of a human or animal to the effects of a drug, as a result of continued administration. [NIH] Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from drug resistance wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from maximum tolerated dose and no-observed-adverse-effect level. [NIH] Drug Toxicity: Manifestations of the adverse effects of drugs administered therapeutically or in the course of diagnostic techniques. It does not include accidental or intentional poisoning for which specific headings are available. [NIH] Duct: A tube through which body fluids pass. [NIH] Duodenum: The first part of the small intestine. [NIH] Dura mater: The outermost, toughest, and most fibrous of the three membranes (meninges) covering the brain and spinal cord; called also pachymeninx. [EU] Dyspepsia: Impaired digestion, especially after eating. [NIH] Ectoderm: The outer of the three germ layers of the embryo. [NIH]
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Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Elastic: Susceptible of resisting and recovering from stretching, compression or distortion applied by a force. [EU] Elastin: The protein that gives flexibility to tissues. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electrons: Stable elementary particles having the smallest known negative charge, present in all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the chemical identities of elements. Beams of electrons are called cathode rays or beta rays, the latter being a high-energy biproduct of nuclear decay. [NIH] Electrophoresis: An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. [NIH]
Emboli: Bit of foreign matter which enters the blood stream at one point and is carried until it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] Embolization: The blocking of an artery by a clot or foreign material. Embolization can be done as treatment to block the flow of blood to a tumor. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Emesis: Vomiting; an act of vomiting. Also used as a word termination, as in haematemesis. [EU]
Emulsion: A preparation of one liquid distributed in small globules throughout the body of a second liquid. The dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase. When oil is the dispersed liquid and an aqueous solution is the continuous phase, it is known as an oil-in-water emulsion, whereas when water or aqueous solution is the dispersed phase and oil or oleaginous substance is the continuous phase, it is known as a water-in-oil emulsion. Pharmaceutical emulsions for which official standards have been promulgated include cod liver oil emulsion, cod liver oil emulsion with malt, liquid petrolatum emulsion, and phenolphthalein in liquid petrolatum emulsion. [EU] Encapsulated: Confined to a specific, localized area and surrounded by a thin layer of tissue. [NIH]
Endemic: Present or usually prevalent in a population or geographical area at all times; said of a disease or agent. Called also endemial. [EU] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Endometrial: Having to do with the endometrium (the layer of tissue that lines the uterus). [NIH]
Endometrium: The layer of tissue that lines the uterus. [NIH] Endonucleases: Enzymes that catalyze the hydrolysis of the internal bonds and thereby the formation of polynucleotides or oligonucleotides from ribo- or deoxyribonucleotide chains. EC 3.1.-. [NIH]
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Endorphins: One of the three major groups of endogenous opioid peptides. They are large peptides derived from the pro-opiomelanocortin precursor. The known members of this group are alpha-, beta-, and gamma-endorphin. The term endorphin is also sometimes used to refer to all opioid peptides, but the narrower sense is used here; opioid peptides is used for the broader group. [NIH] Endoscope: A thin, lighted tube used to look at tissues inside the body. [NIH] Endoscopic: A technique where a lateral-view endoscope is passed orally to the duodenum for visualization of the ampulla of Vater. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelium: A layer of epithelium that lines the heart, blood vessels (endothelium, vascular), lymph vessels (endothelium, lymphatic), and the serous cavities of the body. [NIH] Endothelium-derived: Small molecule that diffuses to the adjacent muscle layer and relaxes it. [NIH] Endotoxic: Of, relating to, or acting as an endotoxin (= a heat-stable toxin, associated with the outer membranes of certain gram-negative bacteria. Endotoxins are not secreted and are released only when the cells are disrupted). [EU] Endotoxin: Toxin from cell walls of bacteria. [NIH] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH] Enhancer: Transcriptional element in the virus genome. [NIH] Enkephalins: One of the three major families of endogenous opioid peptides. The enkephalins are pentapeptides that are widespread in the central and peripheral nervous systems and in the adrenal medulla. [NIH] Enteropeptidase: A specialized proteolytic enzyme secreted by intestinal cells. It converts trypsinogen into its active form trypsin by removing the N-terminal peptide. EC 3.4.21.9. [NIH]
Environmental Exposure: The exposure to potentially harmful chemical, physical, or biological agents in the environment or to environmental factors that may include ionizing radiation, pathogenic organisms, or toxic chemicals. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]
Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Eosinophils: Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. [NIH] Epidemic: Occurring suddenly in numbers clearly in excess of normal expectancy; said especially of infectious diseases but applied also to any disease, injury, or other healthrelated event occurring in such outbreaks. [EU] Epidermal: Pertaining to or resembling epidermis. Called also epidermic or epidermoid. [EU] Epidermal Growth Factor: A 6 kD polypeptide growth factor initially discovered in mouse submaxillary glands. Human epidermal growth factor was originally isolated from urine based on its ability to inhibit gastric secretion and called urogastrone. epidermal growth
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factor exerts a wide variety of biological effects including the promotion of proliferation and differentiation of mesenchymal and epithelial cells. [NIH] Epidermal growth factor receptor: EGFR. The protein found on the surface of some cells and to which epidermal growth factor binds, causing the cells to divide. It is found at abnormally high levels on the surface of many types of cancer cells, so these cells may divide excessively in the presence of epidermal growth factor. Also known as ErbB1 or HER1. [NIH] Epidermis: Nonvascular layer of the skin. It is made up, from within outward, of five layers: 1) basal layer (stratum basale epidermidis); 2) spinous layer (stratum spinosum epidermidis); 3) granular layer (stratum granulosum epidermidis); 4) clear layer (stratum lucidum epidermidis); and 5) horny layer (stratum corneum epidermidis). [NIH] Epidermoid carcinoma: A type of cancer in which the cells are flat and look like fish scales. Also called squamous cell carcinoma. [NIH] Epigastric: Having to do with the upper middle area of the abdomen. [NIH] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] Epirubicin: An anthracycline antibiotic which is the 4'-epi-isomer of doxorubicin. The compound exerts its antitumor effects by interference with the synthesis and function of DNA. Clinical studies indicate activity in breast cancer, non-Hodgkin's lymphomas, ovarian cancer, soft-tissue sarcomas, pancreatic cancer, gastric cancer, small-cell lung cancer and acute leukemia. It is equal in activity to doxorubicin but exhibits less acute toxicities and less cardiotoxicity. [NIH] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelial carcinoma: Cancer that begins in the cells that line an organ. [NIH] Epithelial Cells: Cells that line the inner and outer surfaces of the body. [NIH] Epithelial ovarian cancer: Cancer that occurs in the cells lining the ovaries. [NIH] Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which covers the inner or outer surfaces of the body. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Erythropoiesis: The production of erythrocytes. [EU] Erythropoietin: Glycoprotein hormone, secreted chiefly by the kidney in the adult and the liver in the fetus, that acts on erythroid stem cells of the bone marrow to stimulate proliferation and differentiation. [NIH] Escalation: Progressive use of more harmful drugs. [NIH] Esophageal: Having to do with the esophagus, the muscular tube through which food passes from the throat to the stomach. [NIH] Esophagus: The muscular tube through which food passes from the throat to the stomach. [NIH]
Estrogen: One of the two female sex hormones. [NIH] Estrogen receptor: ER. Protein found on some cancer cells to which estrogen will attach. [NIH]
Ethanol: A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical
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disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. [NIH] Ethylene Glycol: A colorless, odorless, viscous dihydroxy alcohol. It has a sweet taste, but is poisonous if ingested. Ethylene glycol is the most important glycol commercially available and is manufactured on a large scale in the United States. It is used as an antifreeze and coolant, in hydraulic fluids, and in the manufacture of low-freezing dynamites and resins. [NIH]
Etoposide: A semisynthetic derivative of podophyllotoxin that exhibits antitumor activity. Etoposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding. Accumulated breaks in DNA prevent entry into the mitotic phase of cell division, and lead to cell death. Etoposide acts primarily in the G2 and S phases of the cell cycle. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Evacuation: An emptying, as of the bowels. [EU] Excipients: Usually inert substances added to a prescription in order to provide suitable consistency to the dosage form; a binder, matrix, base or diluent in pills, tablets, creams, salves, etc. [NIH] Excisional: The surgical procedure of removing a tumor by cutting it out. The biopsy is then examined under a microscope. [NIH] Excitability: Property of a cardiac cell whereby, when the cell is depolarized to a critical level (called threshold), the membrane becomes permeable and a regenerative inward current causes an action potential. [NIH] Excitation: An act of irritation or stimulation or of responding to a stimulus; the addition of energy, as the excitation of a molecule by absorption of photons. [EU] Excitatory: When cortical neurons are excited, their output increases and each new input they receive while they are still excited raises their output markedly. [NIH] Exhaustion: The feeling of weariness of mind and body. [NIH] Exocrine: Secreting outwardly, via a duct. [EU] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Exon: The part of the DNA that encodes the information for the actual amino acid sequence of the protein. In many eucaryotic genes, the coding sequences consist of a series of exons alternating with intron sequences. [NIH] External radiation: Radiation therapy that uses a machine to aim high-energy rays at the cancer. Also called external-beam radiation. [NIH] External-beam radiation: Radiation therapy that uses a machine to aim high-energy rays at the cancer. Also called external radiation. [NIH] Extracellular: Outside a cell or cells. [EU] Extracellular Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. [NIH] Extracorporeal: Situated or occurring outside the body. [EU] Extrapyramidal: Outside of the pyramidal tracts. [EU]
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Extremity: A limb; an arm or leg (membrum); sometimes applied specifically to a hand or foot. [EU] Eye Infections: Infection, moderate to severe, caused by bacteria, fungi, or viruses, which occurs either on the external surface of the eye or intraocularly with probable inflammation, visual impairment, or blindness. [NIH] Facial: Of or pertaining to the face. [EU] Facial Nerve: The 7th cranial nerve. The facial nerve has two parts, the larger motor root which may be called the facial nerve proper, and the smaller intermediate or sensory root. Together they provide efferent innervation to the muscles of facial expression and to the lacrimal and salivary glands, and convey afferent information for taste from the anterior two-thirds of the tongue and for touch from the external ear. [NIH] Fallopian tube: The oviduct, a muscular tube about 10 cm long, lying in the upper border of the broad ligament. [NIH] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fat: Total lipids including phospholipids. [NIH] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]
Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] Fenretinide: A synthetic retinoid that is used orally as a chemopreventive against prostate cancer and in women at risk of developing contralateral breast cancer. It is also effective as an antineoplastic agent. [NIH] Fetoprotein: Transabdominal aspiration of fluid from the amniotic sac with a view to detecting increases of alpha-fetoprotein in maternal blood during pregnancy, as this is an important indicator of open neural tube defects in the fetus. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Filgrastim: A colony-stimulating factor that stimulates the production of neutrophils (a type of white blood cell). It is a cytokine that belongs to the family of drugs called hematopoietic (blood-forming) agents. Also called granulocyte colony-stimulating factor (G-CSF). [NIH] Filtration: The passage of a liquid through a filter, accomplished by gravity, pressure, or vacuum (suction). [EU] Fixation: 1. The act or operation of holding, suturing, or fastening in a fixed position. 2. The condition of being held in a fixed position. 3. In psychiatry, a term with two related but distinct meanings : (1) arrest of development at a particular stage, which like regression (return to an earlier stage), if temporary is a normal reaction to setbacks and difficulties but if protracted or frequent is a cause of developmental failures and emotional problems, and (2) a close and suffocating attachment to another person, especially a childhood figure, such as one's mother or father. Both meanings are derived from psychoanalytic theory and refer to 'fixation' of libidinal energy either in a specific erogenous zone, hence fixation at the oral, anal, or phallic stage, or in a specific object, hence mother or father fixation. 4. The use of a fixative (q.v.) to preserve histological or cytological specimens. 5. In chemistry, the process whereby a substance is removed from the gaseous or solution phase and localized, as in carbon dioxide fixation or nitrogen fixation. 6. In ophthalmology, direction of the gaze so
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that the visual image of the object falls on the fovea centralis. 7. In film processing, the chemical removal of all undeveloped salts of the film emulsion, leaving only the developed silver to form a permanent image. [EU] Flow Cytometry: Technique using an instrument system for making, processing, and displaying one or more measurements on individual cells obtained from a cell suspension. Cells are usually stained with one or more fluorescent dyes specific to cell components of interest, e.g., DNA, and fluorescence of each cell is measured as it rapidly transverses the excitation beam (laser or mercury arc lamp). Fluorescence provides a quantitative measure of various biochemical and biophysical properties of the cell, as well as a basis for cell sorting. Other measurable optical parameters include light absorption and light scattering, the latter being applicable to the measurement of cell size, shape, density, granularity, and stain uptake. [NIH] Fludarabine: An anticancer drug that belongs to the family of drugs called antimetabolites. [NIH]
Fluorescence: The property of emitting radiation while being irradiated. The radiation emitted is usually of longer wavelength than that incident or absorbed, e.g., a substance can be irradiated with invisible radiation and emit visible light. X-ray fluorescence is used in diagnosis. [NIH] Fluorescent Dyes: Dyes that emit light when exposed to light. The wave length of the emitted light is usually longer than that of the incident light. Fluorochromes are substances that cause fluorescence in other substances, i.e., dyes used to mark or label other compounds with fluorescent tags. They are used as markers in biochemistry and immunology. [NIH] Fluorouracil: A pyrimidine analog that acts as an antineoplastic antimetabolite and also has immunosuppressant. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. [NIH] Flutamide: An antiandrogen with about the same potency as cyproterone in rodent and canine species. [NIH] Folate: A B-complex vitamin that is being studied as a cancer prevention agent. Also called folic acid. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Folic Acid: N-(4-(((2-Amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl)amino)benzoyl)-Lglutamic acid. A member of the vitamin B family that stimulates the hematopoietic system. It is present in the liver and kidney and is found in mushrooms, spinach, yeast, green leaves, and grasses. Folic acid is used in the treatment and prevention of folate deficiencies and megaloblastic anemia. [NIH] Foramen: A natural hole of perforation, especially one in a bone. [NIH] Fractionation: Dividing the total dose of radiation therapy into several smaller, equal doses delivered over a period of several days. [NIH] Free Radicals: Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. [NIH] Fungus: A general term used to denote a group of eukaryotic protists, including mushrooms, yeasts, rusts, moulds, smuts, etc., which are characterized by the absence of chlorophyll and by the presence of a rigid cell wall composed of chitin, mannans, and sometimes cellulose. They are usually of simple morphological form or show some reversible cellular specialization, such as the formation of pseudoparenchymatous tissue in
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the fruiting body of a mushroom. The dimorphic fungi grow, according to environmental conditions, as moulds or yeasts. [EU] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Gamma Rays: Very powerful and penetrating, high-energy electromagnetic radiation of shorter wavelength than that of x-rays. They are emitted by a decaying nucleus, usually between 0.01 and 10 MeV. They are also called nuclear x-rays. [NIH] Gamma-Glutamyltransferase: An enzyme that catalyzes reversibly the transfer of a glutamyl group from a glutamyl-peptide and an amino acid to a peptide and a glutamylamino acid. EC 2.3.2.2. [NIH] Ganciclovir: Acyclovir analog that is a potent inhibitor of the Herpesvirus family including cytomegalovirus. Ganciclovir is used to treat complications from AIDS-associated cytomegalovirus infections. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Ganglion: 1. A knot, or knotlike mass. 2. A general term for a group of nerve cell bodies located outside the central nervous system; occasionally applied to certain nuclear groups within the brain or spinal cord, e.g. basal ganglia. 3. A benign cystic tumour occurring on a aponeurosis or tendon, as in the wrist or dorsum of the foot; it consists of a thin fibrous capsule enclosing a clear mucinous fluid. [EU] Ganglioside: Protein kinase C's inhibitor which reduces ischemia-related brain damage. [NIH]
Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gastric: Having to do with the stomach. [NIH] Gastric Emptying: The evacuation of food from the stomach into the duodenum. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]
Gastroesophageal Reflux: Reflux of gastric juice and/or duodenal contents (bile acids, pancreatic juice) into the distal esophagus, commonly due to incompetence of the lower esophageal sphincter. Gastric regurgitation is an extension of this process with entry of fluid into the pharynx or mouth. [NIH] Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gastroparesis: Nerve or muscle damage in the stomach. Causes slow digestion and emptying, vomiting, nausea, or bloating. Also called delayed gastric emptying. [NIH] Gemcitabine: An anticancer drug that belongs to the family of drugs called antimetabolites. [NIH]
Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]
Gene Amplification: A selective increase in the number of copies of a gene coding for a specific protein without a proportional increase in other genes. It occurs naturally via the excision of a copy of the repeating sequence from the chromosome and its extrachromosomal replication in a plasmid, or via the production of an RNA transcript of the entire repeating sequence of ribosomal RNA followed by the reverse transcription of the molecule to produce an additional copy of the original DNA sequence. Laboratory
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techniques have been introduced for inducing disproportional replication by unequal crossing over, uptake of DNA from lysed cells, or generation of extrachromosomal sequences from rolling circle replication. [NIH] Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Gene Silencing: Interruption or suppression of the expression of a gene at transcriptional or translational levels. [NIH] Gene Therapy: The introduction of new genes into cells for the purpose of treating disease by restoring or adding gene expression. Techniques include insertion of retroviral vectors, transfection, homologous recombination, and injection of new genes into the nuclei of single cell embryos. The entire gene therapy process may consist of multiple steps. The new genes may be introduced into proliferating cells in vivo (e.g., bone marrow) or in vitro (e.g., fibroblast cultures) and the modified cells transferred to the site where the gene expression is required. Gene therapy may be particularly useful for treating enzyme deficiency diseases, hemoglobinopathies, and leukemias and may also prove useful in restoring drug sensitivity, particularly for leukemia. [NIH] Genetic Code: The specifications for how information, stored in nucleic acid sequence (base sequence), is translated into protein sequence (amino acid sequence). The start, stop, and order of amino acids of a protein is specified by consecutive triplets of nucleotides called codons (codon). [NIH] Genetic Techniques: Chromosomal, biochemical, intracellular, and other methods used in the study of genetics. [NIH] Genetic testing: Analyzing DNA to look for a genetic alteration that may indicate an increased risk for developing a specific disease or disorder. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genistein: An isoflavonoid derived from soy products. It inhibits protein-tyrosine kinase and topoisomerase-ii (dna topoisomerase (atp-hydrolysing)) activity and is used as an antineoplastic and antitumor agent. Experimentally, it has been shown to induce G2 phase arrest in human and murine cell lines. [NIH] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Germ cell tumors: Tumors that begin in the cells that give rise to sperm or eggs. They can occur virtually anywhere in the body and can be either benign or malignant. [NIH] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Germinoma: The most frequent type of germ-cell tumor in the brain. [NIH] Germline mutation: A gene change in the body's reproductive cells (egg or sperm) that becomes incorporated into the DNA of every cell in the body of offspring; germline mutations are passed on from parents to offspring. Also called hereditary mutation. [NIH] Gestational: Psychosis attributable to or occurring during pregnancy. [NIH] Gestational trophoblastic disease: A rare cancer in women of child-bearing age in which cancer cells grow in the tissues that are formed in the uterus after conception. Also called gestational trophoblastic tumor, gestational trophoblastic neoplasia, molar pregnancy, or choriocarcinoma. [NIH] Gestational trophoblastic neoplasia: A rare cancer in women of child-bearing age in which cancer cells grow in the tissues that are formed in the uterus after conception. Also called gestational trophoblastic disease, gestational trophoblastic tumor, molar pregnancy, or
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choriocarcinoma. [NIH] Gestational trophoblastic tumor: A rare cancer in women of child-bearing age in which cancer cells grow in the tissues that are formed in the uterus after conception. Also called gestational trophoblastic disease, gestational trophoblastic neoplasia, molar pregnancy, or choriocarcinoma. [NIH] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Glioblastoma: A malignant form of astrocytoma histologically characterized by pleomorphism of cells, nuclear atypia, microhemorrhage, and necrosis. They may arise in any region of the central nervous system, with a predilection for the cerebral hemispheres, basal ganglia, and commissural pathways. Clinical presentation most frequently occurs in the fifth or sixth decade of life with focal neurologic signs or seizures. [NIH] Glioblastoma multiforme: A type of brain tumor that forms from glial (supportive) tissue of the brain. It grows very quickly and has cells that look very different from normal cells. Also called grade IV astrocytoma. [NIH] Glioma: A cancer of the brain that comes from glial, or supportive, cells. [NIH] Glomerular: Pertaining to or of the nature of a glomerulus, especially a renal glomerulus. [EU]
Glomerular Filtration Rate: The volume of water filtered out of plasma through glomerular capillary walls into Bowman's capsules per unit of time. It is considered to be equivalent to inulin clearance. [NIH] Glomerulus: A tiny set of looping blood vessels in the nephron where blood is filtered in the kidney. [NIH] Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs). [NIH] Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] Glutamate: Excitatory neurotransmitter of the brain. [NIH] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [NIH]
Glutathione Peroxidase: An enzyme catalyzing the oxidation of 2 moles of glutathione in the presence of hydrogen peroxide to yield oxidized glutathione and water. EC 1.11.1.9. [NIH]
Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Glycosidic: Formed by elimination of water between the anomeric hydroxyl of one sugar and a hydroxyl of another sugar molecule. [NIH] Gonad: A sex organ, such as an ovary or a testicle, which produces the gametes in most multicellular animals. [NIH] Gonadal: Pertaining to a gonad. [EU]
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Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Grade: The grade of a tumor depends on how abnormal the cancer cells look under a microscope and how quickly the tumor is likely to grow and spread. Grading systems are different for each type of cancer. [NIH] Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body. [NIH] Graft Rejection: An immune response with both cellular and humoral components, directed against an allogeneic transplant, whose tissue antigens are not compatible with those of the recipient. [NIH] Graft-versus-host disease: GVHD. A reaction of donated bone marrow or peripheral stem cells against a person's tissue. [NIH] Granisetron: A serotonin receptor (5HT-3 selective) antagonist that has been used as an antiemetic for cancer chemotherapy patients. [NIH] Granulocyte: A type of white blood cell that fights bacterial infection. Neutrophils, eosinophils, and basophils are granulocytes. [NIH] Granulocyte Colony-Stimulating Factor: A glycoprotein of MW 25 kDa containing internal disulfide bonds. It induces the survival, proliferation, and differentiation of neutrophilic granulocyte precursor cells and functionally activates mature blood neutrophils. Among the family of colony-stimulating factors, G-CSF is the most potent inducer of terminal differentiation to granulocytes and macrophages of leukemic myeloid cell lines. [NIH] Granulocytopenia: A deficiency in the number of granulocytes, a type of white blood cell. [NIH]
Grasses: A large family, Gramineae, of narrow-leaved herbaceous monocots. Many grasses produce highly allergenic pollens and are hosts to cattle parasites and toxic fungi. [NIH] Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Guanine: One of the four DNA bases. [NIH] Guanylate Cyclase: An enzyme that catalyzes the conversion of GTP to 3',5'-cyclic GMP and pyrophosphate. It also acts on ITP and dGTP. (From Enzyme Nomenclature, 1992) EC 4.6.1.2. [NIH] Gynecologic cancer: Cancer of the female reproductive tract, including the cervix, endometrium, fallopian tubes, ovaries, uterus, and vagina. [NIH] Habitual: Of the nature of a habit; according to habit; established by or repeated by force of habit, customary. [EU] Haematemesis: The vomiting of blood. [EU] Haemodialysis: The removal of certain elements from the blood by virtue of the difference in the rates of their diffusion through a semipermeable membrane, e.g., by means of a haemodialyzer. [EU] Hair Cells: Mechanoreceptors located in the organ of Corti that are sensitive to auditory stimuli and in the vestibular apparatus that are sensitive to movement of the head. In each case the accessory sensory structures are arranged so that appropriate stimuli cause movement of the hair-like projections (stereocilia and kinocilia) which relay the information centrally in the nervous system. [NIH] Half-Life: The time it takes for a substance (drug, radioactive nuclide, or other) to lose half
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of its pharmacologic, physiologic, or radiologic activity. [NIH] Haploid: An organism with one basic chromosome set, symbolized by n; the normal condition of gametes in diploids. [NIH] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] Headache: Pain in the cranial region that may occur as an isolated and benign symptom or as a manifestation of a wide variety of conditions including subarachnoid hemorrhage; craniocerebral trauma; central nervous system infections; intracranial hypertension; and other disorders. In general, recurrent headaches that are not associated with a primary disease process are referred to as headache disorders (e.g., migraine). [NIH] Health Behavior: Behaviors expressed by individuals to protect, maintain or promote their health status. For example, proper diet, and appropriate exercise are activities perceived to influence health status. Life style is closely associated with health behavior and factors influencing life style are socioeconomic, educational, and cultural. [NIH] Health Status: The level of health of the individual, group, or population as subjectively assessed by the individual or by more objective measures. [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Hematogenous: Originating in the blood or spread through the bloodstream. [NIH] Hematologic malignancies: Cancers of the blood or bone marrow, including leukemia and lymphoma. Also called hematologic cancers. [NIH] Hemodialysis: The use of a machine to clean wastes from the blood after the kidneys have failed. The blood travels through tubes to a dialyzer, which removes wastes and extra fluid. The cleaned blood then flows through another set of tubes back into the body. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemoglobin C: A commonly occurring abnormal hemoglobin in which lysine replaces a glutamic acid residue at the sixth position of the beta chains. It results in reduced plasticity of erythrocytes. [NIH] Hemoglobinopathies: A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. [NIH] Hemolytic: A disease that affects the blood and blood vessels. It destroys red blood cells, cells that cause the blood to clot, and the lining of blood vessels. HUS is often caused by the Escherichia coli bacterium in contaminated food. People with HUS may develop acute renal failure. [NIH] Hemostasis: The process which spontaneously arrests the flow of blood from vessels carrying blood under pressure. It is accomplished by contraction of the vessels, adhesion and aggregation of formed blood elements, and the process of blood or plasma coagulation. [NIH]
Hepatic: Refers to the liver. [NIH]
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Hepatic Artery: A branch of the celiac artery that distributes to the stomach, pancreas, duodenum, liver, gallbladder, and greater omentum. [NIH] Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [NIH] Hepatocellular: Pertaining to or affecting liver cells. [EU] Hepatocellular carcinoma: A type of adenocarcinoma, the most common type of liver tumor. [NIH] Hepatocytes: The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. [NIH] Hepatoma: A liver tumor. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Hereditary mutation: A gene change in the body's reproductive cells (egg or sperm) that becomes incorporated into the DNA of every cell in the body of offspring; hereditary mutations are passed on from parents to offspring. Also called germline mutation. [NIH] Hereditary nonpolyposis colon cancer: An inherited disorder in which affected individuals have a higher-than-normal chance of developing colon cancer and certain other types of cancer, usually before the age of 60. Also called Lynch syndrome. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] Herpes: Any inflammatory skin disease caused by a herpesvirus and characterized by the formation of clusters of small vesicles. When used alone, the term may refer to herpes simplex or to herpes zoster. [EU] Herpes Zoster: Acute vesicular inflammation. [NIH] Heterodimer: Zippered pair of nonidentical proteins. [NIH] Heterogeneity: The property of one or more samples or populations which implies that they are not identical in respect of some or all of their parameters, e. g. heterogeneity of variance. [NIH]
Histamine: 1H-Imidazole-4-ethanamine. A depressor amine derived by enzymatic decarboxylation of histidine. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter. [NIH] Histones: Small chromosomal proteins (approx 12-20 kD) possessing an open, unfolded structure and attached to the DNA in cell nuclei by ionic linkages. Classification into the various types (designated histone I, histone II, etc.) is based on the relative amounts of arginine and lysine in each. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Hormone therapy: Treatment of cancer by removing, blocking, or adding hormones. Also called endocrine therapy. [NIH]
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Horseradish Peroxidase: An enzyme isolated from horseradish which is able to act as an antigen. It is frequently used as a histochemical tracer for light and electron microscopy. Its antigenicity has permitted its use as a combined antigen and marker in experimental immunology. [NIH] Hybridization: The genetic process of crossbreeding to produce a hybrid. Hybrid nucleic acids can be formed by nucleic acid hybridization of DNA and RNA molecules. Protein hybridization allows for hybrid proteins to be formed from polypeptide chains. [NIH] Hybridomas: Cells artificially created by fusion of activated lymphocytes with neoplastic cells. The resulting hybrid cells are cloned and produce pure or "monoclonal" antibodies or T-cell products, identical to those produced by the immunologically competent parent, and continually grow and divide as the neoplastic parent. [NIH] Hydration: Combining with water. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrogen Peroxide: A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time unless stabilized by the addition of acetanilide or similar organic materials. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hydrophilic: Readily absorbing moisture; hygroscopic; having strongly polar groups that readily interact with water. [EU] Hydroxylation: Hydroxylate, to introduce hydroxyl into (a compound or radical) usually by replacement of hydrogen. [EU] Hydroxylysine: A hydroxylated derivative of the amino acid lysine that is present in certain collagens. [NIH] Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ascorbic acid can result in impaired hydroxyproline formation. [NIH] Hydroxyurea: An antineoplastic agent that inhibits DNA synthesis through the inhibition of ribonucleoside diphosphate reductase. [NIH] Hypercalcemia: Abnormally high level of calcium in the blood. [NIH] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hyperthermia: A type of treatment in which body tissue is exposed to high temperatures to damage and kill cancer cells or to make cancer cells more sensitive to the effects of radiation and certain anticancer drugs. [NIH] Hypotension: Abnormally low blood pressure. [NIH] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU] Hypoxic: Having too little oxygen. [NIH] Hysterectomy: Excision of the uterus. [NIH]
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Ifosfamide: Positional isomer of cyclophosphamide which is active as an alkylating agent and an immunosuppressive agent. [NIH] Imaging procedures: Methods of producing pictures of areas inside the body. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]
Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]
effects
of
foreign
Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] Immunoblotting: Immunologic methods for isolating and quantitatively measuring immunoreactive substances. When used with immune reagents such as monoclonal antibodies, the process is known generically as western blot analysis (blotting, western). [NIH]
Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunofluorescence: A technique for identifying molecules present on the surfaces of cells or in tissues using a highly fluorescent substance coupled to a specific antibody. [NIH] Immunogenic: Producing immunity; evoking an immune response. [EU] Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents. [NIH] Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunology: The study of the body's immune system. [NIH] Immunomodulator: New type of drugs mainly using biotechnological methods. Treatment of cancer. [NIH] Immunosuppressant: An agent capable of suppressing immune responses. [EU] Immunosuppression: Deliberate prevention or diminution of the host's immune response. It may be nonspecific as in the administration of immunosuppressive agents (drugs or radiation) or by lymphocyte depletion or may be specific as in desensitization or the simultaneous administration of antigen and immunosuppressive drugs. [NIH] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunosuppressive Agents: Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of suppressor T-cell populations or by inhibiting the activation of helper cells. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of interleukins and other cytokines are emerging. [NIH] Immunosuppressive therapy: Therapy used to decrease the body's immune response, such as drugs given to prevent transplant rejection. [NIH] Immunotherapy: Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to
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prevent graft rejection. [NIH] Immunotoxins: Semisynthetic conjugates of various toxic molecules, including radioactive isotopes and bacterial or plant toxins, with specific immune substances such as immunoglobulins, monoclonal antibodies, and antigens. The antitumor or antiviral immune substance carries the toxin to the tumor or infected cell where the toxin exerts its poisonous effect. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implant radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called [NIH] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH] Incompetence: Physical or mental inadequacy or insufficiency. [EU] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]
Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Inflammatory breast cancer: A type of breast cancer in which the breast looks red and swollen and feels warm. The skin of the breast may also show the pitted appearance called peau d'orange (like the skin of an orange). The redness and warmth occur because the cancer cells block the lymph vessels in the skin. [NIH] Information Science: The field of knowledge, theory, and technology dealing with the collection of facts and figures, and the processes and methods involved in their manipulation, storage, dissemination, publication, and retrieval. It includes the fields of communication, publishing, library science and informatics. [NIH] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Ingestion: Taking into the body by mouth [NIH] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a
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step in a carcinogenic process. [NIH] Initiator: A chemically reactive substance which may cause cell changes if ingested, inhaled or absorbed into the body; the substance may thus initiate a carcinogenic process. [NIH] Inner ear: The labyrinth, comprising the vestibule, cochlea, and semicircular canals. [NIH] Innervation: 1. The distribution or supply of nerves to a part. 2. The supply of nervous energy or of nerve stimulus sent to a part. [EU] Inoperable: Not suitable to be operated upon. [EU] Inorganic: Pertaining to substances not of organic origin. [EU] Inotropic: Affecting the force or energy of muscular contractions. [EU] Insertional: A technique in which foreign DNA is cloned into a restriction site which occupies a position within the coding sequence of a gene in the cloning vector molecule. Insertion interrupts the gene's sequence such that its original function is no longer expressed. [NIH] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Insulin-like: Muscular growth factor. [NIH] Interferon: A biological response modifier (a substance that can improve the body's natural response to disease). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and gamma. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases. [NIH] Interferon-alpha: One of the type I interferons produced by peripheral blood leukocytes or lymphoblastoid cells when exposed to live or inactivated virus, double-stranded RNA, or bacterial products. It is the major interferon produced by virus-induced leukocyte cultures and, in addition to its pronounced antiviral activity, it causes activation of NK cells. [NIH] Interleukin-6: Factor that stimulates the growth and differentiation of human B-cells and is also a growth factor for hybridomas and plasmacytomas. It is produced by many different cells including T-cells, monocytes, and fibroblasts. [NIH] Internal Medicine: A medical specialty concerned with the diagnosis and treatment of diseases of the internal organ systems of adults. [NIH] Internal radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called brachytherapy, implant radiation, or interstitial radiation therapy. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intestinal: Having to do with the intestines. [NIH] Intestinal Obstruction: Any impairment, arrest, or reversal of the normal flow of intestinal contents toward the anus. [NIH] Intestine: A long, tube-shaped organ in the abdomen that completes the process of
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digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] Intracellular Membranes: Membranes of subcellular structures. [NIH] Intracranial tumors: Tumors that occur in the brain. [NIH] Intramuscular: IM. Within or into muscle. [NIH] Intraperitoneal: IP. Within the peritoneal cavity (the area that contains the abdominal organs). [NIH] Intraperitoneal chemotherapy: Treatment in which anticancer drugs are put directly into the abdominal cavity through a thin tube. [NIH] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Intubation: Introduction of a tube into a hollow organ to restore or maintain patency if obstructed. It is differentiated from catheterization in that the insertion of a catheter is usually performed for the introducing or withdrawing of fluids from the body. [NIH] Inulin: A starch found in the tubers and roots of many plants. Since it is hydrolyzable to fructose, it is classified as a fructosan. It has been used in physiologic investigation for determination of the rate of glomerular function. [NIH] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]
Iodine: A nonmetallic element of the halogen group that is represented by the atomic symbol I, atomic number 53, and atomic weight of 126.90. It is a nutritionally essential element, especially important in thyroid hormone synthesis. In solution, it has anti-infective properties and is used topically. [NIH] Iodine-131: Radioactive isotope of iodine. [NIH] Ion Channels: Gated, ion-selective glycoproteins that traverse membranes. The stimulus for channel gating can be a membrane potential, drug, transmitter, cytoplasmic messenger, or a mechanical deformation. Ion channels which are integral parts of ionotropic neurotransmitter receptors are not included. [NIH] Ionization: 1. Any process by which a neutral atom gains or loses electrons, thus acquiring a net charge, as the dissociation of a substance in solution into ions or ion production by the passage of radioactive particles. 2. Iontophoresis. [EU] Ionizing: Radiation comprising charged particles, e. g. electrons, protons, alpha-particles, etc., having sufficient kinetic energy to produce ionization by collision. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Irinotecan: An anticancer drug that belongs to a family of anticancer drugs called topoisomerase inhibitors. It is a camptothecin analogue. Also called CPT 11. [NIH] Irradiation: The use of high-energy radiation from x-rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation,
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interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Irradiation is also called radiation therapy, radiotherapy, and x-ray therapy. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Isozymes: The multiple forms of a single enzyme. [NIH] Job Satisfaction: Personal satisfaction relative to the work situation. [NIH] Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [NIH] Kidney Cortex: The outer zone of the kidney, beneath the capsule, consisting of kidney glomerulus; kidney tubules, distal; and kidney tubules, proximal. [NIH] Kidney Disease: Any one of several chronic conditions that are caused by damage to the cells of the kidney. People who have had diabetes for a long time may have kidney damage. Also called nephropathy. [NIH] Kidney Failure: The inability of a kidney to excrete metabolites at normal plasma levels under conditions of normal loading, or the inability to retain electrolytes under conditions of normal intake. In the acute form (kidney failure, acute), it is marked by uremia and usually by oliguria or anuria, with hyperkalemia and pulmonary edema. The chronic form (kidney failure, chronic) is irreversible and requires hemodialysis. [NIH] Kidney stone: A stone that develops from crystals that form in urine and build up on the inner surfaces of the kidney, in the renal pelvis, or in the ureters. [NIH] Kinetic: Pertaining to or producing motion. [EU] Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Labyrinth: The internal ear; the essential part of the organ of hearing. It consists of an osseous and a membranous portion. [NIH] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] Laryngeal: Having to do with the larynx. [NIH] Larynx: An irregularly shaped, musculocartilaginous tubular structure, lined with mucous membrane, located at the top of the trachea and below the root of the tongue and the hyoid bone. It is the essential sphincter guarding the entrance into the trachea and functioning secondarily as the organ of voice. [NIH] Laser therapy: The use of an intensely powerful beam of light to kill cancer cells. [NIH] Lassitude: Weakness; exhaustion. [EU] Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH] Lectin: A complex molecule that has both protein and sugars. Lectins are able to bind to the outside of a cell and cause biochemical changes in it. Lectins are made by both animals and plants. [NIH] Lens: The transparent, double convex (outward curve on both sides) structure suspended between the aqueous and vitreous; helps to focus light on the retina. [NIH] Lesion: An area of abnormal tissue change. [NIH]
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Lethal: Deadly, fatal. [EU] Leucocyte: All the white cells of the blood and their precursors (myeloid cell series, lymphoid cell series) but commonly used to indicate granulocytes exclusive of lymphocytes. [NIH]
Leucovorin: The active metabolite of folic acid. Leucovorin is used principally as its calcium salt as an antidote to folic acid antagonists which block the conversion of folic acid to folinic acid. [NIH] Leukaemia: An acute or chronic disease of unknown cause in man and other warm-blooded animals that involves the blood-forming organs, is characterized by an abnormal increase in the number of leucocytes in the tissues of the body with or without a corresponding increase of those in the circulating blood, and is classified according of the type leucocyte most prominently involved. [EU] Leukemia: Cancer of blood-forming tissue. [NIH] Leukopenia: A condition in which the number of leukocytes (white blood cells) in the blood is reduced. [NIH] Levo: It is an experimental treatment for heroin addiction that was developed by German scientists around 1948 as an analgesic. Like methadone, it binds with opioid receptors, but it is longer acting. [NIH] Ligament: A band of fibrous tissue that connects bones or cartilages, serving to support and strengthen joints. [EU] Ligands: A RNA simulation method developed by the MIT. [NIH] Ligation: Application of a ligature to tie a vessel or strangulate a part. [NIH] Linkages: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Lipid: Fat. [NIH] Lipid A: Lipid A is the biologically active component of lipopolysaccharides. It shows strong endotoxic activity and exhibits immunogenic properties. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Lipophilic: Having an affinity for fat; pertaining to or characterized by lipophilia. [EU] Lipopolysaccharides: Substance consisting of polysaccaride and lipid. [NIH] Liposomal: A drug preparation that contains the active drug in very tiny fat particles. This fat-encapsulated drug is absorbed better, and its distribution to the tumor site is improved. [NIH]
Liposome: A spherical particle in an aqueous medium, formed by a lipid bilayer enclosing an aqueous compartment. [EU] Lithium: An element in the alkali metals family. It has the atomic symbol Li, atomic number 3, and atomic weight 6.94. Salts of lithium are used in treating manic-depressive disorders. [NIH]
Lithium Chloride: A salt of lithium that has been used experimentally as an immunomodulator. [NIH] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver cancer: A disease in which malignant (cancer) cells are found in the tissues of the liver. [NIH]
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Liver metastases: Cancer that has spread from the original (primary) tumor to the liver. [NIH]
Liver scan: An image of the liver created on a computer screen or on film. A radioactive substance is injected into a blood vessel and travels through the bloodstream. It collects in the liver, especially in abnormal areas, and can be detected by the scanner. [NIH] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Locoregional: The characteristic of a disease-producing organism to transfer itself, but typically to the same region of the body (a leg, the lungs, .) [EU] Loop: A wire usually of platinum bent at one end into a small loop (usually 4 mm inside diameter) and used in transferring microorganisms. [NIH] Loss of Heterozygosity: The loss of one allele at a specific locus, caused by a deletion mutation; or loss of a chromosome from a chromosome pair. It is detected when heterozygous markers for a locus appear monomorphic because one of the alleles was deleted. When this occurs at a tumor suppressor gene locus where one of the alleles is already abnormal, it can result in neoplastic transformation. [NIH] Lower Esophageal Sphincter: The muscle between the esophagus and stomach. When a person swallows, this muscle relaxes to let food pass from the esophagus to the stomach. It stays closed at other times to keep stomach contents from flowing back into the esophagus. [NIH]
Luciferase: Any one of several enzymes that catalyze the bioluminescent reaction in certain marine crustaceans, fish, bacteria, and insects. The enzyme is a flavoprotein; it oxidizes luciferins to an electronically excited compound that emits energy in the form of light. The color of light emitted varies with the organism. The firefly enzyme is a valuable reagent for measurement of ATP concentration. (Dorland, 27th ed) EC 1.13.12.-. [NIH] Lung metastases: Cancer that has spread from the original (primary) tumor to the lung. [NIH]
Lyases: A class of enzymes that catalyze the cleavage of C-C, C-O, and C-N, and other bonds by other means than by hydrolysis or oxidation. (Enzyme Nomenclature, 1992) EC 4. [NIH] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH] Lymph node: A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue. Also known as a lymph gland. Lymph nodes are spread out along lymphatic vessels and contain many lymphocytes, which filter the lymphatic fluid (lymph). [NIH]
Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphatic system: The tissues and organs that produce, store, and carry white blood cells that fight infection and other diseases. This system includes the bone marrow, spleen, thymus, lymph nodes and a network of thin tubes that carry lymph and white blood cells. These tubes branch, like blood vessels, into all the tissues of the body. [NIH] Lymphoblastic: One of the most aggressive types of non-Hodgkin lymphoma. [NIH] Lymphoblasts: Interferon produced predominantly by leucocyte cells. [NIH] Lymphocyte Depletion: Immunosuppression by reduction of circulating lymphocytes or by T-cell depletion of bone marrow. The former may be accomplished in vivo by thoracic duct
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drainage or administration of antilymphocyte serum. The latter is performed ex vivo on bone marrow before its transplantation. [NIH] Lymphocytes: White blood cells formed in the body's lymphoid tissue. The nucleus is round or ovoid with coarse, irregularly clumped chromatin while the cytoplasm is typically pale blue with azurophilic (if any) granules. Most lymphocytes can be classified as either T or B (with subpopulations of each); those with characteristics of neither major class are called null cells. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH] Lysine: An essential amino acid. It is often added to animal feed. [NIH] Lysosome: A sac-like compartment inside a cell that has enzymes that can break down cellular components that need to be destroyed. [NIH] Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [NIH] Malignancy: A cancerous tumor that can invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant mesothelioma: A rare type of cancer in which malignant cells are found in the sac lining the chest or abdomen. Exposure to airborne asbestos particles increases one's risk of developing malignant mesothelioma. [NIH] Malignant tumor: A tumor capable of metastasizing. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]
Mammary: Pertaining to the mamma, or breast. [EU] Manic: Affected with mania. [EU] Mannans: Polysaccharides consisting of mannose units. [NIH] Mannitol: A diuretic and renal diagnostic aid related to sorbitol. It has little significant energy value as it is largely eliminated from the body before any metabolism can take place. It can be used to treat oliguria associated with kidney failure or other manifestations of inadequate renal function and has been used for determination of glomerular filtration rate. Mannitol is also commonly used as a research tool in cell biological studies, usually to control osmolarity. [NIH] Maximum Tolerated Dose: The highest dose level eliciting signs of toxicity without having major effects on survival relative to the test in which it is used. [NIH] Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Mediator: An object or substance by which something is mediated, such as (1) a structure of the nervous system that transmits impulses eliciting a specific response; (2) a chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle; or (3) a substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitized lymphocyte. [EU] Medical Informatics: The field of information science concerned with the analysis and dissemination of medical data through the application of computers to various aspects of
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health care and medicine. [NIH] Medical Oncology: A subspecialty of internal medicine concerned with the study of neoplasms. [NIH] Medical Records: Recording of pertinent information concerning patient's illness or illnesses. [NIH] Medicament: A medicinal substance or agent. [EU] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Megaloblastic: A large abnormal red blood cell appearing in the blood in pernicious anaemia. [EU] Meiosis: A special method of cell division, occurring in maturation of the germ cells, by means of which each daughter nucleus receives half the number of chromosomes characteristic of the somatic cells of the species. [NIH] Melanin: The substance that gives the skin its color. [NIH] Melanocytes: Epidermal dendritic pigment cells which control long-term morphological color changes by alteration in their number or in the amount of pigment they produce and store in the pigment containing organelles called melanosomes. Melanophores are larger cells which do not exist in mammals. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Melphalan: An alkylating nitrogen mustard that is used as an antineoplastic in the form of the levo isomer - melphalan, the racemic mixture - merphalan, and the dextro isomer medphalan; toxic to bone marrow, but little vesicant action; potential carcinogen. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Meningitis: Inflammation of the meninges. When it affects the dura mater, the disease is termed pachymeningitis; when the arachnoid and pia mater are involved, it is called leptomeningitis, or meningitis proper. [EU] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] Mercury: A silver metallic element that exists as a liquid at room temperature. It has the atomic symbol Hg (from hydrargyrum, liquid silver), atomic number 80, and atomic weight 200.59. Mercury is used in many industrial applications and its salts have been employed therapeutically as purgatives, antisyphilitics, disinfectants, and astringents. It can be absorbed through the skin and mucous membranes which leads to mercury poisoning. Because of its toxicity, the clinical use of mercury and mercurials is diminishing. [NIH] Mesenchymal: Refers to cells that develop into connective tissue, blood vessels, and lymphatic tissue. [NIH] Mesenteric: Pertaining to the mesentery : a membranous fold attaching various organs to the body wall. [EU]
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Mesothelial: It lines the peritonealla and pleural cavities. [NIH] Mesothelioma: A benign (noncancerous) or malignant (cancerous) tumor affecting the lining of the chest or abdomen. Exposure to asbestos particles in the air increases the risk of developing malignant mesothelioma. [NIH] Meta-Analysis: A quantitative method of combining the results of independent studies (usually drawn from the published literature) and synthesizing summaries and conclusions which may be used to evaluate therapeutic effectiveness, plan new studies, etc., with application chiefly in the areas of research and medicine. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metallothionein: A low-molecular-weight (approx. 10 kD) protein occurring in the cytoplasm of kidney cortex and liver. It is rich in cysteinyl residues and contains no aromatic amino acids. Metallothionein shows high affinity for bivalent heavy metals. [NIH] Metastasis: The spread of cancer from one part of the body to another. Tumors formed from cells that have spread are called "secondary tumors" and contain cells that are like those in the original (primary) tumor. The plural is metastases. [NIH] Metastasize: To spread from one part of the body to another. When cancer cells metastasize and form secondary tumors, the cells in the metastatic tumor are like those in the original (primary) tumor. [NIH] Metastatic: Having to do with metastasis, which is the spread of cancer from one part of the body to another. [NIH] Metastatic cancer: Cancer that has spread from the place in which it started to other parts of the body. [NIH] Methotrexate: An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of dihydrofolate reductase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. [NIH] Methylprednisolone: (6 alpha,11 beta)-11,17,21-Trihydroxy-6-methylpregna-1,4-diene-3,2dione. A prednisolone derivative which has pharmacological actions similar to prednisolone. [NIH] Methyltransferase: A drug-metabolizing enzyme. [NIH] Metoclopramide: A dopamine D2 antagonist that is used as an antiemetic. [NIH] Micelle: A colloid particle formed by an aggregation of small molecules. [EU] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] Microglia: The third type of glial cell, along with astrocytes and oligodendrocytes (which together form the macroglia). Microglia vary in appearance depending on developmental stage, functional state, and anatomical location; subtype terms include ramified, perivascular, ameboid, resting, and activated. Microglia clearly are capable of phagocytosis and play an important role in a wide spectrum of neuropathologies. They have also been suggested to act in several other roles including in secretion (e.g., of cytokines and neural growth factors), in immunological processing (e.g., antigen presentation), and in central nervous system development and remodeling. [NIH] Micronuclei: Nuclei, separate from and additional to the main nucleus of a cell, produced during the telophase of mitosis or meiosis by lagging chromosomes or chromosome fragments derived from spontaneous or experimentally induced chromosomal structural
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changes. This concept also includes the smaller, reproductive nuclei found in multinucleate protozoans. [NIH] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] Microspheres: Small uniformly-sized spherical particles frequently radioisotopes or various reagents acting as tags or markers. [NIH]
labeled
with
Microtubules: Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein tubulin. [NIH] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] Mitochondria: Parts of a cell where aerobic production (also known as cell respiration) takes place. [NIH] Mitomycin: An antineoplastic antibiotic produced by Streptomyces caespitosus. It acts as a bi- or trifunctional alkylating agent causing cross-linking of DNA and inhibition of DNA synthesis. [NIH] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Mitotic: Cell resulting from mitosis. [NIH] Mitotic inhibitors: Drugs that kill cancer cells by interfering with cell division (mitostis). [NIH]
Mitoxantrone: An anthracenedione-derived antineoplastic agent. [NIH] Mobility: Capability of movement, of being moved, or of flowing freely. [EU] Mobilization: The process of making a fixed part or stored substance mobile, as by separating a part from surrounding structures to make it accessible for an operative procedure or by causing release into the circulation for body use of a substance stored in the body. [EU] Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Modiolus: The central pillar or axis of the cochlea, around which the spiral canal makes two and one-half turns. [NIH] Modulator: A specific inductor that brings out characteristics peculiar to a definite region. [EU]
Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH]
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Monoclonal: An antibody produced by culturing a single type of cell. It therefore consists of a single species of immunoglobulin molecules. [NIH] Monoclonal antibodies: Laboratory-produced substances that can locate and bind to cancer cells wherever they are in the body. Many monoclonal antibodies are used in cancer detection or therapy; each one recognizes a different protein on certain cancer cells. Monoclonal antibodies can be used alone, or they can be used to deliver drugs, toxins, or radioactive material directly to a tumor. [NIH] Monocytes: Large, phagocytic mononuclear leukocytes produced in the vertebrate bone marrow and released into the blood; contain a large, oval or somewhat indented nucleus surrounded by voluminous cytoplasm and numerous organelles. [NIH] Mononuclear: A cell with one nucleus. [NIH] Monophosphate: So called second messenger for neurotransmitters and hormones. [NIH] Morphological: Relating to the configuration or the structure of live organs. [NIH] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Motility: The ability to move spontaneously. [EU] Motion Sickness: Sickness caused by motion, as sea sickness, train sickness, car sickness, and air sickness. [NIH] Mucinous: Containing or resembling mucin, the main compound in mucus. [NIH] Mucosa: A mucous membrane, or tunica mucosa. [EU] Mucositis: A complication of some cancer therapies in which the lining of the digestive system becomes inflamed. Often seen as sores in the mouth. [NIH] Multicenter study: A clinical trial that is carried out at more than one medical institution. [NIH]
Multidrug resistance: Adaptation of tumor cells to anticancer drugs in ways that make the drugs less effective. [NIH] Multimodality treatment: Therapy that combines more than one method of treatment. [NIH] Muscle Fibers: Large single cells, either cylindrical or prismatic in shape, that form the basic unit of muscle tissue. They consist of a soft contractile substance enclosed in a tubular sheath. [NIH] Mutagen: Any agent, such as X-rays, gamma rays, mustard gas, TCDD, that can cause abnormal mutation in living cells; having the power to cause mutations. [NIH] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Mutagenic: Inducing genetic mutation. [EU] Mutagenicity: Ability to damage DNA, the genetic material; the power to cause mutations. [NIH]
Myelosuppression: A condition in which bone marrow activity is decreased, resulting in fewer red blood cells, white blood cells, and platelets. Myelosuppression is a side effect of some cancer treatments. [NIH] Myocardial infarction: Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH]
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Myotonia: Prolonged failure of muscle relaxation after contraction. This may occur after voluntary contractions, muscle percussion, or electrical stimulation of the muscle. Myotonia is a characteristic feature of myotonic disorders. [NIH] Natural selection: A part of the evolutionary process resulting in the survival and reproduction of the best adapted individuals. [NIH] Nausea: An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. [NIH] NCI: National Cancer Institute. NCI, part of the National Institutes of Health of the United States Department of Health and Human Services, is the federal government's principal agency for cancer research. NCI conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the NCI Web site at http://cancer.gov. [NIH] Necrosis: A pathological process caused by the progressive degradative action of enzymes that is generally associated with severe cellular trauma. It is characterized by mitochondrial swelling, nuclear flocculation, uncontrolled cell lysis, and ultimately cell death. [NIH] Neoadjuvant Therapy: Preliminary cancer therapy (chemotherapy, radiation therapy, hormone/endocrine therapy, immunotherapy, hyperthermia, etc.) that precedes a necessary second modality of treatment. [NIH] Neoplasia: Abnormal and uncontrolled cell growth. [NIH] Neoplasm: A new growth of benign or malignant tissue. [NIH] Nephrolithiasis: Kidney stones. [NIH] Nephropathy: Disease of the kidneys. [EU] Nephrotoxic: Toxic or destructive to kidney cells. [EU] Nerve Fibers: Slender processes of neurons, especially the prolonged axons that conduct nerve impulses. [NIH] Nerve Growth Factor: Nerve growth factor is the first of a series of neurotrophic factors that were found to influence the growth and differentiation of sympathetic and sensory neurons. It is comprised of alpha, beta, and gamma subunits. The beta subunit is responsible for its growth stimulating activity. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neural Crest: A strip of specialized ectoderm flanking each side of the embryonal neural plate, which after the closure of the neural tube, forms a column of isolated cells along the dorsal aspect of the neural tube. Most of the cranial and all of the spinal sensory ganglion cells arise by differentiation of neural crest cells. [NIH] Neural Pathways: Neural tracts connecting one part of the nervous system with another. [NIH]
Neuroblastoma: Cancer that arises in immature nerve cells and affects mostly infants and children. [NIH] Neuroleptic: A term coined to refer to the effects on cognition and behaviour of antipsychotic drugs, which produce a state of apathy, lack of initiative, and limited range of emotion and in psychotic patients cause a reduction in confusion and agitation and normalization of psychomotor activity. [EU]
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Neurologic: Having to do with nerves or the nervous system. [NIH] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neuropathy: A problem in any part of the nervous system except the brain and spinal cord. Neuropathies can be caused by infection, toxic substances, or disease. [NIH] Neurophysiology: The scientific discipline concerned with the physiology of the nervous system. [NIH] Neurotoxic: Poisonous or destructive to nerve tissue. [EU] Neurotoxicity: The tendency of some treatments to cause damage to the nervous system. [NIH]
Neurotoxins: Toxic substances from microorganisms, plants or animals that interfere with the functions of the nervous system. Most venoms contain neurotoxic substances. Myotoxins are included in this concept. [NIH] Neurotransmitter: Any of a group of substances that are released on excitation from the axon terminal of a presynaptic neuron of the central or peripheral nervous system and travel across the synaptic cleft to either excite or inhibit the target cell. Among the many substances that have the properties of a neurotransmitter are acetylcholine, norepinephrine, epinephrine, dopamine, glycine, y-aminobutyrate, glutamic acid, substance P, enkephalins, endorphins, and serotonin. [EU] Neutrons: Electrically neutral elementary particles found in all atomic nuclei except light hydrogen; the mass is equal to that of the proton and electron combined and they are unstable when isolated from the nucleus, undergoing beta decay. Slow, thermal, epithermal, and fast neutrons refer to the energy levels with which the neutrons are ejected from heavier nuclei during their decay. [NIH] Neutrophils: Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. [NIH] Nilutamide: A drug that blocks the effects of male hormones in the body. It belongs to the family of drugs called antiandrogens. [NIH] Nitric Oxide: A free radical gas produced endogenously by a variety of mammalian cells. It is synthesized from arginine by a complex reaction, catalyzed by nitric oxide synthase. Nitric oxide is endothelium-derived relaxing factor. It is released by the vascular endothelium and mediates the relaxation induced by some vasodilators such as acetylcholine and bradykinin. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic GMP. [NIH]
Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. [NIH] Non-small cell lung cancer: A group of lung cancers that includes squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. [NIH] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in
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the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Oliguria: Clinical manifestation of the urinary system consisting of a decrease in the amount of urine secreted. [NIH] Omentum: A fold of the peritoneum (the thin tissue that lines the abdomen) that surrounds the stomach and other organs in the abdomen. [NIH] Oncogene: A gene that normally directs cell growth. If altered, an oncogene can promote or allow the uncontrolled growth of cancer. Alterations can be inherited or caused by an environmental exposure to carcinogens. [NIH] Oncologist: A doctor who specializes in treating cancer. Some oncologists specialize in a particular type of cancer treatment. For example, a radiation oncologist specializes in treating cancer with radiation. [NIH] Oncology: The study of cancer. [NIH] Oncolysis: The destruction of or disposal by absorption of any neoplastic cells. [NIH] Oncolytic: Pertaining to, characterized by, or causing oncolysis (= the lysis or destruction of tumour cells). [EU] Ondansetron: A competitive serotonin type 3 receptor antagonist. It is effective in the treatment of nausea and vomiting caused by cytotoxic chemotherapy drugs, including cisplatin, and it has reported anxiolytic and neuroleptic properties. [NIH] Ophthalmic: Pertaining to the eye. [EU] Opsin: A protein formed, together with retinene, by the chemical breakdown of metarhodopsin. [NIH] Orderly: A male hospital attendant. [NIH] Organ Preservation: The process by which organs are kept viable outside of the organism from which they were removed (i.e., kept from decay by means of a chemical agent, cooling, or a fluid substitute that mimics the natural state within the organism). [NIH] Organelles: Specific particles of membrane-bound organized living substances present in eukaryotic cells, such as the mitochondria; the golgi apparatus; endoplasmic reticulum; lysomomes; plastids; and vacuoles. [NIH] Osmolarity: The concentration of osmotically active particles expressed in terms of osmoles of solute per litre of solution. [EU] Osmotic: Pertaining to or of the nature of osmosis (= the passage of pure solvent from a solution of lesser to one of greater solute concentration when the two solutions are separated by a membrane which selectively prevents the passage of solute molecules, but is permeable to the solvent). [EU]
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Osteogenic sarcoma: A malignant tumor of the bone. Also called osteosarcoma. [NIH] Osteosarcoma: A cancer of the bone that affects primarily children and adolescents. Also called osteogenic sarcoma. [NIH] Ototoxic: Having a deleterious effect upon the eighth nerve, or upon the organs of hearing and balance. [EU] Ovarian epithelial cancer: Cancer that occurs in the cells lining the ovaries. [NIH] Ovaries: The pair of female reproductive glands in which the ova, or eggs, are formed. The ovaries are located in the pelvis, one on each side of the uterus. [NIH] Ovary: Either of the paired glands in the female that produce the female germ cells and secrete some of the female sex hormones. [NIH] Overall survival: The percentage of subjects in a study who have survived for a defined period of time. Usually reported as time since diagnosis or treatment. Often called the survival rate. [NIH] Overexpress: An excess of a particular protein on the surface of a cell. [NIH] Oxaliplatin: An anticancer drug that belongs to the family of drugs called platinum compounds. [NIH] Oxidants: Oxidizing agents or electron-accepting molecules in chemical reactions in which electrons are transferred from one molecule to another (oxidation-reduction). In vivo, it appears that phagocyte-generated oxidants function as tumor promoters or cocarcinogens rather than as complete carcinogens perhaps because of the high levels of endogenous antioxidant defenses. It is also thought that oxidative damage in joints may trigger the autoimmune response that characterizes the persistence of the rheumatoid disease process. [NIH]
Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]
Oxidation-Reduction: A chemical reaction in which an electron is transferred from one molecule to another. The electron-donating molecule is the reducing agent or reductant; the electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471). [NIH] Oxidative Stress: A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products (Sies, Oxidative Stress, 1991, pxv-xvi). [NIH] P53 gene: A tumor suppressor gene that normally inhibits the growth of tumors. This gene is altered in many types of cancer. [NIH] Pachymeningitis: Inflammation of the dura mater of the brain, the spinal cord or the optic nerve. [NIH] Paclitaxel: Antineoplastic agent isolated from the bark of the Pacific yew tree, Taxus brevifolia. Paclitaxel stabilizes microtubules in their polymerized form and thus mimics the action of the proto-oncogene proteins c-mos. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior
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abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Pancreatic: Having to do with the pancreas. [NIH] Pancreatic cancer: Cancer of the pancreas, a salivary gland of the abdomen. [NIH] Pancreatic Juice: The fluid containing digestive enzymes secreted by the pancreas in response to food in the duodenum. [NIH] Papilloma: A benign epithelial neoplasm which may arise from the skin, mucous membranes or glandular ducts. [NIH] Parathyroid: 1. Situated beside the thyroid gland. 2. One of the parathyroid glands. 3. A sterile preparation of the water-soluble principle(s) of the parathyroid glands, ad-ministered parenterally as an antihypocalcaemic, especially in the treatment of acute hypoparathyroidism with tetany. [EU] Parathyroid hormone: A substance made by the parathyroid gland that helps the body store and use calcium. Also called parathormone, parathyrin, or PTH. [NIH] Parenteral: Not through the alimentary canal but rather by injection through some other route, as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intravenous, etc. [EU] Parietal: 1. Of or pertaining to the walls of a cavity. 2. Pertaining to or located near the parietal bone, as the parietal lobe. [EU] Parotid: The space that contains the parotid gland, the facial nerve, the external carotid artery, and the retromandibular vein. [NIH] Partial remission: The shrinking, but not complete disappearance, of a tumor in response to therapy. Also called partial response. [NIH] Particle: A tiny mass of material. [EU] Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Patient Advocacy: Promotion and protection of the rights of patients, frequently through a legal process. [NIH] Peau d'orange: A dimpled condition of the skin of the breast, resembling the skin of an orange, sometimes found in inflammatory breast cancer. [NIH] Pelvic: Pertaining to the pelvis. [EU] Pelvis: The lower part of the abdomen, located between the hip bones. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Perineural: Around a nerve or group of nerves. [NIH] Peripheral blood: Blood circulating throughout the body. [NIH] Peripheral Nerves: The nerves outside of the brain and spinal cord, including the autonomic, cranial, and spinal nerves. Peripheral nerves contain non-neuronal cells and
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connective tissue as well as axons. The connective tissue layers include, from the outside to the inside, the epineurium, the perineurium, and the endoneurium. [NIH] Peripheral Nervous System: The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. [NIH] Peripheral Neuropathy: Nerve damage, usually affecting the feet and legs; causing pain, numbness, or a tingling feeling. Also called "somatic neuropathy" or "distal sensory polyneuropathy." [NIH] Peritoneal: Having to do with the peritoneum (the tissue that lines the abdominal wall and covers most of the organs in the abdomen). [NIH] Peritoneal Cavity: The space enclosed by the peritoneum. It is divided into two portions, the greater sac and the lesser sac or omental bursa, which lies behind the stomach. The two sacs are connected by the foramen of Winslow, or epiploic foramen. [NIH] Peritoneum: Endothelial lining of the abdominal cavity, the parietal peritoneum covering the inside of the abdominal wall and the visceral peritoneum covering the bowel, the mesentery, and certain of the organs. The portion that covers the bowel becomes the serosal layer of the bowel wall. [NIH] Petrolatum: A colloidal system of semisolid hydrocarbons obtained from petroleum. It is used as an ointment base, topical protectant, and lubricant. [NIH] Phagocyte: An immune system cell that can surround and kill microorganisms and remove dead cells. Phagocytes include macrophages. [NIH] Pharmaceutical Preparations: Drugs intended for human or veterinary use, presented in their finished dosage form. Included here are materials used in the preparation and/or formulation of the finished dosage form. [NIH] Pharmacodynamic: Is concerned with the response of living tissues to chemical stimuli, that is, the action of drugs on the living organism in the absence of disease. [NIH] Pharmacokinetic: The mathematical analysis of the time courses of absorption, distribution, and elimination of drugs. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Pharmacology, Clinical: The branch of pharmacology that deals directly with the effectiveness and safety of drugs in humans. [NIH] Pharmacotherapy: A regimen of using appetite suppressant medications to manage obesity by decreasing appetite or increasing the feeling of satiety. These medications decrease appetite by increasing serotonin or catecholamine—two brain chemicals that affect mood and appetite. [NIH] Pharynx: The hollow tube about 5 inches long that starts behind the nose and ends at the top of the trachea (windpipe) and esophagus (the tube that goes to the stomach). [NIH] Phenolphthalein: An acid-base indicator which is colorless in acid solution, but turns pink to red as the solution becomes alkaline. It is used medicinally as a cathartic. [NIH] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phenyl: Ingredient used in cold and flu remedies. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor
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of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phorbol: Class of chemicals that promotes the development of tumors. [NIH] Phorbol Esters: Tumor-promoting compounds obtained from croton oil (Croton tiglium). Some of these are used in cell biological experiments as activators of protein kinase C. [NIH] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorylated: Attached to a phosphate group. [NIH] Phosphorylates: Attached to a phosphate group. [NIH] Phosphorylating: Attached to a phosphate group. [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Photosensitivity: An abnormal cutaneous response involving the interaction between photosensitizing substances and sunlight or filtered or artificial light at wavelengths of 280400 mm. There are two main types : photoallergy and photoxicity. [EU] Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [NIH] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]
Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Pigment: A substance that gives color to tissue. Pigments are responsible for the color of skin, eyes, and hair. [NIH] Pilot study: The initial study examining a new method or treatment. [NIH] Pink eye: Acute contagious conjunctivitis. [NIH] Piperacillin: Semisynthetic, broad-spectrum, ampicillin-derived ureidopenicillin antibiotic proposed for pseudomonas infections. It is also used in combination with other antibiotics. [NIH]
Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasma protein: One of the hundreds of different proteins present in blood plasma,
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including carrier proteins ( such albumin, transferrin, and haptoglobin), fibrinogen and other coagulation factors, complement components, immunoglobulins, enzyme inhibitors, precursors of substances such as angiotension and bradykinin, and many other types of proteins. [EU] Plasmid: An autonomously replicating, extra-chromosomal DNA molecule found in many bacteria. Plasmids are widely used as carriers of cloned genes. [NIH] Platelet Activation: A series of progressive, overlapping events triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness, aggregation, and release reactions. When carried through to completion, these events lead to the formation of a stable hemostatic plug. [NIH] Platelet Aggregation: The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin, collagen) and is part of the mechanism leading to the formation of a thrombus. [NIH] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Platinum Compounds: Inorganic compounds which contain platinum as the central atom. [NIH]
Pleura: The thin serous membrane enveloping the lungs and lining the thoracic cavity. [NIH] Pleural: A circumscribed area of hyaline whorled fibrous tissue which appears on the surface of the parietal pleura, on the fibrous part of the diaphragm or on the pleura in the interlobar fissures. [NIH] Ploidy: The number of sets of chromosomes in a cell or an organism. For example, haploid means one set and diploid means two sets. [NIH] Pneumonia: Inflammation of the lungs. [NIH] Podophyllotoxin: The main active constituent of the resin from the roots of may apple or mandrake (Podophyllum peltatum and P. emodi). It is a potent spindle poison, toxic if taken internally, and has been used as a cathartic. It is very irritating to skin and mucous membranes, has keratolytic actions, has been used to treat warts and keratoses, and may have antineoplastic properties, as do some of its congeners and derivatives. [NIH] Point Mutation: A mutation caused by the substitution of one nucleotide for another. This results in the DNA molecule having a change in a single base pair. [NIH] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Pollen: The male fertilizing element of flowering plants analogous to sperm in animals. It is released from the anthers as yellow dust, to be carried by insect or other vectors, including wind, to the ovary (stigma) of other flowers to produce the embryo enclosed by the seed. The pollens of many plants are allergenic. [NIH] Polycystic: An inherited disorder characterized by many grape-like clusters of fluid-filled cysts that make both kidneys larger over time. These cysts take over and destroy working kidney tissue. PKD may cause chronic renal failure and end-stage renal disease. [NIH] Polymerase: An enzyme which catalyses the synthesis of DNA using a single DNA strand as a template. The polymerase copies the template in the 5'-3'direction provided that sufficient quantities of free nucleotides, dATP and dTTP are present. [NIH] Polymerase Chain Reaction: In vitro method for producing large amounts of specific DNA or RNA fragments of defined length and sequence from small amounts of short oligonucleotide flanking sequences (primers). The essential steps include thermal denaturation of the double-stranded target molecules, annealing of the primers to their
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complementary sequences, and extension of the annealed primers by enzymatic synthesis with DNA polymerase. The reaction is efficient, specific, and extremely sensitive. Uses for the reaction include disease diagnosis, detection of difficult-to-isolate pathogens, mutation analysis, genetic testing, DNA sequencing, and analyzing evolutionary relationships. [NIH] Polymers: Compounds formed by the joining of smaller, usually repeating, units linked by covalent bonds. These compounds often form large macromolecules (e.g., polypeptides, proteins, plastics). [NIH] Polypeptide: A peptide which on hydrolysis yields more than two amino acids; called tripeptides, tetrapeptides, etc. according to the number of amino acids contained. [EU] Polyposis: The development of numerous polyps (growths that protrude from a mucous membrane). [NIH] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Polyvalent: Having more than one valence. [EU] Polyvinyl Alcohol: A polymer prepared from polyvinyl acetates by replacement of the acetate groups with hydroxyl groups. It is used as a pharmaceutic aid and ophthalmic lubricant as well as in the manufacture of surface coatings artificial sponges, cosmetics, and other products. [NIH] Port: An implanted device through which blood may be withdrawn and drugs may be infused without repeated needle sticks. Also called a port-a-cath. [NIH] Port-a-cath: An implanted device through which blood may be withdrawn and drugs may be infused without repeated needle sticks. Also called a port. [NIH] Portal Vein: A short thick vein formed by union of the superior mesenteric vein and the splenic vein. [NIH] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postoperative: After surgery. [NIH] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] Potentiates: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Potentiating: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Potentiation: An overall effect of two drugs taken together which is greater than the sum of the effects of each drug taken alone. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Precancerous: A term used to describe a condition that may (or is likely to) become cancer.
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Also called premalignant. [NIH] Preclinical: Before a disease becomes clinically recognizable. [EU] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Predictive factor: A situation or condition that may increase a person's risk of developing a certain disease or disorder. [NIH] Predisposition: A latent susceptibility to disease which may be activated under certain conditions, as by stress. [EU] Prednisolone: A glucocorticoid with the general properties of the corticosteroids. It is the drug of choice for all conditions in which routine systemic corticosteroid therapy is indicated, except adrenal deficiency states. [NIH] Premalignant: A term used to describe a condition that may (or is likely to) become cancer. Also called precancerous. [NIH] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Preoperative: Preceding an operation. [EU] Presynaptic: Situated proximal to a synapse, or occurring before the synapse is crossed. [EU] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Primary endpoint: The main result that is measured at the end of a study to see if a given treatment worked (e.g., the number of deaths or the difference in survival between the treatment group and the control group). What the primary endpoint will be is decided before the study begins. [NIH] Primary tumor: The original tumor. [NIH] Probe: An instrument used in exploring cavities, or in the detection and dilatation of strictures, or in demonstrating the potency of channels; an elongated instrument for exploring or sounding body cavities. [NIH] Prodrug: A substance that gives rise to a pharmacologically active metabolite, although not itself active (i. e. an inactive precursor). [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Proline: A non-essential amino acid that is synthesized from glutamic acid. It is an essential component of collagen and is important for proper functioning of joints and tendons. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Promyelocytic leukemia: A type of acute myeloid leukemia, a quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. [NIH]
Prone: Having the front portion of the body downwards. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH]
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Prostaglandin: Any of a group of components derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway that are extremely potent mediators of a diverse group of physiologic processes. The abbreviation for prostaglandin is PG; specific compounds are designated by adding one of the letters A through I to indicate the type of substituents found on the hydrocarbon skeleton and a subscript (1, 2 or 3) to indicate the number of double bonds in the hydrocarbon skeleton e.g., PGE2. The predominant naturally occurring prostaglandins all have two double bonds and are synthesized from arachidonic acid (5,8,11,14-eicosatetraenoic acid) by the pathway shown in the illustration. The 1 series and 3 series are produced by the same pathway with fatty acids having one fewer double bond (8,11,14-eicosatrienoic acid or one more double bond (5,8,11,14,17-eicosapentaenoic acid) than arachidonic acid. The subscript a or ß indicates the configuration at C-9 (a denotes a substituent below the plane of the ring, ß, above the plane). The naturally occurring PGF's have the a configuration, e.g., PGF2a. All of the prostaglandins act by binding to specific cell-surface receptors causing an increase in the level of the intracellular second messenger cyclic AMP (and in some cases cyclic GMP also). The effect produced by the cyclic AMP increase depends on the specific cell type. In some cases there is also a positive feedback effect. Increased cyclic AMP increases prostaglandin synthesis leading to further increases in cyclic AMP. [EU] Prostaglandins A: (13E,15S)-15-Hydroxy-9-oxoprosta-10,13-dien-1-oic acid (PGA(1)); (5Z,13E,15S)-15-hydroxy-9-oxoprosta-5,10,13-trien-1-oic acid (PGA(2)); (5Z,13E,15S,17Z)-15hydroxy-9-oxoprosta-5,10,13,17-tetraen-1-oic acid (PGA(3)). A group of naturally occurring secondary prostaglandins derived from PGE. PGA(1) and PGA(2) as well as their 19hydroxy derivatives are found in many organs and tissues. [NIH] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Prostatectomy: Complete or partial surgical removal of the prostate. Three primary approaches are commonly employed: suprapubic - removal through an incision above the pubis and through the urinary bladder; retropubic - as for suprapubic but without entering the urinary bladder; and transurethral (transurethral resection of prostate). [NIH] Prostatic Intraepithelial Neoplasia: A premalignant change arising in the prostatic epithelium, regarded as the most important and most likely precursor of prostatic adenocarcinoma. The neoplasia takes the form of an intra-acinar or ductal proliferation of secretory cells with unequivocal nuclear anaplasia, which corresponds to nuclear grade 2 and 3 invasive prostate cancer. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protective Agents: Synthetic or natural substances which are given to prevent a disease or disorder or are used in the process of treating a disease or injury due to a poisonous agent. [NIH]
Protein Binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific proteinbinding measures are often used as assays in diagnostic assessments. [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein Kinase C: An enzyme that phosphorylates proteins on serine or threonine residues in the presence of physiological concentrations of calcium and membrane phospholipids.
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The additional presence of diacylglycerols markedly increases its sensitivity to both calcium and phospholipids. The sensitivity of the enzyme can also be increased by phorbol esters and it is believed that protein kinase C is the receptor protein of tumor-promoting phorbol esters. EC 2.7.1.-. [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] Protein-Tyrosine Kinase: An enzyme that catalyzes the phosphorylation of tyrosine residues in proteins with ATP or other nucleotides as phosphate donors. EC 2.7.1.112. [NIH] Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH] Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Proto-Oncogene Proteins: Products of proto-oncogenes. Normally they do not have oncogenic or transforming properties, but are involved in the regulation or differentiation of cell growth. They often have protein kinase activity. [NIH] Proto-Oncogene Proteins c-mos: Cellular proteins encoded by the c-mos genes. They function in the cell cycle to maintain maturation promoting factor in the active state and have protein-serine/threonine kinase activity. Oncogenic transformation can take place when c-mos proteins are expressed at the wrong time. [NIH] Protozoa: A subkingdom consisting of unicellular organisms that are the simplest in the animal kingdom. Most are free living. They range in size from submicroscopic to macroscopic. Protozoa are divided into seven phyla: Sarcomastigophora, Labyrinthomorpha, Apicomplexa, Microspora, Ascetospora, Myxozoa, and Ciliophora. [NIH] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Pseudomonas: A genus of gram-negative, aerobic, rod-shaped bacteria widely distributed in nature. Some species are pathogenic for humans, animals, and plants. [NIH] Pseudomonas Infections: Infections with bacteria of the genus Pseudomonas. [NIH] Psoralen: A substance that binds to the DNA in cells and stops them from multiplying. It is being studied in the treatment of graft-versus-host disease and is used in the treatment of psoriasis and vitiligo. [NIH] Psoriasis: A common genetically determined, chronic, inflammatory skin disease characterized by rounded erythematous, dry, scaling patches. The lesions have a predilection for nails, scalp, genitalia, extensor surfaces, and the lumbosacral region. Accelerated epidermopoiesis is considered to be the fundamental pathologic feature in psoriasis. [NIH] Psychoactive: Those drugs which alter sensation, mood, consciousness or other psychological or behavioral functions. [NIH] Public Health: Branch of medicine concerned with the prevention and control of disease
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and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Publishing: "The business or profession of the commercial production and issuance of literature" (Webster's 3d). It includes the publisher, publication processes, editing and editors. Production may be by conventional printing methods or by electronic publishing. [NIH]
Pulmonary: Relating to the lungs. [NIH] Pulmonary Edema: An accumulation of an excessive amount of watery fluid in the lungs, may be caused by acute exposure to dangerous concentrations of irritant gasses. [NIH] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [NIH]
Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] Pyrimidine Dimers: Dimers found in DNA chains damaged by ultraviolet irradiation. They consist of two adjacent pyrimidine nucleotides, usually thymine nucleotides, in which the pyrimidine residues are covalently joined by a cyclobutane ring. These dimers stop DNA replication. [NIH] Pyrimidines: A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (cytosine, thymine, and uracil) and form the basic structure of the barbiturates. [NIH] Pyruvate Kinase: ATP:pyruvate 2-O-phosphotransferase. A phosphotransferase that catalyzes reversibly the phosphorylation of pyruvate to phosphoenolpyruvate in the presence of ATP. It has four isozymes (L, R, M1, and M2). Deficiency of the enzyme results in hemolytic anemia. EC 2.7.1.40. [NIH] Quality of Life: A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral and social environment. [NIH] Quercetin: Aglucon of quercetrin, rutin, and other glycosides. It is widely distributed in the plant kingdom, especially in rinds and barks, clover blossoms, and ragweed pollen. [NIH] Quinidine: An optical isomer of quinine, extracted from the bark of the Cinchona tree and similar plant species. This alkaloid dampens the excitability of cardiac and skeletal muscles by blocking sodium and potassium currents across cellular membranes. It prolongs cellular action potential, and decreases automaticity. Quinidine also blocks muscarinic and alphaadrenergic neurotransmission. [NIH] Quinine: An alkaloid derived from the bark of the cinchona tree. It is used as an antimalarial drug, and is the active ingredient in extracts of the cinchona that have been used for that purpose since before 1633. Quinine is also a mild antipyretic and analgesic and has been used in common cold preparations for that purpose. It was used commonly and as a bitter and flavoring agent, and is still useful for the treatment of babesiosis. Quinine is also useful in some muscular disorders, especially nocturnal leg cramps and myotonia congenita, because of its direct effects on muscle membrane and sodium channels. The mechanisms of its antimalarial effects are not well understood. [NIH] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not
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sufficiently so as to achieve the status of a taxon. [NIH] Racemic: Optically inactive but resolvable in the way of all racemic compounds. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radiation oncologist: A doctor who specializes in using radiation to treat cancer. [NIH] Radiation therapy: The use of high-energy radiation from x-rays, gamma rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body in the area near cancer cells (internal radiation therapy, implant radiation, or brachytherapy). Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Also called radiotherapy. [NIH] Radical cystectomy: Surgery to remove the bladder as well as nearby tissues and organs. [NIH]
Radioactive: Giving off radiation. [NIH] Radiography: Examination of any part of the body for diagnostic purposes by means of roentgen rays, recording the image on a sensitized surface (such as photographic film). [NIH] Radioimmunotherapy: Radiotherapy where cytotoxic radionuclides are linked to antibodies in order to deliver toxins directly to tumor targets. Therapy with targeted radiation rather than antibody-targeted toxins (immunotoxins) has the advantage that adjacent tumor cells, which lack the appropriate antigenic determinants, can be destroyed by radiation cross-fire. Radioimmunotherapy is sometimes called targeted radiotherapy, but this latter term can also refer to radionuclides linked to non-immune molecules (radiotherapy). [NIH] Radioisotope: An unstable element that releases radiation as it breaks down. Radioisotopes can be used in imaging tests or as a treatment for cancer. [NIH] Radiolabeled: Any compound that has been joined with a radioactive substance. [NIH] Radiotherapy: The use of ionizing radiation to treat malignant neoplasms and other benign conditions. The most common forms of ionizing radiation used as therapy are x-rays, gamma rays, and electrons. A special form of radiotherapy, targeted radiotherapy, links a cytotoxic radionuclide to a molecule that targets the tumor. When this molecule is an antibody or other immunologic molecule, the technique is called radioimmunotherapy. [NIH] Random Allocation: A process involving chance used in therapeutic trials or other research endeavor for allocating experimental subjects, human or animal, between treatment and control groups, or among treatment groups. It may also apply to experiments on inanimate objects. [NIH] Randomization: Also called random allocation. Is allocation of individuals to groups, e.g., for experimental and control regimens, by chance. Within the limits of chance variation, random allocation should make the control and experimental groups similar at the start of an investigation and ensure that personal judgment and prejudices of the investigator do not influence allocation. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Randomized clinical trial: A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively.
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At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial. [NIH] Reactive Oxygen Species: Reactive intermediate oxygen species including both radicals and non-radicals. These substances are constantly formed in the human body and have been shown to kill bacteria and inactivate proteins, and have been implicated in a number of diseases. Scientific data exist that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. [NIH] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [EU] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Receptors, Serotonin: Cell-surface proteins that bind serotonin and trigger intracellular changes which influence the behavior of cells. Several types of serotonin receptors have been recognized which differ in their pharmacology, molecular biology, and mode of action. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Recur: To occur again. Recurrence is the return of cancer, at the same site as the original (primary) tumor or in another location, after the tumor had disappeared. [NIH] Recurrence: The return of a sign, symptom, or disease after a remission. [NIH] Red blood cells: RBCs. Cells that carry oxygen to all parts of the body. Also called erythrocytes. [NIH] Red Nucleus: A pinkish-yellow portion of the midbrain situated in the rostral mesencephalic tegmentum. It receives a large projection from the contralateral half of the cerebellum via the superior cerebellar peduncle and a projection from the ipsilateral motor cortex. [NIH] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] Refractory: Not readily yielding to treatment. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Regional cancer: Refers to cancer that has grown beyond the original (primary) tumor to nearby lymph nodes or organs and tissues. [NIH] Regurgitation: A backward flowing, as the casting up of undigested food, or the backward flowing of blood into the heart, or between the chambers of the heart when a valve is incompetent. [EU] Relapse: The return of signs and symptoms of cancer after a period of improvement. [NIH] Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be
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cancer in the body. [NIH] Renal failure: Progressive renal insufficiency and uremia, due to irreversible and progressive renal glomerular tubular or interstitial disease. [NIH] Renal pelvis: The area at the center of the kidney. Urine collects here and is funneled into the ureter, the tube that connects the kidney to the bladder. [NIH] Reproductive cells: Egg and sperm cells. Each mature reproductive cell carries a single set of 23 chromosomes. [NIH] Resected: Surgical removal of part of an organ. [NIH] Resection: Removal of tissue or part or all of an organ by surgery. [NIH] Resorption: The loss of substance through physiologic or pathologic means, such as loss of dentin and cementum of a tooth, or of the alveolar process of the mandible or maxilla. [EU] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Response rate: The percentage of patients whose cancer shrinks or disappears after treatment. [NIH] Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH] Retinal: 1. Pertaining to the retina. 2. The aldehyde of retinol, derived by the oxidative enzymatic splitting of absorbed dietary carotene, and having vitamin A activity. In the retina, retinal combines with opsins to form visual pigments. One isomer, 11-cis retinal combines with opsin in the rods (scotopsin) to form rhodopsin, or visual purple. Another, all-trans retinal (trans-r.); visual yellow; xanthopsin) results from the bleaching of rhodopsin by light, in which the 11-cis form is converted to the all-trans form. Retinal also combines with opsins in the cones (photopsins) to form the three pigments responsible for colour vision. Called also retinal, and retinene1. [EU] Retinal pigment epithelium: The pigment cell layer that nourishes the retinal cells; located just outside the retina and attached to the choroid. [NIH] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It occurs in hereditary and nonhereditary (sporadic) forms. [NIH] Retinoblastoma Protein: Product of the retinoblastoma tumor suppressor gene. It is a nuclear phosphoprotein hypothesized to normally act as an inhibitor of cell proliferation. Rb protein is absent in retinoblastoma cell lines. It also has been shown to form complexes with the adenovirus E1A protein, the SV40 T antigen, and the human papilloma virus E7 protein. [NIH]
Retinoid: Vitamin A or a vitamin A-like compound. [NIH] Retinol: Vitamin A. It is essential for proper vision and healthy skin and mucous membranes. Retinol is being studied for cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Retropubic: A potential space between the urinary bladder and the symphisis and body of the pubis. [NIH] Retrospective: Looking back at events that have already taken place. [NIH]
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Retrospective study: A study that looks backward in time, usually using medical records and interviews with patients who already have or had a disease. [NIH] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [NIH] Reversion: A return to the original condition, e. g. the reappearance of the normal or wild type in previously mutated cells, tissues, or organisms. [NIH] Rhabdomyosarcoma: A malignant tumor of muscle tissue. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rhodopsin: A photoreceptor protein found in retinal rods. It is a complex formed by the binding of retinal, the oxidized form of retinol, to the protein opsin and undergoes a series of complex reactions in response to visible light resulting in the transmission of nerve impulses to the brain. [NIH] Ribonucleoside Diphosphate Reductase: An enzyme of the oxidoreductase class that catalyzes the formation of 2'-deoxyribonucleotides from the corresponding ribonucleotides using NADPH as the ultimate electron donor. The deoxyribonucleoside diphosphates are used in DNA synthesis. (From Dorland, 27th ed) EC 1.17.4.1. [NIH] Ribose: A pentose active in biological systems usually in its D-form. [NIH] Ribosome: A granule of protein and RNA, synthesized in the nucleolus and found in the cytoplasm of cells. Ribosomes are the main sites of protein synthesis. Messenger RNA attaches to them and there receives molecules of transfer RNA bearing amino acids. [NIH] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Risk patient: Patient who is at risk, because of his/her behaviour or because of the type of person he/she is. [EU] Rod: A reception for vision, located in the retina. [NIH] Rutin: 3-((6-O-(6-Deoxy-alpha-L-mannopyranosyl)-beta-D-glucopyranosyl)oxy)-2-(3,4dihydroxyphenyl)-5,7-dihydroxy-4H-1-benzopyran-4-one. Found in many plants, including buckwheat, tobacco, forsythia, hydrangea, pansies, etc. It has been used therapeutically to decrease capillary fragility. [NIH] Salicylate: Non-steroidal anti-inflammatory drugs. [NIH] Salicylic: A tuberculosis drug. [NIH] Salicylic Acids: Derivatives and salts of salicylic acid. [NIH] Saline: A solution of salt and water. [NIH] Saliva: The clear, viscous fluid secreted by the salivary glands and mucous glands of the mouth. It contains mucins, water, organic salts, and ptylin. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salvage Therapy: A therapeutic approach, involving chemotherapy, radiation therapy, or surgery, after initial regimens have failed to lead to improvement in a patient's condition. Salvage therapy is most often used for neoplastic diseases. [NIH] Saponin: A substance found in soybeans and many other plants. Saponins may help lower cholesterol and may have anticancer effects. [NIH] Sarcoma: A connective tissue neoplasm formed by proliferation of mesodermal cells; it is usually highly malignant. [NIH] Scans: Pictures of structures inside the body. Scans often used in diagnosing, staging, and monitoring disease include liver scans, bone scans, and computed tomography (CT) or computerized axial tomography (CAT) scans and magnetic resonance imaging (MRI) scans.
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In liver scanning and bone scanning, radioactive substances that are injected into the bloodstream collect in these organs. A scanner that detects the radiation is used to create pictures. In CT scanning, an x-ray machine linked to a computer is used to produce detailed pictures of organs inside the body. MRI scans use a large magnet connected to a computer to create pictures of areas inside the body. [NIH] Scatter: The extent to which relative success and failure are divergently manifested in qualitatively different tests. [NIH] Schizoid: Having qualities resembling those found in greater degree in schizophrenics; a person of schizoid personality. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Schizotypal Personality Disorder: A personality disorder in which there are oddities of thought (magical thinking, paranoid ideation, suspiciousness), perception (illusions, depersonalization), speech (digressive, vague, overelaborate), and behavior (inappropriate affect in social interactions, frequently social isolation) that are not severe enough to characterize schizophrenia. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Second cancer: Refers to a new primary cancer that is caused by previous cancer treatment, or a new primary cancer in a person with a history of cancer. [NIH] Secondary tumor: Cancer that has spread from the organ in which it first appeared to another organ. For example, breast cancer cells may spread (metastasize) to the lungs and cause the growth of a new tumor. When this happens, the disease is called metastatic breast cancer, and the tumor in the lungs is called a secondary tumor. Also called secondary cancer. [NIH] Second-look surgery: Surgery performed after primary treatment to determine whether tumor cells remain. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] Segregation: The separation in meiotic cell division of homologous chromosome pairs and their contained allelomorphic gene pairs. [NIH] Seizures: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as epilepsy or "seizure disorder." [NIH] Selective estrogen receptor modulator: SERM. A drug that acts like estrogen on some tissues, but blocks the effect of estrogen on other tissues. Tamoxifen and raloxifene are SERMs. [NIH] Semen: The thick, yellowish-white, viscid fluid secretion of male reproductive organs discharged upon ejaculation. In addition to reproductive organ secretions, it contains spermatozoa and their nutrient plasma. [NIH] Semicircular canal: Three long canals of the bony labyrinth of the ear, forming loops and opening into the vestibule by five openings. [NIH] Semisynthetic: Produced by chemical manipulation of naturally occurring substances. [EU] Sensitization: 1. Administration of antigen to induce a primary immune response; priming;
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immunization. 2. Exposure to allergen that results in the development of hypersensitivity. 3. The coating of erythrocytes with antibody so that they are subject to lysis by complement in the presence of homologous antigen, the first stage of a complement fixation test. [EU] Sequence Homology: The degree of similarity between sequences. Studies of amino acid and nucleotide sequences provide useful information about the genetic relatedness of certain species. [NIH] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines, pyrimidines, and other amino acids. [NIH] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]
Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signal Transduction: The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GABA-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptormediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. [NIH] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Single-agent: The use of a single drug or other therapy. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH]
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Small cell lung cancer: A type of lung cancer in which the cells appear small and round when viewed under the microscope. Also called oat cell lung cancer. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smallpox: A generalized virus infection with a vesicular rash. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]
Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [NIH] Sodium: An element that is a member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. With a valence of 1, it has a strong affinity for oxygen and other nonmetallic elements. Sodium provides the chief cation of the extracellular body fluids. Its salts are the most widely used in medicine. (From Dorland, 27th ed) Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. [NIH] Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Soft tissue sarcoma: A sarcoma that begins in the muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Solid tumor: Cancer of body tissues other than blood, bone marrow, or the lymphatic system. [NIH] Solvent: 1. Dissolving; effecting a solution. 2. A liquid that dissolves or that is capable of dissolving; the component of a solution that is present in greater amount. [EU] Soma: The body as distinct from the mind; all the body tissue except the germ cells; all the axial body. [NIH] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Sorbitol: A polyhydric alcohol with about half the sweetness of sucrose. Sorbitol occurs naturally and is also produced synthetically from glucose. It was formerly used as a diuretic and may still be used as a laxative and in irrigating solutions for some surgical procedures. It is also used in many manufacturing processes, as a pharmaceutical aid, and in several research applications. [NIH] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] Spectrophotometry: The art or process of comparing photometrically the relative intensities of the light in different parts of the spectrum. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of
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a disease. [EU] Sperm: The fecundating fluid of the male. [NIH] Spinal cord: The main trunk or bundle of nerves running down the spine through holes in the spinal bone (the vertebrae) from the brain to the level of the lower back. [NIH] Spinal Nerves: The 31 paired peripheral nerves formed by the union of the dorsal and ventral spinal roots from each spinal cord segment. The spinal nerve plexuses and the spinal roots are also included. [NIH] Splenic Vein: Vein formed by the union (at the hilus of the spleen) of several small veins from the stomach, pancreas, spleen and mesentery. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Squamous: Scaly, or platelike. [EU] Squamous cell carcinoma: Cancer that begins in squamous cells, which are thin, flat cells resembling fish scales. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. Also called epidermoid carcinoma. [NIH] Squamous cell carcinoma: Cancer that begins in squamous cells, which are thin, flat cells resembling fish scales. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. Also called epidermoid carcinoma. [NIH] Squamous cells: Flat cells that look like fish scales under a microscope. These cells cover internal and external surfaces of the body. [NIH] Staging: Performing exams and tests to learn the extent of the cancer within the body, especially whether the disease has spread from the original site to other parts of the body. [NIH]
Standard therapy: A currently accepted and widely used treatment for a certain type of cancer, based on the results of past research. [NIH] Steel: A tough, malleable, iron-based alloy containing up to, but no more than, two percent carbon and often other metals. It is used in medicine and dentistry in implants and instrumentation. [NIH] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] Sterile: Unable to produce children. [NIH] Sterility: 1. The inability to produce offspring, i.e., the inability to conceive (female s.) or to induce conception (male s.). 2. The state of being aseptic, or free from microorganisms. [EU] Steroids: Drugs used to relieve swelling and inflammation. [NIH] Stimulant: 1. Producing stimulation; especially producing stimulation by causing tension on muscle fibre through the nervous tissue. 2. An agent or remedy that produces stimulation. [EU]
Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Stool: The waste matter discharged in a bowel movement; feces. [NIH]
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Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Stria: 1. A streak, or line. 2. A narrow bandlike structure; a general term for such longitudinal collections of nerve fibres in the brain. [EU] Stria Vascularis: A layer of highly vascular pigmented granular cells on the outer wall of the cochlear duct. [NIH] Stringency: Experimental conditions (e. g. temperature, salt concentration) used during the hybridization of nucleic acids. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] Styrene: A colorless, toxic liquid with a strong aromatic odor. It is used to make rubbers, polymers and copolymers, and polystyrene plastics. [NIH] Subacute: Somewhat acute; between acute and chronic. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] Submandibular: Four to six lymph glands, located between the lower jaw and the submandibular salivary gland. [NIH] Submaxillary: Four to six lymph glands, located between the lower jaw and the submandibular salivary gland. [NIH] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] Substrate: A substance upon which an enzyme acts. [EU] Substrate Specificity: A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts. [NIH] Suction: The removal of secretions, gas or fluid from hollow or tubular organs or cavities by means of a tube and a device that acts on negative pressure. [NIH] Superoxide: Derivative of molecular oxygen that can damage cells. [NIH] Superoxide Dismutase: An oxidoreductase that catalyzes the reaction between superoxide anions and hydrogen to yield molecular oxygen and hydrogen peroxide. The enzyme protects the cell against dangerous levels of superoxide. EC 1.15.1.1. [NIH] Supplementation: Adding nutrients to the diet. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Suramin: A polyanionic compound with an unknown mechanism of action. It is used parenterally in the treatment of African trypanosomiasis and it has been used clinically with diethylcarbamazine to kill the adult Onchocerca. (From AMA Drug Evaluations Annual, 1992, p1643) It has also been shown to have potent antineoplastic properties. [NIH] Surfactant: A fat-containing protein in the respiratory passages which reduces the surface tension of pulmonary fluids and contributes to the elastic properties of pulmonary tissue.
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[NIH]
Survival Rate: The proportion of survivors in a group, e.g., of patients, studied and followed over a period, or the proportion of persons in a specified group alive at the beginning of a time interval who survive to the end of the interval. It is often studied using life table methods. [NIH] Suspensions: Colloids with liquid continuous phase and solid dispersed phase; the term is used loosely also for solid-in-gas (aerosol) and other colloidal systems; water-insoluble drugs may be given as suspensions. [NIH] Sympathomimetic: 1. Mimicking the effects of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. 2. An agent that produces effects similar to those of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. Called also adrenergic. [EU] Symphysis: A secondary cartilaginous joint. [NIH] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Synthetic retinoid: A substance related to vitamin A that is produced in a laboratory. [NIH] Systemic: Affecting the entire body. [NIH] Systemic therapy: Treatment that uses substances that travel through the bloodstream, reaching and affecting cells all over the body. [NIH] Tamoxifen: A first generation selective estrogen receptor modulator (SERM). It acts as an agonist for bone tissue and cholesterol metabolism but is an estrogen antagonist in mammary and uterine. [NIH] Taxanes: Anticancer drugs that inhibit cancer cell growth by stopping cell division. Also called antimitotic or antimicrotubule agents or mitotic inhibitors. [NIH] Tegafur: 5-Fluoro-1-(tetrahydro-2-furanyl)-2,4-(1H,3H)-pyrimidinedione. Congener of fluorouracil with comparable antineoplastic action. It has been suggested especially for the treatment of breast neoplasms. [NIH] Telangiectasia: The permanent enlargement of blood vessels, causing redness in the skin or mucous membranes. [NIH] Telomerase: Essential ribonucleoprotein reverse transcriptase that adds telomeric DNA to the ends of eukaryotic chromosomes. Telomerase appears to be repressed in normal human somatic tissues but reactivated in cancer, and thus may be necessary for malignant transformation. EC 2.7.7.-. [NIH] Telomere: A terminal section of a chromosome which has a specialized structure and which is involved in chromosomal replication and stability. Its length is believed to be a few hundred base pairs. [NIH] Telophase: The final phase of cell division, in which two daughter nuclei are formed, the cytoplasm divides, and the chromosomes lose their distinctness and are transformed into chromatin networks. [NIH] Temozolomide: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Temporal: One of the two irregular bones forming part of the lateral surfaces and base of the
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skull, and containing the organs of hearing. [NIH] Tendon: A discrete band of connective tissue mainly composed of parallel bundles of collagenous fibers by which muscles are attached, or two muscles bellies joined. [NIH] Teratogenic: Tending to produce anomalies of formation, or teratism (= anomaly of formation or development : condition of a monster). [EU] Teratoma: A type of germ cell tumor that may contain several different types of tissue, such as hair, muscle, and bone. Teratomas occur most often in the ovaries in women, the testicles in men, and the tailbone in children. Not all teratomas are malignant. [NIH] Testicles: The two egg-shaped glands found inside the scrotum. They produce sperm and male hormones. Also called testes. [NIH] Testicular: Pertaining to a testis. [EU] Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [NIH] Testosterone: A hormone that promotes the development and maintenance of male sex characteristics. [NIH] Thalamic: Cell that reaches the lateral nucleus of amygdala. [NIH] Thalamic Diseases: Disorders of the centrally located thalamus, which integrates a wide range of cortical and subcortical information. Manifestations include sensory loss, movement disorders; ataxia, pain syndromes, visual disorders, a variety of neuropsychological conditions, and coma. Relatively common etiologies include cerebrovascular disorders; craniocerebral trauma; brain neoplasms; brain hypoxia; intracranial hemorrhages; and infectious processes. [NIH] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thermal: Pertaining to or characterized by heat. [EU] Thoracic: Having to do with the chest. [NIH] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [NIH]
Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thymidine: A chemical compound found in DNA. Also used as treatment for mucositis. [NIH]
Thymidine Kinase: An enzyme that catalyzes the conversion of ATP and thymidine to ADP and thymidine 5'-phosphate. Deoxyuridine can also act as an acceptor and dGTP as a donor. (From Enzyme Nomenclature, 1992) EC 2.7.1.21. [NIH] Thymidine Phosphorylase: The enzyme catalyzing the transfer of 2-deoxy-D-ribose from thymidine to orthophosphate, thereby liberating thymidine. EC 2.4.2.4. [NIH] Thymidylate Synthase: An enzyme of the transferase class that catalyzes the reaction 5,10-
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methylenetetrahydrofolate and dUMP to dihydrofolate and dTMP in the synthesis of thymidine triphosphate. (From Dorland, 27th ed) EC 2.1.1.45. [NIH] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tolerance: 1. The ability to endure unusually large doses of a drug or toxin. 2. Acquired drug tolerance; a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response. [EU] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH] Tone: 1. The normal degree of vigour and tension; in muscle, the resistance to passive elongation or stretch; tonus. 2. A particular quality of sound or of voice. 3. To make permanent, or to change, the colour of silver stain by chemical treatment, usually with a heavy metal. [EU] Tonicity: The normal state of muscular tension. [NIH] Topical: On the surface of the body. [NIH] Topoisomerase inhibitors: A family of anticancer drugs. The topoisomerase enzymes are responsible for the arrangement and rearrangement of DNA in the cell and for cell growth and replication. Inhibiting these enzymes may kill cancer cells or stop their growth. [NIH] Topotecan: An antineoplastic agent used to treat ovarian cancer. It works by inhibiting DNA topoisomerase. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicologic: Pertaining to toxicology. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxin: A poison; frequently used to refer specifically to a protein produced by some higher plants, certain animals, and pathogenic bacteria, which is highly toxic for other living organisms. Such substances are differentiated from the simple chemical poisons and the vegetable alkaloids by their high molecular weight and antigenicity. [EU] Tracer: A substance (such as a radioisotope) used in imaging procedures. [NIH] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] Traction: The act of pulling. [NIH] Transcriptase: An enzyme which catalyses the synthesis of a complementary mRNA molecule from a DNA template in the presence of a mixture of the four ribonucleotides (ATP, UTP, GTP and CTP). [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH]
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Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transfusion: The infusion of components of blood or whole blood into the bloodstream. The blood may be donated from another person, or it may have been taken from the person earlier and stored until needed. [NIH] Transitional cell carcinoma: A type of cancer that develops in the lining of the bladder, ureter, or renal pelvis. [NIH] Translation: The process whereby the genetic information present in the linear sequence of ribonucleotides in mRNA is converted into a corresponding sequence of amino acids in a protein. It occurs on the ribosome and is unidirectional. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Translocation: The movement of material in solution inside the body of the plant. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transurethral: Performed through the urethra. [EU] Transurethral resection: Surgery performed with a special instrument inserted through the urethra. Also called TUR. [NIH] Transurethral Resection of Prostate: Resection of the prostate using a cystoscope passed through the urethra. [NIH] Trastuzumab: A type of monoclonal antibody used in cancer detection or therapy. Monoclonal antibodies are laboratory-produced substances that can locate and bind to cancer cells. Trastuzumab blocks the effects of the growth factor protein HER2, which transmits growth signals to breast cancer cells. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Tropomyosin: A protein found in the thin filaments of muscle fibers. It inhibits contraction of the muscle unless its position is modified by troponin. [NIH] Troponin: One of the minor protein components of skeletal muscle. Its function is to serve as the calcium-binding component in the troponin-tropomyosin B-actin-myosin complex by conferring calcium sensitivity to the cross-linked actin and myosin filaments. [NIH] Trypanosomiasis: Infection with protozoa of the genus Trypanosoma. [NIH] Trypsin: A serine endopeptidase that is formed from trypsinogen in the pancreas. It is converted into its active form by enteropeptidase in the small intestine. It catalyzes hydrolysis of the carboxyl group of either arginine or lysine. EC 3.4.21.4. [NIH] Tryptophan: An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor serotonin and niacin. [NIH] Tumor marker: A substance sometimes found in an increased amount in the blood, other body fluids, or tissues and which may mean that a certain type of cancer is in the body. Examples of tumor markers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and gastrointestinal tract cancers), and PSA (prostate cancer). Also called biomarker. [NIH] Tumor model: A type of animal model which can be used to study the development and
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progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Tumor Necrosis Factor: Serum glycoprotein produced by activated macrophages and other mammalian mononuclear leukocytes which has necrotizing activity against tumor cell lines and increases ability to reject tumor transplants. It mimics the action of endotoxin but differs from it. It has a molecular weight of less than 70,000 kDa. [NIH] Tumor suppressor gene: Genes in the body that can suppress or block the development of cancer. [NIH] Tumor-derived: Taken from an individual's own tumor tissue; may be used in the development of a vaccine that enhances the body's ability to build an immune response to the tumor. [NIH] Tumorigenic: Chemical, viral, radioactive or other agent that causes cancer; carcinogenic. [NIH]
Tumour: 1. Swelling, one of the cardinal signs of inflammations; morbid enlargement. 2. A new growth of tissue in which the multiplication of cells is uncontrolled and progressive; called also neoplasm. [EU] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Ultraviolet radiation: Invisible rays that are part of the energy that comes from the sun. UV radiation can damage the skin and cause melanoma and other types of skin cancer. UV radiation that reaches the earth's surface is made up of two types of rays, called UVA and UVB rays. UVB rays are more likely than UVA rays to cause sunburn, but UVA rays pass deeper into the skin. Scientists have long thought that UVB radiation can cause melanoma and other types of skin cancer. They now think that UVA radiation also may add to skin damage that can lead to skin cancer and cause premature aging. For this reason, skin specialists recommend that people use sunscreens that reflect, absorb, or scatter both kinds of UV radiation. [NIH] Unresectable: Unable to be surgically removed. [NIH] Uracil: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Urea: A compound (CO(NH2)2), formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. [NIH] Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. [NIH] Ureters: Tubes that carry urine from the kidneys to the bladder. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]
Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urinary tract: The organs of the body that produce and discharge urine. These include the kidneys, ureters, bladder, and urethra. [NIH] Urinate: To release urine from the bladder to the outside. [NIH] Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Urokinase: A drug that dissolves blood clots or prevents them from forming. [NIH]
Dictionary 283
Urothelium: The epithelial lining of the urinary tract. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Vaccination: Administration of vaccines to stimulate the host's immune response. This includes any preparation intended for active immunological prophylaxis. [NIH] Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. [NIH] Vagal: Pertaining to the vagus nerve. [EU] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Vagus Nerve: The 10th cranial nerve. The vagus is a mixed nerve which contains somatic afferents (from skin in back of the ear and the external auditory meatus), visceral afferents (from the pharynx, larynx, thorax, and abdomen), parasympathetic efferents (to the thorax and abdomen), and efferents to striated muscle (of the larynx and pharynx). [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vasoconstriction: Narrowing of the blood vessels without anatomic change, for which constriction, pathologic is used. [NIH] Vasodilation: Physiological dilation of the blood vessels without anatomic change. For dilation with anatomic change, dilatation, pathologic or aneurysm (or specific aneurysm) is used. [NIH] Vasodilator: An agent that widens blood vessels. [NIH] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venoms: Poisonous animal secretions forming fluid mixtures of many different enzymes, toxins, and other substances. These substances are produced in specialized glands and secreted through specialized delivery systems (nematocysts, spines, fangs, etc.) for disabling prey or predator. [NIH] Venous: Of or pertaining to the veins. [EU] Ventral: 1. Pertaining to the belly or to any venter. 2. Denoting a position more toward the belly surface than some other object of reference; same as anterior in human anatomy. [EU] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Vertebrae: A bony unit of the segmented spinal column. [NIH] Vesicular: 1. Composed of or relating to small, saclike bodies. 2. Pertaining to or made up of vesicles on the skin. [EU] Vestibular: Pertaining to or toward a vestibule. In dental anatomy, used to refer to the tooth surface directed toward the vestibule of the mouth. [EU] Vestibule: A small, oval, bony chamber of the labyrinth. The vestibule contains the utricle and saccule, organs which are part of the balancing apparatus of the ear. [NIH] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Vinblastine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. It is a mitotic inhibitor. [NIH]
284
Cisplatin
Vinca Alkaloids: A class of alkaloids from the genus of apocyanaceous woody herbs including periwinkles. They are some of the most useful antineoplastic agents. [NIH] Vincristine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. [NIH] Vindesine: Vinblastine derivative with antineoplastic activity against acute leukemia, lung cancer, carcinoma of the breast, squamous cell carcinoma of the esophagus, head, and neck, and Hodgkin's and non-Hodgkin's lymphomas. Major side effects are myelosuppression and neurotoxicity. Vindesine is used extensively in chemotherapy protocols. [NIH] Vinorelbine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Viscera: Any of the large interior organs in any one of the three great cavities of the body, especially in the abdomen. [NIH] Visceral: , from viscus a viscus) pertaining to a viscus. [EU] Vitamin A: A substance used in cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Vitiligo: A disorder consisting of areas of macular depigmentation, commonly on extensor aspects of extremities, on the face or neck, and in skin folds. Age of onset is often in young adulthood and the condition tends to progress gradually with lesions enlarging and extending until a quiescent state is reached. [NIH] Vitreous: Glasslike or hyaline; often used alone to designate the vitreous body of the eye (corpus vitreum). [EU] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] Void: To urinate, empty the bladder. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]
Windpipe: A rigid tube, 10 cm long, extending from the cricoid cartilage to the upper border of the fifth thoracic vertebra. [NIH] Withdrawal: 1. A pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) A substance-specific organic brain syndrome that follows the cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Xanthine: An urinary calculus. [NIH]
Dictionary 285
Xenograft: The cells of one species transplanted to another species. [NIH] Xeroderma Pigmentosum: A rare, pigmentary, and atrophic autosomal recessive disease affecting all races. It is manifested as an extreme photosensitivity to ultraviolet light as the result of a deficiency in the enzyme that permits excisional repair of ultraviolet-damaged DNA. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] X-ray therapy: The use of high-energy radiation from x-rays to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. X-ray therapy is also called radiation therapy, radiotherapy, and irradiation. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Zymogen: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]
287
INDEX 6 6-Aminonicotinamide, 48, 209 A Abdomen, 209, 217, 218, 233, 246, 249, 251, 253, 258, 260, 261, 276, 283, 284 Abdominal, 40, 209, 220, 228, 247, 260, 261 Ablation, 16, 41, 209 Acatalasia, 209, 220 Acceptor, 209, 249, 259, 279 Acetylcholine, 209, 257 Acoustic, 178, 209 Acuity, 209, 215 Acute leukemia, 209, 233, 284 Acute lymphoblastic leukemia, 60, 209 Acute lymphocytic leukemia, 209 Acute myeloid leukemia, 209, 265 Acute renal, 117, 120, 209, 241 Acyl, 209 Acyltransferases, 152, 209 Adaptability, 209, 221 Adaptation, 209, 222, 255 Adduct, 15, 26, 28, 37, 64, 88, 150, 169, 210 Adenine, 210, 268 Adenocarcinoma, 20, 69, 75, 81, 136, 210, 242, 257, 266 Adenosine, 152, 210, 215, 219, 262 Adenovirus, 6, 47, 54, 58, 87, 210, 271 Adjustment, 179, 209, 210 Adjuvant, 4, 16, 30, 34, 51, 67, 82, 113, 114, 115, 118, 126, 129, 132, 133, 164, 210 Adrenal Medulla, 210, 220, 232, 233, 257 Adrenergic, 210, 229, 233, 268, 278 Adverse Effect, 125, 210, 230, 274 Aerobic, 210, 254, 267 Aerosol, 210, 278 Afferent, 40, 210, 235 Affinity, 37, 53, 210, 215, 249, 253, 275 Aggressiveness, 37, 61, 210 Agonist, 173, 210, 229, 278 Albumin, 152, 211, 263 Alertness, 211, 218 Algorithms, 211, 217 Alimentary, 211, 260 Alkaline, 211, 212, 219, 261 Alkalinization, 47, 211 Alkaloid, 211, 219, 268 Alkylating Agents, 6, 22, 48, 146, 151, 211, 218, 220, 278, 282
Alkylation, 147, 211 Alleles, 21, 211, 250 Allergen, 211, 228, 274 Allogeneic, 43, 211, 240 Alopecia, 20, 162, 163, 172, 211, 226 Alpha Particles, 211, 269 Alpha-fetoprotein, 160, 211, 235 Alternative medicine, 182, 211 Ameliorated, 163, 211 Ameliorating, 172, 211 Amenorrhea, 212, 213 Amifostine, 124, 187, 212 Amino Acid Sequence, 212, 213, 234, 238 Amino Acids, 147, 212, 238, 253, 260, 264, 267, 272, 274, 281, 282 Aminocamptothecin, 12, 212 Ammonia, 212, 282 Ampicillin, 212, 262 Amplification, 18, 51, 83, 212 Ampulla, 212, 232 Anaesthesia, 212, 245 Analgesic, 212, 249, 268 Analog, 10, 17, 20, 53, 169, 212, 236, 237 Analogous, 212, 230, 263, 281 Anaphylatoxins, 212, 224 Anaplasia, 212, 266 Anatomical, 8, 212, 245, 253 Anemia, 25, 74, 150, 212, 218, 236, 268 Anemic, 26, 212 Anesthetics, 212, 233 Angiogenesis inhibitor, 59, 213 Animal model, 23, 155, 213, 281 Anions, 211, 213, 247, 277 Annealing, 22, 213, 263 Anorexia, 40, 213 Anorexia Nervosa, 40, 213 Ansa, 52, 213 Antagonism, 213, 219 Anthracycline, 137, 162, 213, 227, 233 Antiandrogens, 213, 257 Antiangiogenic, 163, 173, 213 Antibacterial, 52, 213, 275 Antibiotic, 171, 172, 212, 213, 218, 227, 230, 233, 254, 262, 275 Antibodies, 15, 18, 44, 50, 53, 60, 61, 213, 241, 243, 244, 255, 262, 269 Anticoagulant, 213, 266 Antidote, 186, 213, 249
288
Cisplatin
Antiemetic, 80, 213, 240, 253 Antigen, 16, 32, 41, 62, 210, 213, 214, 224, 242, 243, 244, 245, 251, 253, 271, 273 Antigen-Antibody Complex, 214, 224 Anti-infective, 214, 243, 247 Anti-inflammatory, 179, 214, 220, 228, 239, 272 Anti-Inflammatory Agents, 179, 214, 220 Antimetabolite, 214, 228, 236, 253 Antimitotic, 214, 278 Antineoplastic Agents, 47, 149, 150, 151, 163, 211, 214, 284 Antioxidant, 7, 23, 132, 214, 259 Antiproliferative, 62, 214 Antipyretic, 214, 268 Antitumour, 155, 214 Antiviral, 214, 228, 245, 246 Anus, 214, 223, 246 Anxiolytic, 214, 258 Aponeurosis, 214, 237 Aqueous, 157, 160, 161, 168, 214, 216, 227, 231, 243, 248, 249 Arachidonic Acid, 214, 266 Arginine, 212, 214, 242, 257, 281 Arterial, 70, 72, 83, 84, 88, 90, 96, 97, 121, 153, 160, 161, 214, 220, 243, 267 Arterial embolization, 153, 214 Arteries, 214, 215, 217, 220, 226, 255 Arterioles, 215, 217, 219 Artery, 214, 215, 217, 226, 231, 260, 268 Asbestos, 215, 251, 253 Assay, 10, 14, 31, 35, 37, 53, 60, 146, 147, 215 Astrocytes, 56, 143, 215, 253 Astrocytoma, 215, 239 Asymptomatic, 31, 209, 215 Ataxia, 11, 215, 279 Atony, 3, 215 ATP, 24, 151, 152, 215, 229, 238, 250, 262, 267, 268, 279, 280 Attenuation, 53, 215 Atypical, 28, 49, 120, 215 Audiology, 4, 122, 215 Audiometry, 5, 215 Auditory, 5, 23, 215, 240, 283 Autologous, 124, 215 Axons, 215, 256, 261 B Babesiosis, 215, 268 Bacteria, 209, 213, 216, 217, 231, 232, 235, 250, 253, 254, 263, 267, 270, 275, 280, 281, 283
Bactericidal, 216, 233 Bacterium, 216, 241 Basal Ganglia, 215, 216, 237, 239 Basal Ganglia Diseases, 215, 216 Base, 21, 37, 51, 54, 57, 63, 147, 148, 210, 216, 227, 234, 238, 248, 261, 263, 278 Basophils, 216, 240 Benign, 7, 28, 216, 219, 237, 238, 241, 253, 256, 260, 269 Benzo(a)pyrene, 9, 216 Bile, 216, 237, 249 Bile Acids, 216, 237 Bile duct, 216 Biliary, 95, 216 Biliary Tract, 95, 216 Bilirubin, 211, 216 Binding agent, 36, 216 Bioavailability, 179, 216 Biochemical reactions, 162, 216 Biogenesis, 31, 216 Biological response modifier, 216, 217, 246 Biological therapy, 217, 240 Bioluminescence, 152, 217 Biomarkers, 31, 45, 50, 217 Biopsy, 32, 33, 37, 122, 217, 234 Biopsy specimen, 33, 217 Biosynthesis, 214, 217, 274 Biotechnology, 19, 63, 66, 182, 193, 217 Bivalent, 217, 253 Bleomycin, 57, 69, 115, 116, 134, 167, 217 Bloating, 217, 237 Blood Coagulation, 217, 219, 279 Blood Glucose, 217, 241, 246 Blood Platelets, 217, 274 Blood pressure, 217, 220, 243, 254, 275 Blot, 217, 244 Blotting, Western, 217, 244 Body Fluids, 217, 218, 230, 275, 281 Bolus, 70, 160, 218 Bolus infusion, 218 Bolus injection, 160, 218 Bone scan, 218, 272 Bowel, 51, 129, 218, 229, 247, 261, 276 Brachytherapy, 218, 246, 248, 269, 285 Bradykinin, 218, 257, 263 Brain metastases, 80, 218 Breast Neoplasms, 218, 278 Broad-spectrum, 212, 218, 262 Bronchi, 218, 233, 280 Buccal, 60, 77, 218 Buccal mucosa, 77, 218 Busulfan, 43, 162, 218
289
Bypass, 26, 218 C Cadmium, 156, 218 Cadmium Poisoning, 218 Caffeine, 73, 100, 218, 268 Calcifediol, 219 Calcitriol, 62, 219 Calcium, 111, 178, 215, 219, 224, 243, 249, 260, 266, 274, 281 Camptothecin, 219, 247 Capecitabine, 148, 149, 164, 167, 219 Capillary, 58, 218, 219, 239, 272, 283 Capsules, 219, 239 Carbohydrate, 16, 219, 264 Carcinogen, 25, 210, 216, 219, 252 Carcinogenesis, 9, 50, 73, 219, 222 Carcinogenic, 27, 211, 219, 246, 265, 282 Carcinoid, 120, 219 Carcinostatic, 152, 169, 219 Cardiac, 20, 162, 219, 222, 233, 234, 255, 268 Cardiotoxicity, 219, 233 Cardiovascular, 12, 52, 90, 92, 135, 220, 274 Cardiovascular disease, 52, 220 Carmustine, 68, 220 Carnitine, 152, 220 Carotene, 139, 220, 271 Case report, 67, 90, 220, 223 Case series, 220, 223 Caspase, 8, 41, 49, 53, 56, 71, 78, 81, 105, 220 Catalase, 7, 23, 209, 220 Catecholamine, 220, 229, 261 Catheter, 220, 247 Catheterization, 220, 247 Cations, 220, 247 Cause of Death, 31, 164, 167, 174, 220 Celecoxib, 33, 220 Celiac Artery, 220, 242 Cell Count, 8, 220 Cell Cycle, 6, 9, 11, 34, 36, 51, 58, 59, 62, 65, 75, 87, 99, 159, 220, 226, 234, 267 Cell Death, 8, 30, 36, 37, 39, 40, 49, 55, 91, 109, 148, 159, 214, 221, 234, 256 Cell Differentiation, 221, 274 Cell Division, 146, 159, 216, 221, 234, 240, 252, 254, 262, 273, 278 Cell membrane, 152, 221, 228, 262 Cell proliferation, 11, 32, 120, 135, 151, 174, 221, 271, 274 Cell Respiration, 221, 254, 271
Cell Size, 221, 236 Cell Survival, 14, 40, 49, 159, 221, 240 Central Nervous System, 159, 164, 174, 209, 218, 221, 237, 239, 241, 253, 274 Ceramide, 41, 221 Cerebellar, 215, 221, 270 Cerebral, 215, 216, 221, 233, 239 Cerebral Cortex, 215, 221 Cerebral hemispheres, 216, 221, 239 Cerebrovascular, 216, 220, 221, 279 Cervical, 4, 20, 30, 72, 90, 99, 114, 117, 121, 128, 129, 131, 221 Cervix, 26, 30, 76, 87, 90, 103, 115, 221, 240 Character, 29, 221, 228 Chemoembolization, 70, 90, 221 Chemopreventive, 222, 235 Chemotactic Factors, 222, 224 Chlorine, 157, 169, 222 Chlorophyll, 222, 236 Cholesterol, 216, 222, 226, 272, 278 Choriocarcinoma, 222, 238, 239 Choroid, 222, 271 Chromatin, 13, 18, 52, 65, 156, 214, 222, 232, 251, 257, 278 Chromosomal, 39, 212, 222, 238, 242, 253, 263, 278 Chromosome, 8, 39, 222, 237, 241, 249, 250, 253, 273, 278 Chronic, 40, 222, 232, 245, 248, 249, 263, 267, 277 Chronic Disease, 40, 222, 249 Chronic renal, 222, 263 Chronotherapy, 32, 222 Cinchona, 222, 268 Circadian, 98, 222 Circadian Rhythm, 222 CIS, 13, 28, 35, 36, 149, 150, 155, 156, 157, 158, 159, 161, 163, 168, 169, 172, 173, 223, 271 Clamp, 63, 223 Cleave, 148, 223 Clinical Protocols, 15, 223 Clinical study, 14, 76, 78, 129, 223 Cloning, 217, 223, 246 Cochlea, 5, 7, 23, 178, 223, 246, 254 Cochlear, 8, 23, 177, 223, 277 Cochlear Duct, 223, 277 Cofactor, 42, 223, 267, 279 Collagen, 77, 96, 223, 235, 263, 265 Colloidal, 211, 223, 231, 261, 278 Colon, 38, 48, 81, 83, 85, 97, 102, 109, 120, 138, 166, 223, 224, 242, 248
290
Cisplatin
Colony-Stimulating Factors, 223, 240 Colorectal, 18, 83, 134, 167, 223, 224 Colorectal Cancer, 18, 134, 224 Combination chemotherapy, 11, 78, 81, 95, 96, 101, 108, 109, 120, 133, 164, 224 Combination Therapy, 19, 96, 150, 224 Combinatorial, 14, 224 Combined Modality Therapy, 46, 135, 224 Complement, 28, 212, 224, 263, 274 Complementary and alternative medicine, 113, 140, 224 Complementary medicine, 113, 224 Complementation, 31, 147, 224 Complete remission, 14, 76, 88, 90, 119, 224, 270 Complete response, 14, 85, 224, 225 Computational Biology, 193, 225 Computed tomography, 225, 272 Computerized axial tomography, 225, 272 Conception, 222, 225, 235, 238, 239, 276 Concomitant, 70, 85, 90, 97, 109, 125, 128, 165, 166, 225 Conduction, 215, 225 Cones, 225, 271 Congenita, 225, 268 Conjugated, 165, 225, 227 Conjunctivitis, 225, 262 Connective Tissue, 218, 223, 225, 237, 250, 252, 261, 272, 279 Consciousness, 212, 225, 228, 229, 267 Consolidation, 76, 90, 115, 130, 225 Consolidation therapy, 76, 225 Continuous infusion, 38, 46, 60, 93, 101, 103, 225 Contraindications, ii, 225 Contralateral, 225, 235, 270 Contrast Media, 179, 225 Control group, 45, 225, 265, 269 Conventional treatment, 44, 225 Cooperative group, 60, 226 Coordination, 28, 36, 42, 150, 151, 226 Coronary, 220, 226, 255 Coronary heart disease, 220, 226 Coronary Thrombosis, 226, 255 Cortical, 226, 234, 273, 279 Corticosteroids, 226, 239, 265 Cortisol, 211, 226 Cortisone, 226, 228 Cranial, 226, 235, 241, 256, 260, 261, 283 Creatinine, 152, 226 Crossing-over, 226, 270 Cultured cells, 38, 39, 226
Curative, 55, 84, 226, 279 Cyclic, 219, 226, 240, 257, 266 Cyclin, 36, 51, 59, 75, 226 Cyclophosphamide, 33, 43, 76, 78, 89, 113, 115, 124, 139, 151, 163, 167, 173, 226, 244 Cyclosporine, 179, 226 Cyproterone, 226, 236 Cystectomy, 34, 227 Cysteine, 7, 49, 58, 139, 140, 227 Cysteinyl, 227, 253 Cystine, 227 Cytarabine, 102, 227 Cytochrome, 11, 121, 165, 227 Cytokine, 26, 27, 65, 227, 235 Cytomegalovirus, 227, 237 Cytomegalovirus Infections, 227, 237 Cytoplasm, 19, 214, 216, 221, 227, 232, 251, 253, 255, 257, 272, 278 Cytosine, 167, 227, 268 Cytostatic, 12, 78, 227 Cytotoxic chemotherapy, 40, 227, 258 Cytotoxicity, 6, 8, 10, 22, 25, 48, 53, 57, 86, 88, 93, 99, 102, 109, 121, 158, 159, 227 Cytotoxins, 159, 227 D Daunorubicin, 227, 230 Deamination, 227, 282 Degenerative, 228, 242 Dehydration, 52, 228 Deletion, 31, 39, 53, 214, 228, 250 Dementia, 152, 228 Denaturation, 228, 263 Dendrites, 228, 257 Deoxyglucose, 48, 228 Depolarization, 228, 274 Depressive Disorder, 228, 249 Desensitization, 228, 244 Detoxification, 80, 156, 228 Deuterium, 228, 243 Dexamethasone, 62, 83, 101, 228 Diabetes Mellitus, 228, 241 Diagnostic procedure, 145, 183, 228 Dialyzer, 228, 241 Diaphragm, 228, 263 Diethylcarbamazine, 228, 277 Diffusion, 228, 240 Digestion, 211, 216, 218, 228, 230, 237, 247, 249, 276 Digestive system, 229, 255 Digestive tract, 229, 275, 276 Dihydrotestosterone, 229, 270 Dihydroxy, 229, 234, 272
291
Diploid, 224, 229, 262, 263 Direct, iii, 6, 19, 22, 29, 32, 57, 148, 159, 177, 185, 229, 268, 270 Discrimination, 22, 229 Disinfectant, 229, 234 Dissociation, 210, 229, 247 Distal, 229, 237, 248, 261, 267 Diuresis, 168, 219, 229 Diuretic, 172, 229, 251, 275 DNA Topoisomerase, 229, 238 Dopamine, 3, 178, 229, 253, 257, 262 Dorsal, 35, 229, 256, 264, 276 Dorsum, 229, 237 Dose-dependent, 24, 230 Dose-limiting, 24, 49, 68, 150, 162, 163, 166, 230 Dosimetry, 16, 230 Double-blind, 66, 76, 88, 230 DPPE, 155, 230 Drive, ii, vi, 23, 25, 35, 37, 57, 58, 107, 230 Drug Delivery Systems, 19, 230 Drug Design, 42, 186, 187, 230 Drug Interactions, 3, 186, 230 Drug Resistance, 7, 15, 22, 32, 43, 56, 69, 146, 230 Drug Tolerance, 230, 280 Drug Toxicity, 33, 45, 162, 230 Duct, 212, 220, 230, 234, 250, 272 Duodenum, 216, 230, 232, 237, 242, 260, 276 Dura mater, 230, 252, 259 Dyspepsia, 40, 230 E Ectoderm, 230, 256 Effector, 209, 224, 231 Elastic, 231, 277 Elastin, 223, 231 Electrolyte, 231, 264, 275 Electrons, 214, 216, 231, 247, 259, 269 Electrophoresis, 15, 231 Emboli, 58, 160, 231 Embolization, 160, 231 Embryo, 9, 221, 230, 231, 245, 263 Emesis, 66, 72, 74, 76, 80, 101, 231 Emulsion, 157, 160, 231, 236 Encapsulated, 18, 172, 231, 249 Endemic, 231, 276 Endogenous, 6, 20, 23, 27, 51, 73, 229, 231, 232, 259, 266, 280 Endometrial, 30, 78, 98, 131, 132, 231 Endometrium, 231, 240 Endonucleases, 147, 231
Endorphins, 232, 257 Endoscope, 232 Endoscopic, 38, 232 Endothelial cell, 62, 163, 174, 232, 279 Endothelium, 232, 257 Endothelium-derived, 232, 257 Endotoxic, 232, 249 Endotoxin, 232, 282 End-stage renal, 222, 232, 263 Enhancer, 146, 232 Enkephalins, 232, 257 Enteropeptidase, 232, 281 Environmental Exposure, 232, 258 Environmental Health, 192, 194, 232 Enzymatic, 219, 220, 224, 232, 242, 264, 271 Eosinophils, 232, 240 Epidemic, 232, 276 Epidermal, 14, 17, 33, 55, 70, 232, 233, 252 Epidermal Growth Factor, 14, 17, 33, 55, 232, 233 Epidermal growth factor receptor, 14, 17, 33, 55, 233 Epidermis, 232, 233 Epidermoid carcinoma, 233, 276 Epigastric, 233, 260 Epinephrine, 88, 210, 222, 229, 233, 257, 282 Epirubicin, 67, 79, 84, 108, 118, 121, 127, 182, 233 Epithelial, 14, 27, 32, 49, 76, 81, 82, 104, 121, 159, 173, 210, 233, 242, 260, 283 Epithelial carcinoma, 121, 233 Epithelial Cells, 27, 32, 233, 242 Epithelial ovarian cancer, 76, 81, 82, 104, 233 Epithelium, 222, 232, 233, 266 Erythrocytes, 212, 215, 218, 233, 241, 270, 274 Erythropoiesis, 25, 233 Erythropoietin, 27, 233 Escalation, 43, 75, 135, 233 Esophageal, 38, 43, 92, 119, 124, 127, 128, 135, 153, 181, 233 Esophagus, 93, 129, 134, 229, 233, 237, 250, 261, 276, 284 Estrogen, 135, 226, 233, 273, 278 Estrogen receptor, 135, 233 Ethanol, 20, 233 Ethylene Glycol, 169, 234 Eukaryotic Cells, 158, 234, 258 Evacuation, 234, 237 Excipients, 158, 234
292
Cisplatin
Excisional, 234, 285 Excitability, 234, 268 Excitation, 234, 236, 257 Excitatory, 178, 234, 239 Exhaustion, 213, 234, 248 Exocrine, 69, 234, 259 Exogenous, 152, 231, 234, 266 Exon, 147, 234 External radiation, 160, 234 External-beam radiation, 234, 247, 269, 285 Extracellular, 50, 80, 215, 225, 234, 235, 275 Extracellular Matrix, 225, 234, 235 Extracorporeal, 98, 234 Extrapyramidal, 229, 234 Extremity, 84, 235 Eye Infections, 210, 235 F Facial, 235, 260 Facial Nerve, 235, 260 Fallopian tube, 235, 240 Family Planning, 193, 235 Fat, 214, 218, 220, 221, 226, 231, 235, 249, 275, 277 Fatigue, 4, 235 Fatty acids, 152, 157, 211, 235, 266 Fenretinide, 59, 235 Fetoprotein, 235 Fetus, 211, 233, 235, 265, 283 Fibroblasts, 39, 47, 235, 246 Filgrastim, 78, 131, 235 Filtration, 169, 235 Fixation, 235, 274 Flow Cytometry, 15, 236 Fludarabine, 43, 236 Fluorescence, 27, 35, 236 Fluorescent Dyes, 236 Flutamide, 151, 173, 236 Folate, 62, 151, 236 Fold, 10, 13, 28, 53, 153, 156, 157, 236, 252, 258 Folic Acid, 62, 149, 236, 249 Foramen, 236, 261 Fractionation, 24, 236 Free Radicals, 214, 229, 236 Fungus, 108, 236 G Gallbladder, 81, 209, 216, 229, 237, 242 Gamma Rays, 237, 255, 269 Gamma-Glutamyltransferase, 74, 237 Ganciclovir, 172, 237 Ganglia, 209, 212, 216, 237, 256, 261
Ganglion, 35, 237, 256 Ganglioside, 16, 237 Gas, 212, 222, 228, 237, 243, 255, 257, 277, 278 Gastric Emptying, 3, 237 Gastrin, 237, 242 Gastroesophageal Reflux, 3, 237 Gastrointestinal tract, 21, 233, 237, 274, 281 Gastroparesis, 3, 40, 179, 237 Gene Amplification, 8, 237 Gene Expression, 23, 28, 38, 44, 58, 65, 75, 238 Gene Silencing, 17, 50, 238 Gene Therapy, 6, 14, 19, 31, 56, 58, 83, 89, 210, 238 Genetic Code, 238, 258 Genetic Techniques, 28, 238 Genetic testing, 238, 264 Genetics, 37, 39, 238 Genistein, 55, 122, 238 Genotype, 238, 261 Germ cell tumors, 20, 57, 65, 96, 126, 238 Germ Cells, 238, 252, 259, 275, 279 Germinoma, 92, 238 Germline mutation, 11, 238, 242 Gestational, 135, 238, 239 Gestational trophoblastic disease, 135, 238, 239 Gestational trophoblastic neoplasia, 238, 239 Gestational trophoblastic tumor, 238, 239 Gland, 4, 9, 210, 222, 226, 239, 250, 259, 260, 266, 273, 276, 277, 280 Glioblastoma, 79, 83, 95, 239 Glioblastoma multiforme, 79, 95, 239 Glioma, 47, 56, 84, 182, 239 Glomerular, 169, 179, 239, 247, 251, 271 Glomerular Filtration Rate, 179, 239, 251 Glomerulus, 239, 248 Glucocorticoid, 25, 228, 239, 265 Glucose, 20, 29, 48, 169, 217, 228, 239, 241, 246, 275 Glutamate, 20, 239 Glutamic Acid, 169, 236, 239, 241, 257, 265 Glutathione Peroxidase, 23, 239 Glycine, 239, 257, 274 Glycoprotein, 233, 239, 240, 279, 282 Glycosidic, 148, 239 Gonad, 239 Gonadal, 57, 239 Governing Board, 240, 264
293
Grade, 4, 84, 239, 240, 266 Graft, 240, 245, 267 Graft Rejection, 240, 245 Graft-versus-host disease, 240, 267 Granisetron, 66, 240 Granulocyte, 119, 223, 235, 240 Granulocyte Colony-Stimulating Factor, 119, 223, 235, 240 Granulocytopenia, 20, 240 Grasses, 236, 240 Growth factors, 5, 24, 36, 240, 253 Guanine, 95, 240, 268 Guanylate Cyclase, 240, 257 Gynecologic cancer, 30, 240 H Habitual, 221, 240 Haematemesis, 231, 240 Haemodialysis, 78, 240 Hair Cells, 5, 240 Half-Life, 179, 240 Haploid, 241, 262, 263 Haptens, 210, 241 Headache, 219, 241 Health Behavior, 13, 241 Health Status, 241 Heart attack, 220, 241 Hematogenous, 58, 241 Hematologic malignancies, 54, 241 Hemodialysis, 89, 228, 241, 248 Hemoglobin, 27, 92, 212, 233, 241 Hemoglobin C, 212, 241 Hemoglobinopathies, 238, 241 Hemolytic, 162, 241, 268 Hemostasis, 241, 274 Hepatic, 83, 84, 90, 96, 153, 160, 211, 220, 241, 242 Hepatic Artery, 160, 242 Hepatitis, 160, 242 Hepatocellular, 70, 77, 78, 84, 85, 90, 91, 96, 102, 108, 161, 242 Hepatocellular carcinoma, 70, 77, 78, 84, 85, 90, 91, 96, 102, 108, 242 Hepatocytes, 32, 242 Hepatoma, 160, 161, 242 Hereditary, 24, 238, 242, 271 Hereditary mutation, 238, 242 Hereditary nonpolyposis colon cancer, 24, 242 Heredity, 237, 238, 242 Herpes, 58, 242 Herpes Zoster, 242 Heterodimer, 24, 242
Heterogeneity, 210, 242 Histamine, 212, 222, 242 Histones, 222, 242 Homeostasis, 48, 56, 242 Homologous, 39, 211, 217, 226, 238, 242, 273, 274, 278 Hormonal, 173, 242 Hormone, 62, 151, 173, 219, 222, 226, 233, 237, 242, 246, 247, 252, 256, 274, 279, 280 Hormone therapy, 151, 242 Horseradish Peroxidase, 102, 243 Hybridization, 243, 277 Hybridomas, 243, 246 Hydration, 64, 87, 168, 243 Hydrogen, 37, 209, 216, 219, 220, 228, 239, 243, 249, 254, 257, 259, 267, 277 Hydrogen Peroxide, 220, 239, 243, 249, 277 Hydrolysis, 86, 231, 243, 250, 262, 264, 267, 281 Hydrophilic, 154, 243 Hydroxylation, 219, 243 Hydroxylysine, 223, 243 Hydroxyproline, 223, 243 Hydroxyurea, 74, 243 Hypercalcemia, 62, 243 Hypersensitivity, 29, 86, 152, 211, 228, 243, 274 Hypertension, 220, 241, 243 Hyperthermia, 93, 243, 256 Hypotension, 20, 243 Hypoxia, 27, 30, 57, 212, 243, 279 Hypoxic, 27, 30, 243 Hysterectomy, 114, 243 I Ifosfamide, 58, 60, 77, 81, 84, 90, 93, 94, 101, 103, 113, 123, 124, 129, 131, 136, 137, 151, 244 Imaging procedures, 244, 280 Immune response, 41, 210, 213, 226, 240, 241, 244, 273, 282, 283, 284 Immune system, 41, 217, 244, 261, 283, 284 Immunity, 227, 244 Immunization, 244, 274 Immunoblotting, 54, 244 Immunodeficiency, 17, 32, 244 Immunofluorescence, 14, 29, 244 Immunogenic, 16, 46, 244, 249 Immunohistochemistry, 20, 27, 60, 244 Immunologic, 222, 244, 269 Immunology, 48, 61, 210, 236, 243, 244 Immunomodulator, 244, 249
294
Cisplatin
Immunosuppressant, 211, 236, 244, 253 Immunosuppression, 43, 244, 250 Immunosuppressive, 226, 239, 244 Immunosuppressive Agents, 244 Immunosuppressive therapy, 244 Immunotherapy, 16, 217, 228, 244, 256 Immunotoxins, 245, 269 Impairment, 16, 29, 48, 162, 170, 177, 215, 235, 245, 246 Implant radiation, 245, 246, 247, 269, 285 In situ, 14, 27, 178, 245 Incision, 35, 148, 245, 247, 266 Incompetence, 237, 245 Infarction, 245 Infection, 17, 47, 217, 222, 227, 235, 240, 244, 245, 250, 257, 275, 277, 281, 284 Inflammation, 132, 211, 214, 225, 235, 242, 245, 252, 259, 263, 276 Inflammatory breast cancer, 59, 245, 260 Information Science, 245, 251 Infusion, 20, 83, 84, 92, 96, 121, 127, 153, 160, 218, 245, 281 Ingestion, 218, 245, 263 Initiation, 18, 21, 24, 40, 41, 245, 280 Initiator, 8, 56, 246 Inner ear, 178, 246 Innervation, 40, 178, 235, 246 Inoperable, 16, 20, 97, 103, 108, 115, 129, 246 Inorganic, 42, 86, 246, 263 Inotropic, 229, 246 Insertional, 7, 246 Insight, 9, 11, 25, 41, 246 Insulin, 56, 246 Insulin-dependent diabetes mellitus, 246 Insulin-like, 56, 246 Interferon, 12, 70, 77, 78, 246, 250 Interferon-alpha, 77, 78, 246 Interleukin-6, 146, 246 Internal Medicine, 31, 33, 43, 109, 159, 246, 252 Internal radiation, 246, 247, 269, 285 Interstitial, 39, 218, 246, 248, 271, 285 Intestinal, 3, 40, 219, 220, 232, 246 Intestinal Obstruction, 40, 246 Intestine, 40, 218, 224, 246, 248 Intoxication, 247, 284 Intracellular Membranes, 247, 252 Intracranial tumors, 56, 247 Intramuscular, 247, 260 Intraperitoneal, 16, 76, 86, 88, 115, 247 Intraperitoneal chemotherapy, 86, 247
Intravenous, 3, 72, 88, 115, 123, 153, 160, 161, 163, 168, 172, 218, 245, 247, 260 Intrinsic, 62, 156, 210, 247 Intubation, 3, 220, 247 Inulin, 239, 247 Invasive, 13, 16, 27, 32, 34, 91, 108, 244, 247, 251, 266 Iodine, 53, 108, 247 Iodine-131, 53, 108, 247 Ion Channels, 215, 247 Ionization, 247 Ionizing, 9, 11, 39, 73, 83, 154, 174, 211, 232, 247, 269 Ions, 42, 156, 165, 216, 229, 231, 243, 247 Irinotecan, 12, 43, 79, 108, 109, 114, 117, 123, 124, 127, 128, 129, 130, 132, 137, 166, 247 Irradiation, 4, 8, 56, 65, 73, 114, 128, 133, 158, 247, 268, 285 Ischemia, 237, 248 Isozymes, 11, 49, 248, 268 J Job Satisfaction, 170, 248 K Kb, 192, 248 Kidney Cortex, 248, 253 Kidney Disease, 39, 178, 179, 192, 248 Kidney Failure, 232, 248, 251 Kidney stone, 179, 248, 256 Kinetic, 13, 33, 42, 53, 89, 247, 248 L Labile, 156, 224, 248 Labyrinth, 223, 246, 248, 273, 283 Large Intestine, 224, 229, 247, 248, 270, 275 Laryngeal, 85, 87, 123, 181, 248 Larynx, 248, 280, 283 Laser therapy, 16, 248 Lassitude, 4, 248 Latent, 15, 155, 248, 265 Lectin, 248, 252 Lens, 134, 225, 248 Lesion, 37, 78, 148, 156, 159, 248, 250 Lethal, 58, 216, 249 Leucocyte, 249, 250 Leucovorin, 12, 66, 67, 69, 79, 84, 93, 95, 104, 113, 126, 127, 249 Leukaemia, 109, 249 Leukemia, 61, 93, 109, 168, 171, 209, 230, 238, 241, 249 Leukopenia, 150, 249 Levo, 249, 252 Ligament, 235, 249, 266
295
Ligands, 17, 55, 155, 171, 249 Ligation, 61, 148, 249 Linkages, 241, 242, 249 Lipid, 13, 51, 172, 246, 249, 259 Lipid A, 13, 249 Lipid Peroxidation, 249, 259 Lipophilic, 170, 249 Lipopolysaccharides, 249 Liposomal, 56, 154, 182, 249 Liposome, 64, 118, 154, 160, 172, 249 Lithium, 40, 249 Lithium Chloride, 40, 249 Liver, 23, 32, 83, 133, 134, 153, 160, 209, 211, 214, 216, 219, 220, 226, 227, 229, 231, 233, 236, 237, 241, 242, 249, 250, 253, 272, 282 Liver cancer, 211, 249 Liver metastases, 83, 250 Liver scan, 250, 272 Localization, 29, 53, 58, 75, 244, 250 Localized, 58, 62, 109, 127, 231, 235, 245, 250, 262 Locoregional, 59, 119, 160, 250 Loop, 47, 172, 250 Loss of Heterozygosity, 39, 250 Lower Esophageal Sphincter, 3, 237, 250 Luciferase, 151, 152, 250 Lung metastases, 91, 250 Lyases, 148, 250 Lymph, 4, 221, 232, 245, 250, 270, 277 Lymph node, 4, 221, 250, 270 Lymphatic, 232, 245, 250, 252, 275 Lymphatic system, 250, 275 Lymphoblastic, 250 Lymphoblasts, 209, 250 Lymphocyte Depletion, 244, 250 Lymphocytes, 41, 213, 243, 244, 249, 250, 251, 284 Lymphoid, 60, 213, 226, 249, 251 Lymphoma, 33, 53, 60, 82, 91, 126, 241, 250, 251 Lysine, 241, 242, 243, 251, 281 Lysosome, 19, 251 M Magnetic Resonance Imaging, 251, 272 Malignancy, 40, 86, 127, 251 Malignant, 19, 28, 30, 31, 50, 56, 58, 116, 122, 125, 151, 156, 164, 166, 174, 210, 214, 222, 238, 239, 249, 251, 253, 256, 259, 269, 272, 278, 279 Malignant mesothelioma, 251, 253
Malignant tumor, 19, 166, 222, 251, 259, 272 Malnutrition, 211, 251 Mammary, 251, 278 Manic, 249, 251 Mannans, 236, 251 Mannitol, 157, 163, 251 Maximum Tolerated Dose, 38, 230, 251 Mediate, 31, 42, 47, 55, 229, 251 Mediator, 41, 52, 251, 274 Medical Informatics, 30, 251 Medical Records, 252, 272 Medicament, 171, 252 MEDLINE, 193, 252 Megaloblastic, 236, 252 Meiosis, 217, 252, 253, 278 Melanin, 252, 262, 282 Melanocytes, 252 Melanoma, 36, 71, 73, 78, 95, 98, 122, 149, 150, 164, 174, 252, 282 Melphalan, 29, 48, 252 Membrane Proteins, 92, 252 Memory, 213, 228, 252 Meninges, 221, 230, 252 Meningitis, 68, 252 Mental, iv, 6, 192, 194, 221, 228, 229, 235, 245, 252, 268, 273, 282 Mercury, 236, 252 Mesenchymal, 159, 233, 252 Mesenteric, 252, 264 Mesothelial, 54, 253 Mesothelioma, 117, 182, 251, 253 Meta-Analysis, 72, 253 Metabolite, 219, 249, 253, 265 Metallothionein, 89, 136, 157, 171, 253 Metastasis, 19, 30, 55, 58, 253 Metastasize, 151, 253, 273 Metastatic cancer, 150, 253 Methotrexate, 33, 58, 79, 84, 90, 93, 108, 109, 131, 134, 135, 140, 151, 152, 167, 253 Methylprednisolone, 82, 253 Methyltransferase, 95, 253 Metoclopramide, 3, 72, 253 Micelle, 169, 253 Microbe, 253, 280 Microbiology, 210, 215, 253 Microglia, 215, 253 Micronuclei, 77, 253 Microorganism, 223, 254, 284 Microscopy, 23, 65, 101, 243, 254 Microspheres, 96, 254 Microtubules, 254, 259
296
Cisplatin
Migration, 41, 61, 254 Mitochondria, 71, 152, 254, 258 Mitomycin, 39, 43, 91, 103, 108, 115, 118, 129, 130, 131, 146, 162, 166, 167, 254 Mitosis, 214, 253, 254 Mitotic, 21, 36, 39, 229, 234, 254, 278, 283 Mitotic inhibitors, 229, 254, 278 Mitoxantrone, 118, 254 Mobility, 13, 254 Mobilization, 115, 254 Modeling, 25, 230, 254 Modification, 254, 268 Modiolus, 136, 254 Modulator, 168, 254 Monitor, 5, 35, 42, 226, 254, 258 Monoclonal, 12, 14, 15, 18, 21, 243, 244, 245, 248, 255, 269, 281, 285 Monoclonal antibodies, 21, 244, 245, 255, 281 Monocytes, 62, 246, 255 Mononuclear, 43, 60, 255, 282 Monophosphate, 167, 255 Morphological, 23, 231, 236, 252, 255 Morphology, 101, 255 Motility, 3, 62, 255, 274 Motion Sickness, 255, 256 Mucinous, 237, 255 Mucosa, 255 Mucositis, 12, 255, 279 Multicenter study, 122, 255 Multidrug resistance, 38, 83, 92, 255 Multimodality treatment, 114, 255 Muscle Fibers, 255, 281 Mutagen, 216, 255 Mutagenesis, 14, 26, 73, 100, 148, 174, 255 Mutagenic, 211, 255 Mutagenicity, 25, 255 Myelosuppression, 150, 162, 255, 284 Myocardial infarction, 94, 226, 255 Myocardium, 255 Myotonia, 256, 268 N Natural selection, 216, 256 Nausea, 3, 20, 40, 99, 164, 168, 171, 213, 237, 256, 258, 282 NCI, 1, 30, 191, 223, 256 Necrosis, 132, 214, 239, 245, 255, 256 Neoadjuvant Therapy, 67, 256 Neoplasia, 55, 256, 266 Neoplasm, 154, 159, 256, 260, 272, 282 Nephrolithiasis, 179, 256 Nephropathy, 98, 248, 256
Nephrotoxic, 45, 152, 171, 256 Nerve Fibers, 40, 256 Nerve Growth Factor, 36, 256 Nervous System, 210, 221, 240, 251, 256, 257, 261, 278 Neural, 8, 40, 136, 172, 210, 235, 253, 256 Neural Crest, 8, 256 Neural Pathways, 40, 256 Neuroblastoma, 8, 87, 94, 109, 256 Neuroleptic, 256, 258 Neurologic, 113, 239, 257 Neuronal, 35, 257, 260 Neurons, 36, 228, 234, 237, 256, 257, 278 Neuropathy, 126, 173, 257, 261 Neurophysiology, 40, 228, 257 Neurotoxic, 257 Neurotoxicity, 19, 35, 94, 124, 136, 162, 168, 178, 257, 284 Neurotoxins, 35, 257 Neurotransmitter, 40, 209, 210, 218, 229, 239, 242, 247, 257, 274 Neutrons, 211, 247, 257, 269 Neutrophils, 235, 240, 257 Nilutamide, 173, 257 Nitric Oxide, 73, 94, 257 Nitrogen, 166, 211, 226, 235, 252, 257, 281 Norepinephrine, 210, 229, 257 Nuclei, 40, 58, 211, 231, 238, 242, 251, 253, 254, 257, 258, 267, 278 Nucleic acid, 102, 156, 227, 238, 243, 257, 258, 268, 277 O Oliguria, 248, 251, 258 Omentum, 242, 258 Oncogene, 26, 67, 100, 174, 258 Oncologist, 16, 46, 75, 258 Oncolysis, 258 Oncolytic, 148, 164, 258 Ondansetron, 72, 80, 258 Ophthalmic, 258, 264 Opsin, 258, 271, 272 Orderly, 28, 258 Organ Preservation, 44, 70, 123, 258 Organelles, 227, 252, 255, 258 Osmolarity, 251, 258 Osmotic, 211, 258 Osteogenic sarcoma, 259 Osteosarcoma, 58, 84, 88, 90, 93, 109, 259 Ototoxic, 5, 23, 259 Ovarian epithelial cancer, 105, 259 Ovaries, 157, 233, 240, 259, 279 Ovary, 23, 28, 147, 239, 259, 263
297
Overall survival, 27, 34, 45, 59, 102, 133, 259 Overexpress, 50, 259 Oxaliplatin, 15, 25, 38, 76, 85, 89, 94, 104, 167, 169, 259 Oxidants, 9, 259 Oxidation, 153, 209, 214, 227, 239, 249, 250, 259 Oxidation-Reduction, 259 Oxidative Stress, 9, 259 P P53 gene, 6, 28, 47, 174, 259 Pachymeningitis, 252, 259 Palliative, 226, 259, 279 Pancreas, 55, 69, 209, 217, 229, 242, 246, 259, 260, 276, 281 Pancreatic, 36, 55, 68, 72, 96, 104, 108, 114, 127, 220, 233, 237, 260 Pancreatic cancer, 55, 68, 96, 104, 108, 114, 127, 233, 260 Pancreatic Juice, 237, 260 Papilloma, 260, 271 Parathyroid, 219, 260 Parathyroid hormone, 219, 260 Parenteral, 157, 161, 260 Parietal, 260, 261, 263 Parotid, 4, 260 Partial remission, 260, 270 Particle, 249, 253, 260, 281 Pathologic, 19, 34, 76, 133, 214, 217, 226, 243, 260, 267, 271, 283 Pathologic Processes, 214, 260 Patient Advocacy, 34, 260 Peau d'orange, 245, 260 Pelvic, 128, 260, 266 Pelvis, 209, 259, 260, 283 Peptide, 16, 232, 237, 260, 264, 266, 267 Perfusion, 58, 86, 243, 260 Perineural, 4, 260 Peripheral blood, 43, 60, 62, 96, 246, 260 Peripheral Nerves, 260, 276 Peripheral Nervous System, 232, 257, 261 Peripheral Neuropathy, 116, 135, 261 Peritoneal, 16, 54, 86, 117, 247, 261 Peritoneal Cavity, 54, 247, 261 Peritoneum, 258, 261 Petrolatum, 231, 261 Phagocyte, 259, 261 Pharmaceutical Preparations, 169, 234, 261 Pharmacodynamic, 43, 59, 60, 261 Pharmacokinetic, 18, 24, 43, 59, 126, 261
Pharmacologic, 15, 97, 149, 162, 241, 261, 280 Pharmacology, Clinical, 3, 261 Pharmacotherapy, 136, 149, 261 Pharynx, 237, 261, 283 Phenolphthalein, 231, 261 Phenotype, 8, 21, 157, 224, 261 Phenyl, 143, 155, 261 Phenylalanine, 261, 282 Phorbol, 262, 267 Phorbol Esters, 262, 267 Phospholipases, 262, 274 Phospholipids, 235, 262, 266 Phosphorus, 219, 262 Phosphorylated, 33, 62, 262 Phosphorylates, 262, 266 Phosphorylating, 24, 262 Phosphorylation, 26, 30, 36, 47, 53, 60, 85, 87, 262, 267, 268 Photosensitivity, 262, 285 Physical Examination, 13, 262 Physiologic, 210, 217, 241, 247, 262, 266, 270, 271 Physiology, 40, 210, 257, 262 Pigment, 122, 216, 252, 262, 271 Pilot study, 84, 108, 262 Pink eye, 9, 262 Piperacillin, 65, 262 Plants, 211, 227, 239, 247, 248, 255, 257, 258, 262, 263, 267, 272, 280 Plasma, 23, 59, 60, 70, 89, 153, 211, 213, 221, 223, 239, 241, 248, 262, 273 Plasma cells, 213, 262 Plasma protein, 211, 262 Plasmid, 237, 263, 283 Platelet Activation, 263, 274 Platelet Aggregation, 52, 212, 257, 263 Platelets, 255, 257, 263 Platinum Compounds, 14, 36, 94, 146, 259, 263 Pleura, 263 Pleural, 86, 253, 263 Ploidy, 108, 263 Pneumonia, 225, 263 Podophyllotoxin, 234, 263 Point Mutation, 21, 39, 174, 263 Poisoning, 218, 230, 247, 252, 256, 263 Pollen, 263, 268 Polycystic, 39, 263 Polymerase, 24, 25, 54, 63, 65, 68, 71, 78, 100, 263 Polymerase Chain Reaction, 63, 263
298
Cisplatin
Polymers, 264, 267, 277 Polypeptide, 148, 212, 223, 232, 243, 264, 285 Polyposis, 224, 264 Polysaccharide, 213, 264 Polyvalent, 16, 264 Polyvinyl Alcohol, 160, 264 Port, 91, 264 Port-a-cath, 264 Portal Vein, 84, 264 Posterior, 215, 222, 229, 259, 264 Postnatal, 264, 276 Postoperative, 3, 132, 166, 264 Postsynaptic, 264, 274 Potassium, 98, 111, 264, 268 Potentiates, 62, 64, 136, 264 Potentiating, 158, 264 Potentiation, 48, 51, 109, 158, 264, 274 Practice Guidelines, 194, 264 Precancerous, 222, 264, 265 Preclinical, 6, 15, 17, 18, 20, 43, 54, 60, 68, 265 Precursor, 214, 226, 229, 231, 232, 240, 257, 261, 265, 266, 281, 282 Predictive factor, 108, 265 Predisposition, 5, 265 Prednisolone, 253, 265 Premalignant, 27, 265, 266 Prenatal, 231, 265 Preoperative, 71, 92, 119, 132, 135, 166, 265 Presynaptic, 257, 265 Prevalence, 151, 170, 265 Primary endpoint, 14, 66, 265 Primary tumor, 37, 83, 164, 166, 172, 174, 265 Probe, 52, 265 Prodrug, 58, 265 Progression, 6, 17, 27, 30, 33, 34, 50, 58, 59, 62, 63, 213, 265, 282 Progressive, 82, 221, 222, 228, 230, 233, 256, 263, 265, 271, 282 Proline, 223, 243, 265 Promoter, 11, 22, 28, 50, 56, 58, 65, 265 Promyelocytic leukemia, 71, 265 Prone, 25, 100, 265 Prophylaxis, 80, 265, 283 Prospective study, 34, 70, 93, 265 Prostaglandin, 154, 266 Prostaglandins A, 266 Prostate, 51, 62, 134, 139, 167, 172, 217, 235, 266, 281 Prostatectomy, 62, 266
Prostatic Intraepithelial Neoplasia, 62, 266 Protease, 224, 266 Protective Agents, 5, 162, 171, 266 Protein Binding, 179, 266 Protein C, 6, 10, 14, 156, 211, 212, 266, 281, 282 Protein Kinase C, 53, 135, 266 Protein S, 42, 47, 217, 238, 267, 272 Protein-Tyrosine Kinase, 238, 267 Proteolytic, 49, 71, 98, 224, 232, 267 Protocol, 10, 59, 267 Protons, 211, 243, 247, 267, 269 Proto-Oncogene Proteins, 259, 267 Proto-Oncogene Proteins c-mos, 259, 267 Protozoa, 217, 254, 267, 281 Proximal, 32, 45, 49, 80, 165, 229, 248, 265, 267 Pseudomonas, 262, 267 Pseudomonas Infections, 262, 267 Psoralen, 64, 73, 267 Psoriasis, 267 Psychoactive, 267, 284 Public Health, 194, 216, 267 Public Policy, 193, 268 Publishing, 63, 245, 268 Pulmonary, 58, 92, 162, 217, 222, 248, 268, 277 Pulmonary Edema, 222, 248, 268 Pulse, 254, 268 Purines, 268, 274 Pyrimidine Dimers, 64, 148, 268 Pyrimidines, 268, 274 Pyruvate Kinase, 73, 268 Q Quality of Life, 10, 15, 40, 44, 103, 162, 170, 268 Quercetin, 111, 132, 136, 268 Quinidine, 172, 222, 268 Quinine, 172, 222, 268 R Race, 12, 252, 254, 268, 269 Racemic, 252, 269 Radiation oncologist, 258, 269 Radical cystectomy, 34, 269 Radioactive, 160, 161, 218, 240, 243, 245, 246, 247, 248, 250, 255, 258, 269, 273, 282, 285 Radiography, 225, 269 Radioimmunotherapy, 46, 53, 224, 269 Radioisotope, 269, 280 Radiolabeled, 16, 41, 46, 53, 217, 248, 269, 285
299
Random Allocation, 269 Randomization, 34, 269 Randomized clinical trial, 14, 115, 269 Reactive Oxygen Species, 5, 21, 270 Reagent, 151, 152, 222, 250, 270 Receptors, Serotonin, 270, 274 Recombinant, 27, 58, 148, 270, 283 Recombination, 9, 21, 28, 32, 39, 238, 270 Rectum, 214, 223, 224, 229, 237, 248, 266, 270 Recur, 44, 270 Recurrence, 34, 38, 40, 44, 62, 222, 270 Red blood cells, 233, 241, 255, 270 Red Nucleus, 215, 270 Reductase, 7, 23, 65, 253, 270 Refer, 1, 218, 224, 232, 235, 242, 250, 256, 257, 269, 270, 280, 283 Refraction, 270, 275 Refractory, 22, 43, 57, 62, 83, 119, 124, 130, 137, 270 Regional cancer, 161, 270 Regurgitation, 237, 270 Relapse, 10, 15, 20, 44, 60, 133, 156, 169, 173, 270 Remission, 159, 161, 270 Renal failure, 179, 271 Renal pelvis, 248, 271, 281 Reproductive cells, 238, 242, 271 Resected, 30, 118, 131, 271 Resection, 14, 40, 72, 84, 91, 271, 281 Resorption, 219, 271 Respiration, 254, 271 Response rate, 43, 84, 160, 161, 173, 271 Retina, 222, 225, 248, 271, 272 Retinal, 9, 271, 272 Retinal pigment epithelium, 9, 271 Retinoblastoma, 36, 47, 90, 271 Retinoblastoma Protein, 47, 271 Retinoid, 59, 271 Retinol, 271, 272 Retropubic, 266, 271 Retrospective, 4, 94, 98, 271, 272 Retrospective study, 4, 272 Retroviral vector, 238, 272 Reversion, 9, 272 Rhabdomyosarcoma, 60, 272 Rheumatoid, 259, 272 Rhodopsin, 258, 271, 272 Ribonucleoside Diphosphate Reductase, 243, 272 Ribose, 54, 68, 210, 272, 279 Ribosome, 272, 281
Risk factor, 4, 5, 12, 90, 265, 272 Risk patient, 34, 272 Rod, 216, 223, 267, 272 Rutin, 268, 272 S Salicylate, 272 Salicylic, 272 Salicylic Acids, 272 Saline, 153, 163, 168, 272 Saliva, 272 Salivary, 4, 227, 229, 235, 260, 272, 277 Salvage Therapy, 20, 135, 224, 272 Saponin, 16, 272 Sarcoma, 60, 84, 272, 275 Scans, 161, 272 Scatter, 273, 282 Schizoid, 273, 284 Schizophrenia, 273, 284 Schizotypal Personality Disorder, 273, 284 Screening, 18, 26, 31, 32, 43, 45, 223, 273 Second cancer, 10, 273 Secondary tumor, 253, 273 Second-look surgery, 16, 273 Secretion, 222, 232, 242, 246, 253, 273 Secretory, 266, 273 Segregation, 270, 273 Seizures, 239, 273 Selective estrogen receptor modulator, 273, 278 Semen, 266, 273 Semicircular canal, 246, 273 Semisynthetic, 219, 234, 245, 262, 273 Sensitization, 29, 57, 273 Sequence Homology, 39, 274 Sequencing, 134, 264, 274 Serine, 10, 26, 48, 52, 266, 267, 274, 281 Serotonin, 178, 240, 257, 258, 261, 270, 274, 281 Serum, 24, 44, 62, 95, 211, 212, 224, 251, 274, 282 Shock, 10, 56, 99, 274, 281 Signal Transduction, 14, 36, 47, 49, 274 Signs and Symptoms, 270, 274 Single-agent, 117, 274 Skeletal, 223, 268, 274, 281 Skeleton, 52, 266, 274 Skull, 274, 279 Small cell lung cancer, 11, 14, 18, 19, 33, 36, 40, 66, 67, 68, 77, 82, 92, 95, 97, 98, 100, 101, 103, 114, 115, 117, 118, 123, 128, 129, 130, 135, 137, 150, 257, 275 Small intestine, 230, 242, 247, 275, 281
300
Cisplatin
Smallpox, 198, 275 Smooth muscle, 212, 219, 242, 275 Social Environment, 268, 275 Sodium, 98, 163, 173, 186, 268, 275 Soft tissue, 60, 218, 274, 275 Soft tissue sarcoma, 60, 275 Solid tumor, 12, 20, 23, 30, 32, 59, 60, 127, 149, 156, 157, 164, 165, 213, 217, 230, 275 Solvent, 5, 153, 234, 258, 275 Soma, 275 Somatic, 39, 252, 254, 261, 275, 278, 283 Sorbitol, 251, 275 Specialist, 199, 275 Species, 86, 148, 211, 233, 236, 252, 254, 255, 267, 268, 270, 274, 275, 277, 284, 285 Specificity, 22, 24, 28, 54, 147, 210, 275 Spectrophotometry, 24, 275 Spectrum, 39, 48, 170, 253, 275 Sperm, 222, 238, 242, 263, 271, 276, 279 Spinal cord, 40, 215, 221, 222, 230, 237, 252, 256, 257, 259, 260, 261, 276 Spinal Nerves, 40, 260, 261, 276 Splenic Vein, 264, 276 Sporadic, 24, 271, 276 Squamous, 17, 20, 30, 37, 69, 74, 77, 83, 93, 95, 97, 103, 115, 125, 127, 129, 134, 159, 233, 257, 276, 284 Squamous cells, 276 Staging, 272, 276 Standard therapy, 38, 276 Steel, 96, 223, 276 Stem Cells, 21, 96, 136, 233, 240, 276 Sterile, 157, 161, 260, 276 Sterility, 226, 276 Steroids, 226, 239, 276 Stimulant, 218, 242, 276 Stimulus, 230, 234, 246, 247, 276, 279 Stomach, 40, 43, 209, 229, 233, 237, 242, 250, 256, 258, 261, 275, 276 Stool, 223, 248, 276 Strand, 7, 9, 15, 21, 22, 24, 35, 39, 66, 105, 156, 263, 277 Stress, 9, 25, 29, 30, 45, 48, 52, 56, 73, 99, 220, 226, 256, 259, 265, 277 Stria, 5, 7, 23, 94, 277 Stria Vascularis, 5, 23, 94, 277 Stringency, 39, 277 Stroke, 192, 220, 277 Styrene, 178, 277 Subacute, 245, 277 Subclinical, 12, 245, 273, 277 Subcutaneous, 16, 54, 56, 260, 277
Submandibular, 4, 277 Submaxillary, 232, 277 Subspecies, 275, 277 Substrate, 49, 53, 277 Substrate Specificity, 53, 277 Suction, 235, 277 Superoxide, 23, 277 Superoxide Dismutase, 23, 277 Supplementation, 63, 94, 277 Suppression, 21, 47, 71, 77, 163, 168, 238, 277 Suramin, 12, 277 Surfactant, 159, 277 Survival Rate, 17, 161, 259, 278 Suspensions, 159, 278 Sympathomimetic, 229, 233, 258, 278 Symphysis, 266, 278 Synaptic, 257, 274, 278 Synergistic, 10, 18, 20, 53, 97, 99, 148, 149, 164, 278 Synthetic retinoid, 235, 278 Systemic, 16, 18, 19, 36, 43, 46, 70, 83, 166, 186, 217, 233, 245, 248, 265, 269, 278, 285 Systemic therapy, 18, 166, 278 T Tamoxifen, 12, 135, 149, 151, 273, 278 Taxanes, 14, 32, 278 Tegafur, 91, 278 Telangiectasia, 11, 278 Telomerase, 32, 56, 278 Telomere, 13, 278 Telophase, 253, 278 Temozolomide, 56, 79, 150, 182, 278 Temporal, 27, 278 Tendon, 237, 279 Teratogenic, 209, 211, 279 Teratoma, 92, 222, 279 Testicles, 279 Testicular, 12, 13, 35, 58, 65, 78, 91, 124, 149, 150, 153, 156, 159, 173, 279 Testis, 13, 28, 222, 279 Testosterone, 270, 279 Thalamic, 215, 279 Thalamic Diseases, 215, 279 Therapeutics, 12, 17, 19, 59, 61, 95, 186, 279 Thermal, 15, 64, 215, 229, 257, 263, 279 Thoracic, 68, 92, 114, 128, 129, 132, 135, 228, 250, 263, 279, 284 Threonine, 10, 26, 266, 267, 274, 279 Threshold, 78, 234, 243, 279 Thrombin, 263, 266, 279
301
Thrombomodulin, 266, 279 Thrombosis, 52, 267, 277, 279 Thymidine, 33, 58, 123, 279, 280 Thymidine Kinase, 33, 58, 279 Thymidine Phosphorylase, 123, 279 Thymidylate Synthase, 38, 45, 279 Thyroid, 73, 247, 260, 280, 282 Thyroxine, 211, 262, 280 Tolerance, 22, 28, 209, 280 Tomography, 33, 225, 280 Tone, 215, 280 Tonicity, 157, 280 Topical, 233, 243, 261, 280 Topoisomerase inhibitors, 53, 212, 247, 280 Topotecan, 56, 87, 114, 116, 134, 280 Toxicologic, 18, 280 Toxicology, 28, 116, 125, 134, 135, 194, 280 Toxin, 40, 232, 245, 280 Tracer, 160, 243, 280 Trachea, 218, 248, 261, 280 Traction, 223, 280 Transcriptase, 278, 280 Transcription Factors, 10, 28, 30, 57, 280 Transduction, 14, 24, 49, 59, 87, 274, 281 Transfection, 15, 20, 55, 157, 217, 238, 281 Transfusion, 169, 281 Transitional cell carcinoma, 34, 50, 281 Translation, 7, 31, 54, 281 Translational, 16, 18, 30, 37, 61, 238, 281 Translocation, 30, 39, 281 Transmitter, 209, 215, 229, 247, 251, 257, 281 Transurethral, 266, 281 Transurethral resection, 266, 281 Transurethral Resection of Prostate, 266, 281 Trastuzumab, 51, 97, 100, 281 Trauma, 177, 216, 241, 256, 279, 281 Tropomyosin, 20, 281 Troponin, 281 Trypanosomiasis, 277, 281 Trypsin, 121, 232, 281, 285 Tryptophan, 223, 274, 281 Tumor marker, 217, 281 Tumor model, 18, 26, 32, 41, 54, 56, 62, 281 Tumor Necrosis Factor, 54, 282 Tumor suppressor gene, 6, 250, 259, 271, 282 Tumor-derived, 62, 282 Tumorigenic, 159, 282 Tumour, 69, 88, 125, 155, 214, 237, 258, 282
Tyrosine, 10, 17, 18, 68, 229, 267, 282 U Ultraviolet radiation, 11, 148, 282 Unresectable, 20, 67, 77, 78, 81, 83, 84, 91, 96, 109, 127, 130, 282 Uracil, 91, 268, 282 Urea, 152, 282 Uremia, 248, 271, 282 Ureters, 248, 282 Urethra, 266, 281, 282 Urinary, 34, 46, 227, 258, 266, 271, 282, 283, 284 Urinary tract, 282, 283 Urinate, 282, 284 Urine, 45, 151, 152, 217, 223, 226, 229, 232, 248, 258, 271, 282 Urokinase, 61, 282 Urothelium, 34, 131, 283 Uterus, 221, 231, 238, 239, 240, 243, 259, 283 V Vaccination, 16, 283 Vaccine, 16, 210, 267, 282, 283 Vagal, 40, 283 Vagina, 90, 221, 240, 283 Vagus Nerve, 283 Vascular, 90, 102, 136, 222, 232, 245, 257, 277, 283 Vasoconstriction, 233, 283 Vasodilation, 212, 283 Vasodilator, 218, 229, 242, 283 Vector, 6, 54, 56, 174, 246, 281, 283 Vein, 247, 258, 260, 264, 276, 283 Venoms, 227, 257, 283 Venous, 58, 267, 283 Ventral, 276, 283 Venules, 217, 219, 283 Vertebrae, 276, 283 Vesicular, 242, 275, 283 Vestibular, 4, 240, 283 Vestibule, 223, 246, 273, 283 Veterinary Medicine, 193, 283 Vinblastine, 90, 108, 109, 118, 130, 131, 146, 151, 283, 284 Vinca Alkaloids, 283, 284 Vincristine, 115, 116, 129, 137, 151, 167, 284 Vindesine, 103, 125, 131, 284 Viral, 174, 281, 282, 284 Virulence, 280, 284 Virus, 17, 32, 58, 174, 232, 246, 271, 272, 275, 281, 284
302
Cisplatin
Viscera, 275, 284 Visceral, 3, 40, 261, 283, 284 Vitamin A, 111, 209, 271, 284 Vitiligo, 267, 284 Vitreous, 248, 271, 284 Vitro, 13, 17, 18, 21, 22, 25, 27, 28, 30, 31, 32, 36, 41, 42, 44, 45, 49, 53, 54, 56, 57, 61, 62, 64, 66, 69, 76, 77, 85, 86, 87, 105, 136, 238, 245, 263, 284 Vivo, 6, 8, 14, 17, 18, 19, 21, 24, 25, 26, 28, 32, 33, 35, 36, 42, 44, 46, 48, 49, 53, 54, 56, 59, 61, 62, 162, 172, 174, 238, 245, 250, 259, 284 Void, 165, 284 W White blood cell, 209, 213, 235, 240, 249, 250, 251, 255, 262, 284
Windpipe, 261, 280, 284 Withdrawal, 4, 284 Wound Healing, 19, 284 X Xanthine, 147, 284 Xenograft, 8, 21, 30, 54, 60, 213, 282, 285 Xeroderma Pigmentosum, 38, 100, 147, 285 X-ray, 9, 13, 225, 236, 237, 247, 255, 258, 269, 273, 285 X-ray therapy, 248, 285 Y Yeasts, 236, 261, 285 Z Zymogen, 266, 285
303
304
Cisplatin
