CHRONIC
MYELOGENOUS LEUKEMIA 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., 1960Chronic Myelogenous Leukemia: 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: 0-497-00251-5 1. Chronic Myelogenous Leukemia-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 chronic myelogenous leukemia. 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 CHRONIC MYELOGENOUS LEUKEMIA ..................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Chronic Myelogenous Leukemia ................................................... 4 E-Journals: PubMed Central ....................................................................................................... 59 The National Library of Medicine: PubMed ................................................................................ 62 CHAPTER 2. NUTRITION AND CHRONIC MYELOGENOUS LEUKEMIA.......................................... 111 Overview.................................................................................................................................... 111 Finding Nutrition Studies on Chronic Myelogenous Leukemia................................................ 111 Federal Resources on Nutrition ................................................................................................. 114 Additional Web Resources ......................................................................................................... 114 CHAPTER 3. ALTERNATIVE MEDICINE AND CHRONIC MYELOGENOUS LEUKEMIA ................... 117 Overview.................................................................................................................................... 117 National Center for Complementary and Alternative Medicine................................................ 117 Additional Web Resources ......................................................................................................... 128 General References ..................................................................................................................... 130 CHAPTER 4. DISSERTATIONS ON CHRONIC MYELOGENOUS LEUKEMIA ..................................... 131 Overview.................................................................................................................................... 131 Dissertations on Chronic Myelogenous Leukemia..................................................................... 131 Keeping Current ........................................................................................................................ 131 CHAPTER 5. PATENTS ON CHRONIC MYELOGENOUS LEUKEMIA ................................................ 133 Overview.................................................................................................................................... 133 Patents on Chronic Myelogenous Leukemia .............................................................................. 133 Patent Applications on Chronic Myelogenous Leukemia .......................................................... 141 Keeping Current ........................................................................................................................ 154 CHAPTER 6. PERIODICALS AND NEWS ON CHRONIC MYELOGENOUS LEUKEMIA ...................... 157 Overview.................................................................................................................................... 157 News Services and Press Releases.............................................................................................. 157 Academic Periodicals covering Chronic Myelogenous Leukemia .............................................. 159 CHAPTER 7. RESEARCHING MEDICATIONS .................................................................................. 161 Overview.................................................................................................................................... 161 U.S. Pharmacopeia..................................................................................................................... 161 Commercial Databases ............................................................................................................... 162 Researching Orphan Drugs ....................................................................................................... 163 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 167 Overview.................................................................................................................................... 167 NIH Guidelines.......................................................................................................................... 167 NIH Databases........................................................................................................................... 169 Other Commercial Databases..................................................................................................... 171 APPENDIX B. PATIENT RESOURCES ............................................................................................... 173 Overview.................................................................................................................................... 173 Patient Guideline Sources.......................................................................................................... 173 Finding Associations.................................................................................................................. 174 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 177 Overview.................................................................................................................................... 177 Preparation................................................................................................................................. 177 Finding a Local Medical Library................................................................................................ 177 Medical Libraries in the U.S. and Canada ................................................................................. 177 ONLINE GLOSSARIES................................................................................................................ 183
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Online Dictionary Directories ................................................................................................... 185 CHRONIC MYELOGENOUS LEUKEMIA DICTIONARY................................................... 187 INDEX .............................................................................................................................................. 243
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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 chronic myelogenous leukemia 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 chronic myelogenous leukemia, 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 chronic myelogenous leukemia, 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 chronic myelogenous leukemia. 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 chronic myelogenous leukemia, 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 chronic myelogenous leukemia. 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 CHRONIC MYELOGENOUS LEUKEMIA Overview In this chapter, we will show you how to locate peer-reviewed references and studies on chronic myelogenous leukemia.
The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and chronic myelogenous leukemia, 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 “chronic myelogenous leukemia” (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: •
Low-energy Laser Therapy in Oral Mucositis Source: Journal of Oral Laser Applications. 1(2): 97-101. Autumn 2001. Contact: Available from Quintessence Publishing Co., Inc. 551 Kimberly Drive, Carol Stream, Ill. 60188. (630) 682-3223. Website: www.quintessenz.de. Email:
[email protected]. Summary: The use of high dose chemotherapy as part of the preparative regimen for stem cell transplantation is associated with mucosal damage. Laser irradiation of the oral mucosa may help to decrease the severity of mucositis. This article reports on a pilot trial that was conducted to evaluate the usefulness of low energy laser therapy in
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Chronic Myelogenous Leukemia
the control of pain associated with oral mucositis after stem cell transplantation or high dose chemotherapy. Eleven patients with the diagnosis of chronic myelogenous leukemia (n = 4), non-Hodgkin's lymphoma (n = 3), acute myelocytic leukemia (n = 1), and other malignancies (n = 3) were submitted to high dose chemotherapy for myeloablation. Seven patients received autologous stem cell transplantation, two patients received stem cells from allogeneic sources, and two were given high dose chemotherapy only. The oral cavity of all patients was examined by an oral medicine specialist during the pretransplant and prechemotherapy work up. The patients received irradiation with the mucolaser daily until posttransplant day 5. Mucositis was clinically evaluated according the WHO (World Health Organization) scale, and pain was measured by a visual analog scale (VAS). The laser treatment was well tolerated by the patients. Two patients had mucositis grade I or II, 8 patients had grade III to IV, and 1 patient had none. None of the patients had the maximal pain score. Six patients had grade 0 to 3, and 5 patients had grade 5 to 8 by VAS. The majority of patients associated the daily application of laser with prompt pain relief. The authors conclude that the use of low energy laser therapy may play a role in the control of pain associated with oral mucositis. 3 figures. 2 tables. 23 references.
Federally Funded Research on Chronic Myelogenous Leukemia The U.S. Government supports a variety of research studies relating to chronic myelogenous leukemia. 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 chronic myelogenous leukemia. 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 chronic myelogenous leukemia. The following is typical of the type of information found when searching the CRISP database for chronic myelogenous leukemia: •
Project Title: A NOVEL AUTOTRANSPLANT PROTOCOL FOR CML Principal Investigator & Institution: De Lima, Marcos; Medicine; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 77030 Timing: Fiscal Year 2004; Project Start 08-JUN-2004; Project End 31-MAY-2006 Summary: (provided by applicant): Imatinib mesylate has shown remarkable promise in the treatment of chronic myeloid leukemia (CML); however, in some patients it is clearly insufficient as a single agent to produce long-term disease-free or overall survival. AIIogeneic hematopoietic cell transplant-based therapies remain an established curative approach, but complications such as graft-versus-host disease and the need for
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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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a suitable donor limit its application. The use of autografts to support high-dose chemotherapy was being explored extensively prior to the introduction of imatinib and promising results with both in vitro and in vivo-purged autologous cells were reported. In the interim, our understanding of the abnormal biology of CML stem cells has advanced significantly and methods for quantitating different types of transplantable normal and leukemic stem cells and for expanding normal cells with rapid, short-term reconstituting potential have been devised. These advances provide an attractive basis for designing an improved strategy for purging CML stem cells from patients' autografts for use with myeloablative chemotherapy in patients without other therapeutic options. Here we will evaluate three purging methods to selectively eliminate CML stem cells: ex vivo pharmacologic treatment with Gleevec and mafosfamide; a novel culture-purging method that exploits the known intrinsically determined, highly defective self-renewal property of CML stem cells under conditions that are predicted to simultaneously amplify residual normal short-term repopulating cells typically present in many CML patients; and a combination of these. We plan to proceed as rapidly as possible to a clinical test of these approaches, in which we will compare the results obtained when patients are randomly assigned to one of the three purging methods. Key to the success of this project is the commitment of two leading groups with complementary expertise in the biology of normal and CML stem cells and the development and clinical evaluation of cultured autografts. The proposed work will thus build on an exciting history in these areas in an attempt to address an emerging need for innovative and broadly applicable approaches to the treatment of CML prompted by a growing recognition of the limitations of imatinib mesylate as a single therapeutic agent. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ABNORMALITIES/SIGNAL TRANSDUCTION/HEMATOPOIETIC DISEASE Principal Investigator & Institution: D'andrea, Alan D.; Professor; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 23-AUG-1996; Project End 31-JUL-2007 Summary: There is no text on file for this abstract. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ACTION OF INTERFERON IN CHRONIC MYELOGENOUS LEUKEMIA Principal Investigator & Institution: Platanias, Leonidas C.; Professor of Medicine; Robert H. Lurie Comprehensive Cancer Center; Northwestern University Office of Sponsored Research Chicago, Il 60611 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2006 Summary: (provided by applicant): Interferon alpha (IFNa) has significant clinical activity in the treatment of chronic myelogenous leukemia (CML), but the mechanisms by which it exhibits its antileukemic effects remain unknown. We have identified a novel signaling cascade activated by the Type I IFN receptor, involving the small GTPase Rac1 and the p38 Map kinase. This pathway acts independently of the Statpathway, but in cooperation with it, to regulate transcriptional regulation of IFNasensitive genes. Our data demonstrate that this signaling cascade is activated in primary granulocytes from CML patients and that pharmacological blockade of its activation reverses the growth inhibitory effects of IFNa on primary leukemia bone marrow
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Chronic Myelogenous Leukemia
progenitors. This proposal is a systematic approach to identify the signaling mechanisms by which IFNa exhibits its antileukemic effects. Specific aim A is to determine the mechanisms of regulation of activation of the p38 pathway by the Type I IFN receptor in BCR-ABL expressing cells and to identify downstream effector mechanisms. Studies will be performed to determine the roles of Jak kinases and the vav proto-oncogene product on the activation of the Rac1/p38 pathway in BCR-ABL expressing cells and to define the role of p38-dependent nuclear histone serine phosphorylation in the induction of IFNa-responses in CML cells. Specific aim B is to determine the biological consequences of activation of p38 in CML. It will involve studies to determine whether Rac1 and p38 are essential for the generation of the growth inhibitory effects of IFNa on primary leukemic progenitors and whether defective activation of this pathway correlates with IFNa-resistance. It will also examine the hypothesis that IFNa downregulates BCR-ABL protein expression via a p38dependent mechanism. Specific aim C includes studies to identify the mechanisms by which the BCR-ABL-tyrosine kinase antagonizes IFNa-dependent gene transcription and determine whether the BCR-ABL specific inhibitor, STI571, augments the growth inhibitory effects of IFNa via regulatory effects on the Rac1/p38 and Jak/Stat pathways. Altogether, these studies should provide important information on the mechanisms by which signals are transduced by the Type 1 IFN receptor in CML cells and advance our knowledge on the mechanisms of development of IFNa resistance. Identifying such mechanisms will facilitate the development of novel therapeutic approaches to overcome IFNa-resistance and the design of new pharmacologic agents for the treatment of CML. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ACTIVATION & PROLIFERATION OF HEMATOPOIETIC STEM CELLS Principal Investigator & Institution: Lansdorp, Peter M.; Professor of Medicine; British Columbia Cancer Research Centre 601 W 10Th Ave Vancouver, Bc Timing: Fiscal Year 2002; Project Start 01-AUG-1990; Project End 31-MAY-2007 Summary: (provided by applicant): Hematopoietic stern cells (HSC), unlike e.g. embryonic stem cells, have a finite potential to divide. Limitations in the replication potential of HSC appear to be important in hematological disorders such as aplastic anemia and chronic myeloid leukemia. Such limitations could furthermore hamper the development of novel therapeutic strategies, including ex vivo stem cell expansion and gene therapy. Based on these considerations, studies that may help define and extend the replicative potential of HSC are important and a general interest. Previous studies with purified human "candidate" HSC funded by this grant have shown that the functional properties of HSC change dramatically during ontogeny and that the loss in HSC proliferative potential with age correlates with measurable shortening of telomeres. Here we propose to further examine the role of telomerase and telomeres in hematopoiesis. Specifically, we want to test the hypothesis that the replication history of HSC can be traced by studies of their telomere length. In order to test this hypothesis, we will examine the telomere length in subsets of purified HSC and their cultured progeny relative to defined populations of more mature cells using refined flow cytometry techniques developed in our laboratory. These techniques will also be used to further study the age related decline in telomere length in nucleated blood cells from normal individuals, patients with various hematological disorders and pedigrees of genotyped normal baboons. We will furthermore attempt to manipulate the telomere length in HSC using gene transfer and protein transduction strategies and study the
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functional properties of cells with extended telomeres in vitro and in vivo. The specific aims are:1) To study the telomere length in purified HSC and nucleated blood cells from normal individuals and patients with various hematological disorders before and after therapy.2) To study the telomere length in nucleated blood cells from baboons in relation to their age and genotype.3) To study the effect of artificial telomere elongation and telomerase inhibition on the proliferation, differentiation and replicative potential of purified "candidate" HSC in vitro and in vivo.Taken together, these studies will provide crucial baseline information on the role of telomeres in the biology of HSC. Such information is relevant for a basic understanding of hematopoiesis as well as applications of stem cells in and outside hematology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ACTIVATION OF SIGNAL TRANSDUCTION PATHWAYS IN STABLE PHASE CHRONIC MYELOID Principal Investigator & Institution: Griffin, James D.; Professor; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2007 Summary: (provided by applicant): Chronic myeloid leukemias are caused by activated tyrosine kinase oncogenes, most often by BCR/ABL, or the related oncogenes TEL/ABL, TEL/JAK2, or TEL/PDGFR. The goal of this project is to understand in detail the signal transduction pathways activated by BCR/ABL and related oncogenes that are relevant for transformation of hematopoietic cells. Using BCR/ABL as the best-studied example, this kinase is believed to function by phosphorylating itself and adjacent cell proteins, and by phosphorylating other proteins that are brought in by adapter molecules. This results in activation of a variety of signaling pathways that ultimately block apoptosis, deregulate cell cycle control, alter adhesion and homing, and cause genetic instability. A particular focus of this project period will be phosphotidylinositol signaling, which we and others have shown is required for transformation, probably because of prominent effects on apoptosis and cell cycle deregulation. We would like to understand how PI3K is activated and determine the downstream targets particularly those related to viability signaling. Also, in preliminary studies we have shown that SHIP, an inositol 5-phophatase, is downregulated by BCR/ABL. SHIP activity would be expected to modulate the lipids that accumulated downstream of PI3K. This is of interest since a SHIP knock out mouse develops a myeloproliferative syndrome, suggesting that there may be certain PI3K products that are more important for hematopoiesis than others. Finally, efforts will be focused on understanding the differences in signaling by the 3 known forms of BCR/ABL, encoding p190, p210, or p230; and understanding the differences between BCR/ABL and v-ABL. In particular, pathways initiated because of phosphorylation of Y177 of BCR seem to be of particular interest, as this single tyrosine residue is needed to generate a myeloproliferative disorder in mice. Overall, identification of critical signaling intermediates will be useful for many reasons, but particularly to identify potential targets for drug development, especially for drugs that would be synergistic with STI571. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ALLOIMMUNITY TO CML IN A NOVEL MURINE MODEL Principal Investigator & Institution: Shlomchik, Warren D.; Assistant Professor; Internal Medicine; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2002; Project Start 01-SEP-1998; Project End 31-AUG-2003
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Chronic Myelogenous Leukemia
Summary: (Applicant's Description): This proposal outlines a 5 year plan for the candidate to develop the necessary skills and experience to become an independent investigator studying the alloimmunology of bone marrow transplantation. Dr. Shlomchik is board certified in Internal Medicine and Hematology, and is board eligible in Oncology. He has been in the sponsor's lab for 3 years studying Graft-vs.Host Disease (GVHD), T cell tolerance post alloBMT, and methods of gene transfer into human T cells. Chronic myelogenous leukemia (CML) is uniquely sensitive to T cell alloimmune therapies, yet the scientific basis for CML's remarkable susceptibility is unknown. Understanding the details of this anti-CML response, including the nature of antigen presentation, critical effectors, and factors that render CML cells vulnerable to immune attack, may facilitate the development of strategies to enhance alloimmune responses against other less immunogenic neoplasms. The identification of factors that render CML sensitive have been impeded by the absence of: 1) tools needed to isolate individual components of alloimmune responses; and 2) a relevant murine CML model. The first obstacle can now be approached using mice deficient in genes critical for antigen presentation and T cell effector function. For example, the applicants have exploited mice lacking the beta-2-microblobulin gene to demonstrate that radioresistant host cells are critical for initiating GVHD responses. The second problem has been addressed by a new CML murine model wherein bone marrow infected ex vivo with retrovirus expressing the bcr-abl fusion cDNA is transferred into irradiated syngeneic recipients. They will combine these approaches to determine: 1) the identity of anti-CML effectors; 2) the identity of antigen presenting cells in anti-CML responses, and 3) the roles of molecules accessory for target cell vulnerability such as Fas and TNF-R by establishing CML in mice genetically deficient in them. Dr. Shlomchik's sponsor, Dr. Emerson, is chief of the hematology and oncology section. He has a Ph.D. in immunology and was scientific director of the alloBMT program at the University of Michigan. He has launched a new alloBMT program at Penn and is committed to Dr. Shlomchik's development into an independent clinician scientist. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ANTILEUKEMIA ACTIVITY OF PERILLYL ALCOHOL Principal Investigator & Institution: Clark, Steven S.; Associate Professor; Human Oncology; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2002; Project Start 01-JAN-2000; Project End 31-DEC-2003 Summary: The Bcr/Abl oncogene encodes a tyrosine kinase that is expressed in leukemias that carry the Philadelphia chromosome translocation (Ph+). The kinase interacts with different cell signaling pathways to cause factor-independent growth, resistance to apoptosis and oncogenic transformation. These pleiotropic activities of Bcr/Abl affect the pathogenesis of Ph+ leukemias by inhibiting the normal rate of cell death and by enabling Ph+ cells to resist conventional chemotherapy that induces apoptosis in other leukemias. A central hypothesis of this proposal is that inhibition of signaling pathways downstream of the Bcr/Abl kinase should render leukemia cells dependent on growth factors and sensitive to apoptosis. Perillyl alcohol (POH) belongs to a new family of chemotherapy agents and has shown excellent therapeutic rations in rodent carcinoma models. The range of potential anti-tumor activities of POH overlaps with some signaling pathways that are affected by the Bcr/Abl kinase. Thus, POH is a logical compound to test for anti- leukemia activity in Bcr/Abl-induced leukemia. Preliminary experiments demonstrated that in Bcr/Abl-transformed cells, POH rapidly induced G1 arrest and apoptosis. In contrast, Bcr/Abl- transformed cells were resistant to apoptosis induced by different conventional chemotherapy agents. This anti-leukemia
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activity of POH closely correlated with inhibition of the Raf-ERK signaling pathway downstream of Bcl/Abl. On the other hand, POH treatment did not affect other Bcr/Abl signals that are responsible for maintaining expression of c- Myc. Normally, expression of c-Myc is cell cycle regulated, however, when c-Myc expression is enforced during G1 arrest, cells undergo apoptosis. Therefore, POH may uncouple a Bcr/Abl signaling pathway through Raf that is necessary for maintaining cell growth, while not affecting other Bcr/Abl signals that induce constitutive c-Myc expression. This combination may lead to apoptosis in leukemia cells. This model will be evaluated further by examining 1) the role of the Bcr/Abl oncogene in sensitizing cells to POH, 2) how POH affects signaling through Raf, and 3) whether POH induces Myc-dependent apoptosis in leukemia cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ARSENIC BASED THERAPY OF BCR ABL POSITIVE LEUKEMIAS Principal Investigator & Institution: Bhalla, Kapil N.; Professor of Medicine; Moffitt Cancer Center; University of South Florida 4202 E Fowler Ave Tampa, Fl 33620 Timing: Fiscal Year 2002; Project Start 15-JUN-2001; Project End 31-MAY-2004 Summary: The leukemic clone in virtually all of the patients with chronic myeloid leukemia with blast crisis (CML-BC) and approximately one-third of the adults with acute lymphoblastic leukemia (ALL) expresses the bcr-abl fusion gene encoded p210 and p185 Bcr-Abl tyrosine kinase (TK), respectively. Although the chemotherapeutic regimens or bone marrow stem cell transplantation employed against acute leukemias can also produce complete remissions in Bcr-Abl positive ALL and CML-BC, these remissions are not durable and the overall clinical outcome remains dismal. This creates a strong rationale to test novel strategies in this clinical setting. Arsenic Trioxide (As2O3 or AT) is clinically active against relapsed or refractory acute promyelocytic leukemia (APL), where it downregulates the levels of the fusion protein PML-RARdelta causing partial differentiation and apoptosis of APL cells. Recently, we have demonstrated that clinically achievable levels of AT can also reduce p210 or p185 Bcr-Abl fusion protein levels and induce apoptosis of CML-BC cells. Based on these findings, we propose to conduct a Phase II clinical-pharmacologic trial of AT (NCI/CTEP sponsored) as the induction therapy for relapsed and refractory; Bcr-Abl positive adult ALL and CML-BC. In vitro studies on the patient derived leukemic blasts are proposed to determine the molecular correlates of the clinical response and apoptosis induced by AT. We have also shown that STI571, a relatively specific inhibitor of Bcr-Abl TK activity, induces differentiation and apoptosis of Bcr-Abl positive leukemic cells. Therefore, we also propose to investigate the in vitro apoptotic and differentiation effects of a combination of AT and STI571 in Bcr-Abl positive leukemic blasts. The specific aims of this proposal are: AIM 1: To determine the clinical efficacy, i.e., the rate and duration of clinical and hematologic response and overall survival, secondary to treatment with daily intravenous AT in adult patients with Philadelphia chromosome (bcr-abl fusion gene) positive relapsed or refractory ALL or CML-BC. AIM 2: To determine the pharmacokinetic parameters of AT, i.e., AUC and Css and correlate these with the clinical and cytogenetic response in patients with Bcr-Abl positive ALL or CMLBC. AIM 3: To correlate the clinical response to AT with the decline in the bcr-abl mRNA levels determined by real-time RT-PCR. AIM 4: To correlate the clinical and in vivo molecular response to AT with AT-induced in vitro downregulation of Bcr-Abl and Akt protein levels, histone hyperacetylation as well as differentiation and apoptosis, utilizing the pre-treatment samples of leukemic blasts. AIM 5: To determine the in vitro differentiation and apoptotic effects of STI-571 alone and in combination with AT in the
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pre-treatment samples of Bcr-Abl positive leukemic blasts. These in vitro and in vivo studies are designed to evaluate AT-based novel strategies against Bcr-Abl positive human leukemias. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ASSAYING TYROSINE KINASE ACTIVITY: A NEW PARADIGM Principal Investigator & Institution: Sims, Christopher E.; Physiology and Biophysics; University of California Irvine Irvine, Ca 926977600 Timing: Fiscal Year 2004; Project Start 16-APR-2004; Project End 31-MAR-2005 Summary: (provided by applicant): New approaches are needed in the molecular analyses of the growth-promoting signal transduction pathways involved in the development and maintenance of cancer. The Laser Micropipet System (LMS), a new technology for the biochemical assay of kinases, holds the promise of directly assaying the activities of protein tyrosine kinases in primary patient cells. The LMS was developed for the assay of serine/threonine kinases in individual cells grown in tissue culture. This R21/R33 application proposes to expand the applications of this instrumentation to directly determine the activity of oncogenic tyrosine kinases in primary cells from patients. Assay of Bcr-Abl in chronic myelogenous leukemia (CML) will demonstrate the power of this tool for research, clinical, and pharmacologic applications. While this assay will be of value in the study of the biology and resistance mechanisms in CML, the studies will lay the groundwork for a new paradigm in the study of molecular mechanisms in cancer signal transduction and will have general applicability. The R21 phase of this proposal is designed to establish the feasibility of assaying Bcr-Abl activity and to demonstrate the necessary assay conditions for measurements in cells derived from a patient with CML. The specific aims are to: 1) identify and characterize a reporter of intracellular Bcr-Ab1 kinase activity, 2) define and optimize conditions for measuring Bcr-Ab1 activity in human cells, 3) compare reporter phosphorylation in cells expressing Bcr-Ab1 vs. cells lacking this kinase, and 4) demonstrate the feasibility of using primary patient cells in kinase assays. The goal of the R33 phase is to demonstrate the potential for the LMS-based kinase assay in applications for the study of the biology of pharmacologic resistance in CML, including from primary patient cells. The R33 specific aims are to: 1) develop a membranepermeant Bcr-Ab1 kinase reporter, 2) demonstrate the ability to detect imatinib resistance in CML cell lines, 3) determine Bcr-Ab1 activity in primary cells from patients with CML and their response to pharmacologic inhibition, and 4) determine if the assay can detect the emergence of imatinib resistance in CML patients and can differentiate the mechanisms of drug resistance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ATTACKING ANTHRAX ACTION BY BLOCKING RECEPTOR SIGNALING Principal Investigator & Institution: Chan, Joanne; Research Associate & Instructor; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant): Application for R21, NOT-AI-02-023, Biodefense and Emerging Infectious Diseases Research Anthrax toxin, isolated from the bacterium, Bacillus anthracis, enters human cells and disrupts cellular function. The toxin consists of a receptor binding component, protective antigen (PA) which can associate with the enzymatic components, edema factor (EF) and/or lethal factor (LF) to form the anthrax
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toxin. The toxin binds a cell surface receptor which mediates the internalization of the toxin complex. Recently, work from the laboratories of John Young and John Collier identified the receptor for the anthrax toxin, named the anthrax toxin receptor (ATR; Bradley et al., 2001). Since the ability of the anthrax toxin to cause harm is dependent upon receptor binding, targeting the anthrax receptor might provide additional therapies that could be useful even after suspected exposure to anthrax spores. In many cases, signaling downstream of cell surface receptors involves the activation of protein and lipid kinases. Successful use of the small molecule kinase inhibitor Gleevec in chronic myelogenous leukemia has shown that targeting kinases might provide an efficient means to treat various diseases. This goal of this project is to study the ATR signaling pathway in order to identify key effector molecules as targets for inhibition. The role of ATR in mediating toxin internalization will be dissected using biochemical and immunofluorescence methods in mammalian cells. The zebrafish will be used as an animal model to study ATR function in vivo and to assess its potential as an animal model for testing drugs aimed at blocking toxin action. The applicant has 3 specific aims which will be undertaken in collaboration with the Young and Collier labs. Aim 1. To investigate the role of the cytoplasmic domain of the anthrax receptor for potential therapeutic intervention. Aim 2. To determine the physiological role of the anthrax receptor by functional interference during normal embryonic development in the zebrafish. Aim 3. To examine anthrax toxicity in the zebrafish for use as an additional inexpensive model system for drug or vaccine testing. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BCR/ABL SIGNALING IN HUMAN LEUKEMIAS Principal Investigator & Institution: Pendergast, Ann M.; Associate Professor; Pharmacology and Cancer Biology; Duke University Durham, Nc 27710 Timing: Fiscal Year 2002; Project Start 15-JUN-1994; Project End 31-JAN-2004 Summary: The long-term objective of this research is to identify the intracellular signaling pathways that are critical for oncogenic transformation by altered forms of the ABL tyrosine kinase. Oncogenic forms of ABL are linked to the development of human, murine and feline leukemias. Activation of ABL may occur as a consequence of chromosomal translocations. The chimeric BCR-ABL oncogene is produced by a reciprocal chromosomal translocation that fuses varying amounts of the BCR gene on chromosome 22 with sequences upstream of the second exon of the c-ABL gene on chromosome 9. Three different BCR-ABL proteins may be produced: P210 which is the causative agent of greater than 95 percent of chronic myelogenous leukemia (CML). P185 which is associated with a subset of acute lymphocytic leukemias (ALL), and P230 which is associated with chronic neutrophilic leukemia (CNL), a rare myeloproliferative disorder characterized by a mild hematologic phenotype. The P185 and P210 forms of BCR-ABL have been proposed to transform cells through their ability to enhance cell proliferation, block apoptosis, alter cell adhesion and increase cell motility. Multiple proteins have been identified as downstream targets of BCR-ABL. However, only a small subset of these proteins have been shown to play critical roles in the biological activities associated with BCR-ABL expression. The specific aims of this proposal are: 1) to test the hypothesis that the ubiquitin-dependent degradation of specific cellular proteins by the oncogenic BCR-ABL tyrosine kinases constitutes a novel mechanism for the functional inactivation of growth inhibitors/tumor suppressors, and 2) to identify intracellular signaling pathways that are differentially regulated by the oncogenic forms of BCR-ABL (such as P210) and by the weakly leukemogenic P230 protein that is associated with an indolent or benign clinical disease. Comparative analysis of the BCR-
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ABL proteins may allow the identification of critical molecular components required for malignant transformation by BCR-ABL. Furthermore, our finding that oncogenic tyrosine kinases trigger the destruction of specific target proteins via the ubiquitin proteasome machinery provides a potentially important pathway for the elimination of growth inhibitors/tumor suppressors during tumor progression. Definition of this pathway may allow for the development of therapeutic reagents for the treatment of leukemias and other cancers that are caused by the activation of nonreceptor tyrosine kinases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BCR-ABL KINASE ASSAYS FOR STI571 SENSITIVITY OF RESPONSE Principal Investigator & Institution: Kron, Stephen J.; Associate Professor; Molecular Genetics & Cell Biol; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2003; Project Start 17-JUL-2003; Project End 31-DEC-2004 Summary: (provided by applicant): This phased innovation award proposal is focused on developing a robust approach to quantitative assay of specific protein tyrosine kinase activities from cancer cells. Our model is the oncogenic BCR-ABL fusion protein, the gene product of the t(9;22) Philadelphia chromosome (Ph1) translocation observed in the vast majority of Chronic Myelogenous Leukemia (CML) and in up to 30% of adults with Acute Lymphoblastic Leukemia and in other hematological neoplastic diseases. The activation of Abl kinase by fusion to BCR that is inferred to underly the malignant transformation of Phl positive CML is effectively opposed by the orally administered tyrosine kinase inhibitor (TKI) Imatinib Mesylate (IM, STI-571, Gleevec). The activity of IM as an Abl kinase inhibitor in vitro is thought to be the critical determinant of its efficacy in vivo. Nonetheless, a clinically useful assay for IM inhibition of BCR-ABL kinase activity in circulating CML leukemia cells is lacking. We propose to develop a protein/peptide chip-based assay for BCR-ABL that can detect the degree of inhibition by IM to evaluate dosing and drug resistance. Insofar as other activated tyrosine kinases may be critical mediators of malignancy in both leukemias and solid tumors, developing such an assay would be a powerful tool in evaluating other TKI drug candidates targeting these kinases for their efficacy in vivo. Thus, this project is directed at two major discovery objectives and three development objectives. First, in the initial project year, we intend to use our established methods for anti-phosphotyrosine antibodybased detection of purified Abl kinase activity on a peptide chip to 1) Recapitulate our Abl kinase assay with undiluted whole cell extracts from cell lines expressing BCR-ABL and 2) Use this assay to measure the inhibition of BCR-ABL by IM both in extracts and intact cells. During the development phase, we intend to use both BCR-ABL expressing cancer cell lines and circulating leukemic cells from treated patients as samples to 1) Optimize the BCR-ABL substrate and reaction conditions to enhance sensitivity and specificity of phosphorylation, 2) Examine alternative detection methods for BCR-ABL activity based on phosphospecific antibodies and thiophosphate targeted chemistry, and 3) Evaluate different chemistries for immobilizing BCR-ABL substrates on a surface and geometries for detection of phosphorylation. By these aims we intend to develop a highly versatile kinase assay system which can be applied to monitoring of patient response to IM and as a tool for discovery and testing of new TKI cancer drugs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: BCR-ABL RNA LEVELS TO MONITOR STI571 LEUKEMIA THERAPY Principal Investigator & Institution: Press, Richard D.; Pathology; Oregon Health & Science University Portland, or 972393098
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Timing: Fiscal Year 2003; Project Start 14-FEB-2003; Project End 31-JAN-2005 Summary: (provided by applicant): The recent discovery, validation, and accelerated FDA approval of the tyrosine kinase inhibitor STI571 (Gleevec) for the treatment of chronic myeloid leukemia (CML), the first such rationally-designed, small molecule cancer therapy, confirms the validity of the molecular targeting approach to cancer drugs. Aberrant CML cell growth is caused by the constitutive expression of the bcr-abl kinase, a chimeric fusion protein resulting from a leukemia-specific chromosomal translocation [t(9;22)]. STI571's targeted inhibition of this kinase activity specifically represses the leukemic clone without the typical toxicity of conventional nonspecific cancer drugs. Although >95% of chronic phase CML patients undergo a complete hematologic response to STI571, only a minority experience a complete cytogenetic response, the best current surrogate marker of long-term survival. After 18 months of daily STI571 therapy, approximately 28% of chronic phase patients lose their complete hematologic response. STI571 also induces an initial hematologic response in approximately 50-80% of CML patients with accelerated phase or blast crisis CML, but again these responses are typically only transient. This heterogeneity of responses suggests the pressing need for better laboratory methods to monitor and predict STI571 treatment efficacy to identify patients likely to have disease progression who may benefit from additional (more toxic) therapies. The considerable institutional resources in expertise and STI571-treated patient volume that have been built by co-investigator and STI571 co-developer Brian Druker represent a unique opportunity to develop and test novel laboratory methods to molecularly monitor STI571's treatment efficacy. This proposal's specific aims are then to: 1) validate a novel, quantitative, ultra-sensitive bcrabl RT-PCR assay for quantifying minimal residual disease in STI571-treated patients, 2) assess whether serial bcr-abl RNA levels in STI571-treated patients can be used to predict and/or monitor clinical disease progression, and 3) establish a storage bank of clinical samples from STI571-treated patients to enable future studies of STI571 drug resistance mechanisms. As STI571 is the first of perhaps many soon-to-come molecularly targeted cancer therapies, the successful achievement of these aims will likely serve as the model by which the efficacy of other novel therapies may be similarly monitored. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BCR-ABL SUBSTRATES AND INHIBITORS Principal Investigator & Institution: Clarkson, Bayard D.; Chief; Sloan-Kettering Institute for Cancer Res New York, Ny 100216007 Timing: Fiscal Year 2003; Project Start 10-JUL-2003; Project End 30-JUN-2008 Summary: It is the broad, long-term goal of this project to understand, on a molecular level, how the p210- bcr-abl protein tyrosine kinase activity ultimately causes a myeloid expansion in chronic phase Chronic Myelogenous Leukemia (CML), and to search for selective therapies efficacious for the treatment of CML. In order to accomplish this, the following Aims are proposed: (1) Expression of Bcr-Abl and its substrates in human primary hematopoietic cells will be determined during hematopoietic differentiation and maturation. CD34+ normal and CML progenitor cells and subpopulations will be stimulated with single and multiple cytokines that induce proliferation and maturation. Expression of Bcr-Abl and its substrates will be assessed and effects of specific inhibitors. (2) The role of SHIP-1 and SHIP-2 in Ber-Abl signaling will be examined. SHIP proteins will be constitutively targeted to the plasma membrane and the effects on Bcr-Abl mediated signaling will be determined in Rat1p210 cells. (3) The role of Dok-1 in c-kit signaling will be determined. The abilities of wt and mutant forms of Dok proteins to interfere with c-kit signaling will be analyzed. The kinase(s) that phosphorylates Dok
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during c-kit stimulation will be identified as well as the site(s) of tyrosine phosphorylation. (4) Binding partners for SHIP proteins in normal and Bcr-Abl expressing hematopoietic cells will be isolated and identified. (5) Analogues of PD173955, a potent inhibitor of Bcr-Abl kinase, will be analyzed in vitro and in vivo. In collaboration with Drs. William Bornmann and John Kuriyan, we will design and synthesize PD173955 analogues and test their activity in hematopoietic cells in vitro and in animal models of CML. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BIOLOGY AND TRANSPLANTATION OF THE HUMAN STEM CELL Principal Investigator & Institution: Mcglave, Philip B.; Professor and Director; Medicine; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 25-AUG-1995; Project End 31-MAY-2005 Summary: The them of this competitive renewal is unchanged: Understanding the biology of human hematopoietic stem cell (HSC) and their progeny will lead to improved stem cell transplantation therapy for a variety of methal malignant and nonmalignant diseases. In Project 1, Dr. Catherine Verfaillie will perform in vitro and xenogeneic transplant experiments to determine how apoptosis, differentiation and proliferation affect symmetrical self-renewal of HSC. She will use this information to develop clinically relevant methods for HSC expansion and gene transfer applicable to clinical trials proposed in Projects 2 and 3. In Project 2, Dr. John Wagner will investigate engraftment of ex vivo expanded umbilical cord blood (UCB) HSC in a xenogeneic transplant model. He will conduct human transplantation trials using a single UCB graft containing a subpopulation of ex vivo expanded and genetically marked UCB. Alternatively, transplants will be performed with two HLA-identical UCB grafts-one expanded and genetically marked UCB. Alternatively, transplants will be performed with two HLA-identical UCB grants-one expanded ex vivo and one unmanipulated These studies will determine if ex vivo expansion of HSC has been achieved and what effects ex vivo expansion have on homing and engraft of HSC to the marrow. In Project 3, Dr. Daniel Weisdorf will examine how mobilization regimen, cell source (marrow or blood) and phenotype (CD34+ or CD34-) influence HSC capacity for expansion, gene transfer and transplantation. These studies will be performed in vitro, in mouse and sheep xenogeneic transplant models and in clinical trials of autologous transplant therapy for lymphoma. Human clinical transplant trials performed in PROJECTS 2 and 3 will also validate the use of surrogate in vitro and in vivo HSC assays. In Project 4, Dr. Jeffrey Miller will investigate the contribution of BCR/ABL-mediated defective natural killer based immune surveillance and therapy in chronic myelogenous leukemia (CML). He will then test our immunotherapy with normal, allogeneic NK cells following autologous HSC transplant therapy for CM;. Finally, our group has demonstrate that marrow stromal cells can be derived in vitro from a mesodermal progenitor cell (MPC), and that in Hurler syndrome MPC- derived stromal cells contain abnormal heparan sulfate (HS) which inhibits normal HSC growth. In Project 5, Dr. Charles Peters and his co- investigators will explore the role of abnormal HS in Hurler stroma on defective hematopoietic support. He will also perform clinical trials in which normal, allogeneic MPC are transplanted in combination with hematopoietic cells (MPC/HCT) in order to "cross/correct" Hurler stromal defects and improve HSC engraftment and clinical outcome. These projects are supported by administrative and biostatistical cores, as well as cores to provide cell collection and processing NOD/SCID and other mouse assays and production of vectors suitable of clinical gene transfer.
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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CAAX PROCESSING ENZYMES AS ANTICANCER TARGETS Principal Investigator & Institution: Bergo, Martin O.; J. David Gladstone Institutes Box 419100, 365 Vermont St San Francisco, Ca 94103 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2006 Summary: (provided by applicant): Many intracellular signaling proteins (e.g., the Ras and Rho proteins) and several nuclear lamins terminate with a carboxyl-terminal CAAX motif. CAAX proteins undergo three sequential posttranslational modifications. First, the cysteine (i.e., the C of the CAAX motif) is farnesylated or geranylgeranylated by a pair of cytosolic enzymes--farnesyltransferase (FTase) and geranylgeranyltransferase I (GGTase I). Second, the last three amino acids (i.e., the -AAX) are cleaved off by Ras and a-factor converting enzyme (Rcel), an integral membrane protease of the endoplasmic reticulum (ER). Third, the newly exposed carboxyl-terminal isoprenylcysteine is methylated by another ER protein, isoprenylcysteine carboxyl methyltransferase (Icmt). These posttranslational modifications render the C-terminus of CAAX proteins more hydrophobic, enhancing the attachment of the proteins to membrane surfaces and facilitating certain protein-protein interactions. Activating Ras mutations have been detected in 30% of all human cancers, and are common in leukemia and myeloproliferative diseases. Inhibitors of FTase have been used to treat cancers that harbor mutationally activated Ras proteins. Unfortunately, K-Ras and N-Ras--the Ras isoforms most often implicated in human cancers--are readily geranylgeranylated by GGTase I in the setting FTase inhibition. This alternate isoprenylation pathway has focused attention on other enzymes in the pathway, such as GGTase I, Rcel, and Icmt. Surprisingly, there are no data on the impact of inhibiting these other enzymes on the development of cancer in mice. In this project, this void will be addressed. In preliminary studies, mice harboring both a Cre-inducible latent oncogenic Kras2 allele (KrasLsL) and the inducible Mx1-Cre transgene have been generated. Induction of Cre in those mice activates the latent Ras allele and results in a full-fledged, lethal, myeloproliferative disease that is reminiscent of chronic myelogenous leukemia or juvenile myelomonocytic leukemia in humans. Recently, conditional "floxed" alleles for the posttranslational processing enzymes (FTase, GGTase I, Rcel, and Icmt) have been generated. Thus, it is now possible to breed mice in which Cre expression can be used to simultaneously activate the latent oncogenic K-Ras allele and inactivate the CAAX processing enzymes. Using these mice, we will define the impact of defective CAAX processing on the development, progression, and lethality of Ras-induced myeloproliferative disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CELL SURVIVAL PATHWAYS AND INHIBITORS IN LEUKEMIA Principal Investigator & Institution: Eastman, Alan R.; Professor and Associate Director; Pharmacology and Toxicology; Dartmouth College 11 Rope Ferry Rd. #6210 Hanover, Nh 03755 Timing: Fiscal Year 2002; Project Start 30-JAN-2002; Project End 30-NOV-2003 Summary: (provided by applicant): Tumors characteristically exhibit mutations that enhance cell proliferation and survival. Two well-recognized cell survival pathways are RAF to MEK to ERK and PI3-kinase to Akt. Many inhibitors of these pathways are now in clinical trials or at earlier stages of development. However, early results suggest these inhibitors are more likely to suppress growth than kill the tumor cells. Our recent
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observations have demonstrated that such inhibitors may be more valuable when used in combination with more traditional anticancer agents. Specifically, it has been shown that a MEK inhibitor can dramatically enhance the rate of apoptosis induced by vinblastine in myeloid leukemia ML-1 cells and HL6O cells. However, U937 cells are insensitive to the MEK inhibitor but are sensitized to vinblastine by an inhibitor of PI3kinase. These observations have led to the hypothesis that different leukemias preferentially use different survival signaling pathways, and that by defining which pathway a specific leukemia uses, effective drug combinations can be individualized for that patient. The goal of this project is to study freshly-isolated human leukemia cells and define the frequency with which they are sensitized to chemotherapy by inhibitors of these two cell survival pathways. The specific aims are to assay leukemia cells for phosphorylation of ERK and Akt as indicators of the signaling pathways used, and to combine inhibitors of these signaling pathways with vinca alkaloids ex vivo to determine the rate of induction of apoptosis. Additional experiments will determine whether normal leukocyte progenitors, which do not have an oncogene-enhanced cell survival pathway, are resistant to these drug combinations thereby suggesting such a therapy may be selective for the tumor. Finally, activation of Jun N-terminal kinase (JNK) will be assayed in leukemia patients receiving vincristine therapy, to confirm that this pathway is activated at drug concentrations tolerated by patients. Activation of the JNK pathway is necessary for the enhanced apoptosis induced by inhibitors of the Erk and Akt pathways. Successful completion of these aims will identify which leukemia patients might benefit from administration of inhibitors of these signaling pathways, and facilitate the design of clinical trials to test their efficacy in combination with other anticancer agents. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: COMMUNITY CLINICAL ONCOLOGY PROGRAM Principal Investigator & Institution: Locker, Gershon Y.; Chief; Evanston Northwestern Healthcare Evanston, Il 60201 Timing: Fiscal Year 2002; Project Start 01-SEP-1983; Project End 31-MAY-2003 Summary: (Applicant's Description) Evanston Hospital Corporation which has been renamed as Evanston Northwestern Health care (ENH), has been a CCOP since 1093 and has participated in studies of the Eastern Cooperative Oncology Group (ECOG), the National Surgical Adjuvant Breast and Bowel Program (NSABP), and propose to accrue patients to the Gynecology Oncology Group (GOG). It accrued 259 patients with 272 credits to therapeutic trials between June of 1992 to May of 1997. ENH also contributed non-COP patients to NIH-sponsored studies on brain tumors. ENH investigators have chaired ECOG protocols in genitourinary, breast, and hematologic malignancies. They have also chaired steering committees and served in leadership roles in these groups. Currently, Dr. Ann Thor is on the Executive and directs the ECOG Pathology Coordination Office. Dr. David Calls chains the Health Behavior and Practices Committee and the Outcomes Subcommittee. The CCOP has participated in approved cancer control projects in the NSABP-sponsored breast cancer prevention trial with tamoxifen, the Prostate Cancer Prevention Trial, and other cancer control studies. During the 5 years, 279.5 cancer control credits were awarded. ENH investigators have been active in several cancer control projects outside the CCOP pertaining to epidemiology, diagnosis, "diagnostic marker" and dietary manipulation. These include a NCI funded study of low- fat diet in post-menopausal breast cancer, and the Women's Health Initiative, treatment of post-mastectomy arm lymphedema. The CCOP has been reorganized to increase accrual by: recruitment of new investigators, adding Swedish
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Covenant Hospital as an affiliate, and GOG as a research base. Efforts are underway to encompass minority enrollment. A 24-bed Clinical Pharmacology Unit sponsored by Searle is operation, with the PI on the advisory committee. We have expanded our education activities through Grand Rounds and lecture series. In the last 4 years, ENH investigators published 63 papers and 10 abstracts pertaining to clinical cancer treatment and control. A research effort in cellular and molecular biology has been developed with the establishment of a program in molecular genetics. Thus, a vertical integration, e.g., from laboratory studies to delivery of care in the local community is being sought. Support is asked for ENH's continued participation in the CCOP. Funding is sought for continued accrual of patients to cancer therapy and cancer control studies of the ECG, NSABP, and GOG. Thus, our participation in cancer control and therapeutic trials will promoter medical advances as well as stimulate better patient care. These in turn will impact favorably on the level of knowledge of staff and physicians within the community. Since 1983, we have successfully participated in the CCOP program, and our record and proposed changes promise continued success in the future. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CORE--CLINICAL RESEARCH SUPPORT COMPONENT Principal Investigator & Institution: Stone, Richard M.; Professor; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-MAR-2003 Summary: (provided by applicant): The ultimate objective of the research projects in this program project application is to improve the therapeutic results for patients with myeloid malignancies including acute myeloid leukemia, myelodysplastic syndrome, and chronic myeloid leukemia. To achieve this objective, tumor cells and other relevant clinical samples from patients will be collected, catalogued, and distributed to the relevant projects for analysis of the expected therapeutic targets and other molecules that might be important in prognosis or pathophysiology. Secondly, a clinical infrastructure is required to carry out the clinical trials described in Project 5 and additional clinical studies that will emanate from the developmental approaches outlined in Projects 1, 8, 9 & 10. Clinical Research Core resources are required to carry out these functions which extend beyond direct patient care and the clinical laboratory. Without the clinical research support provided in the Core it would be impossible to coordinate the proper collection of multiple research specimens, the adherence to novel complex therapeutic schedules and timely follow-up of patients enrolled on research studies. Also critical to this success of the project is the collaboration of individuals in the Core with the staff from the Biostatistics Core who will provide a quality control system for specimen tracking, computerized data entry, quality of control data and will assist in the design and analysis of the clinical research protocols. The purpose of the Clinical Research Support Core is to provide the following services that will be utilized by all the clinical research studies: 1. To collect research specimens and coordinate patient follow-up at Dana- Farber Partners Cancer Center and collaborating institutions. 2. To act as liaison with outside physicians, hospitals, and biotechnology companies to coordinate the collection of research specimens and follow-up data. 3. To insure that study parameters are followed, ancillary specimens are collected on time and processed properly, confirm eligibility, and patient registration. 4. To insure the accuracy of submitted data from outside sources. 5. To provide data management for the collection of individual patient information. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CORE--LEUKEMIA TISSUE BANK Principal Investigator & Institution: Caligiuri, Michael A.; Professor and Director; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2003; Project Start 13-MAY-2003; Project End 31-MAR-2009 Summary: (provided by applicant): The CALGB Leukemia Tissue Bank (LTB) serves as a centralized tissue bank of blood and bone marrow specimens procured from patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL) and other hematologic malignancies enrolled on CALGB treatment protocols. The specific aims of this proposal will be accomplished through CALGB protocol 9665, a protocol for the procurement of relevant tissue specimens. The associated work will be performed in the laboratory of Michael Caligiuri, M.D. at The Ohio State University. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CTCL STAGING USING GENE EXPRESSION PROFILES Principal Investigator & Institution: Showe, Louise C.; Associate Professor, Director Genomics c; Wistar Institute Philadelphia, Pa 191044268 Timing: Fiscal Year 2002; Project Start 30-SEP-1999; Project End 31-MAR-2004 Summary: The cutaneous T-cell lymphomas (CTCL) including Mycosis fungoides (MF) and Sezary syndrome (SS) are indolent lymphomas that progress in stages, starting with skin lesions, sometimes proceeding through a leukemic phase with circulating tumor cells and eventually spreading to the visceral organs. Treatments for CTCL vary in efficacy even for patients with what appears to be similar level of disease, emphasizing the likely existence of undetectable heterogeneity. These characteristics added to a the availability of a large archive of patient samples make it a good candidate for tumor staging by molecular profiles. SS, the leukemia form of CTCL will be the initial focus of these studies as it provides easy access to large numbers of purified malignant cells. RNA from 10 patients, with diverse patterns of disease presentation and progression, will be analyzed during the first year against arrays of cDNA probes for 20,000 sequence verified Unigene clusters in order to determine the global gene expression patterns of these cells. Samples will be selected from newly diagnosed SS patients and from an archive of viably frozen SS cells including samples collected at progressive stages of disease over a period of greater than 10 years. Since CTCL cells represent Th-2 T-cells, RNA from healthy donor PBL, stimulated to develop a TH-2 phenotype will be used as controls. Genes that are over or under-expressed in patient RNAs, compared to controls, will be candidate tumor markers for a reduced panel of genes that will be used to screen a larger group of patient samples. In the second phase of the study, 100 patients will be selected for gene expression studies with a reduced panel of 1000-2000 genes. These expression profiles will be analyzed, using statistical techniques, to identify groups of genes that behave in a similar fashion in subsets of patients. The results of these analyses will be a putative diagnostic panel of genes whose expression levels describe classes of tumors. The correlation between expression levels and tumor groups will be confirmed using alternative methods for measuring gene expression. Finally, clinical information from patient histories will be compared with tumors clustered by gene expression levels to determine whether important clinical outcomes, e.g., responsiveness to treatment, can be predicted from the specific gene expression patterns. Concurrent with the above studies, samples from patients with MF, the skin-associated early form of CTCL, will be queried with the panel of genes identified as being diagnostic for SS to determine
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whether the same genes are also sufficient to characterize different classes of MF. If novel gene clusters are found, they will be added to the data base of candidate markers. If not, up to 10 MF patients will be analyzed on 20,000-gene filters for genes whose expression pattern distinguishes MF from SS patients. If found, these will be added to the panel of candidate SS genes. Finally, techniques will be developed to assay expression profiles in a clinical setting. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CYTOKINE MEDIATED DIFFERENTIATION THERAPY Principal Investigator & Institution: Smith, B D.; Oncology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 01-SEP-2000; Project End 31-AUG-2005 Summary: Dr. Smith is a junior faculty member at Johns Hopkins Oncology Center who has spent the past several years developing an understanding of the basic biology of drug resistance in acute leukemia. His observations have clearly pointed to the association between anti-apoptotic signals and drug resistance in both in vitro and in vivo studies. He has also been involved in developing clinical strategies to overcome the drug resistance that results from inhibited apoptosis. His career development plan is to obtain formal training in the theory and methods of clinical investigation leading to a Master of Health Sciences degree, while conducting translational research with mentorship from Richard Jones, M.D., the Director of the Bone Marrow Transplantation Program. Steven Piantadosi, M.D, Ph.D. will serve as co-mentor with expertise in epidemiology, biostatistics, and clinical trial design. It is now clear that signals that block apoptosis are important mechanisms by which cancers are pan-resistant to cytotoxic anti- cancer agents and result in poor clinical outcomes. Our preliminary data suggest that growth factor-mediated differentiation therapy is one strategy that may circumvent resistance secondary to anti-apoptotic signals. The net effect of growth factors on a tumor cell population is determined by a balance of their pleiotropic effects on cell self-renewal, survival, and differentiation. Preferential enhancement of selfrenewal and/or survival could hasten tumor progression; conversely, selective induction of differentiation would exhaust the neoplastic clone. We have found that growth factors induce selective terminal differentiation of chronic myeloid leukemia (CML) at doses that normal hematopoetic progenitors require for optimal growth. Moreover, agents that induce growth arrest, including interferon and bryostatin-1 enhance growth factor- mediated differentiation of CML and other myeloid malignancies in vitro. Based on pre-clinical work that suggests growth factor- mediated induction of differentiation is an effective anti-tumor strategy in pan-resistant myeloid malignancies, three clinical trials of growth factor-mediated differentiation therapy are proposed: 1) GM-CSF + autologous BMT for CML, 2) interferon + GM- CSF in chronic phase CML and 3) bryostatin-1 + GM-CSF in refractory myeloid leukemias. Throughout the course of our proposed trials, we will have the opportunity to further study the biologic impact of growth factor-mediated differentiation. Our current data suggest that the anti-tumor effects of our therapy results from terminal differentiation, however, the agents we are studying in the clinical trials (e.g., GM-CSF, interferon, bryostatin-1) also have immunomodulatory effects which may contribute to an anti- tumor effect. A major objective of our studies will be to evaluate the relative roles that induction of differentiation and immunomodulation play in the anticipated anti-tumor effects of the growth factors and cytostatic agents in the clinical trials. One intriguing possibility is that the induction of differentiation and immunomodulation could be potentially linked. It is now clear that CML, and even AML, progenitors can be differentiated in vitro into
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Chronic Myelogenous Leukemia
dendritic cells (DC) by cytokines that include GM-CSF; moreover, these leukemic DC can stimulate autologous anti-leukemic T cell responses in vitro. Thus, it is possible that strategies that induce differentiation of myeloid malignancies could lead to eradication of the malignant clone via both induction of terminal differentiation and enhanced immunologic anti-leukemic activity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DESIGN OF ABL SH2 AND SH3 INHIBITORS FOR LEUKEMIA Principal Investigator & Institution: Overduin, Michael J.; Associate Professor; Pharmacology; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 19-APR-2001; Project End 31-MAR-2003 Summary: (provided by applicant) This project targets the src homology domains of the Abl oncogene for rational anti-cancer drug design. The team consists of a partnership between my structural biology research group at the University of Colorado and a drug discovery program at OSI Pharmaceuticals. This biotechnology company has developed a series of peptidomimetic compounds as novel anticancer agents targeted at signaling domains responsible for the localization and regulation of kinases and phosphatases. My laboratory is determining the three-dimensional structures of complexes of lead compounds bound to src homology 2 (SH2) and src homology 3 (SH3) domains by nuclear magnetic resonance (NMR) spectroscopy. The specific targets are the SH2 and SH3 domains of Abl, an oncogenic tyrosine kinase for which inhibitors are in phase II clinical trials. The SH2 domain is inhibited by a pyridone derivative that mimics its natural phosphotyrosine ligand, and the SH3 domain is inhibited by spirolactam-based compound that resembles its polyproline ligands. These templates possess affinities and binding modes comparable to physiological ligands, as demonstrated by nuclear magnetic resonance spectroscopy (NMR) and surface plasmon resonance (SPR). Modifications of these lead compounds that enhance selectivity and potency will be suggested based on protein structures, NMR and SPR data, and computational modeling. Synthetic organic chemistry expertise and access to combinatorial libraries is provided by OSIP. This complementary partnership will allow the rational optimization of lead compounds with significant therapeutic potential for cancers including chronic myelogenous leukemia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DOK IN CELL GROWTH AND P210 BCR-ABL SIGNALING PATHWAYS Principal Investigator & Institution: Van Aelst, Linda; Associate Professor; SloanKettering Institute for Cancer Res New York, Ny 100216007 Timing: Fiscal Year 2003; Project Start 10-JUL-2003; Project End 30-JUN-2008 Summary: The broad long term goal of this project is to define the molecular mechanism(s) by which p62(dok) exerts its effect(s) on p210bcr-abl-mediated transformation and cell proliferation in general, and to obtain a better understanding of the establishment of the myeloproliferative phenotype of p210 bcr-abl in CML at a molecular level. p62(dok) is a protein identified as being constitutively tyrosine phosphorylated in chronic phase progenitor cells of CML patients and has been found to be a common substrate of many receptor and membrane-associated tyrosine kinases. Several lines of evidence indicate that p62(dok) plays a negative role in growth factorinduced cell proliferation, and in p210bcr-abl mediated transformation. An intriguing
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possibility is that p62(dok) could influence the establishment or duration of the chronic phase of CML. In light of this, the characterization of the mechanism(s) by which p62(dok) exerts its effect on growth factor and p210bcr-abl-mediated signaling is essential, as is comprehensive knowledge of bcr-abl-induced signaling pathways, and aberrations therein. To this end, we propose the following specific aims: 1) To map and compare the sites of p62(dok) tyrosine phosphorylated by p210 bcr-abl with those phoshorylated upon PDGF stimulation, 2) To define mechanisms by which p62(dok) [suppresses PDGF-triggered proliferation and p210bcr-abl-nduced transformation, 3) To identify and characterize p62(dok)-interacting signaling components which mediate the negative effect of p62(dok) on PDGF-triggered proliferation and p210bcr-abl-induced transformation, 4) To define signal transduction pathways affected by p210 bcr-abl by microarray analysis and clustering resulting data, and 5) To characterize the target genes involved in the p210 bcr-abl signal transduction pathways identified. This project offers biochemical, molecular and cellular approaches to the study of p62(dok) with respect to its involvement in CML and to the identification of bcr-abl target genes. The health-relatedness of this project is that defining the role of p62(dok) in p210 bcr-abl signaling, and the identification of novel target genes of bcr-abl, will contribute to a better understanding of the establishment of human CML. Furthermore the identification of novel target genes of p210 bcr-abl signaling may provide new potential targets for therapeutic intervention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DOK PROTEINS IN ONTOGENESIS AND LEUKEMOGENESIS Principal Investigator & Institution: Pandolfi, Pier Paolo; Professor; Sloan-Kettering Institute for Cancer Res New York, Ny 100216007 Timing: Fiscal Year 2003; Project Start 10-JUL-2003; Project End 30-JUN-2008 Summary: Chronic myelogenous leukemia (CML) is characterized by the presence of the chimeric p210bcr-abl protein which shows elevated protein tyrosine kinase activity relative to the normal c-abl tyrosine kinase. Although many of the p210bcr-abl substrates have now been identified, the relevance of these phosphorylation events in the pathogenesis of CML and the normal function of these p210bcr-abl substrates and are still poorly understood. The focus of this proposal is to elucidate, in vivo in the mouse, the functions of three p210bcr-abl phosphorylation targets, Dok1, 2 and 3, and to determine how these relate to the pathogenesis of CML by a direct genetic approach with the following Specific Aims: 1) To define, in single knock out mice and null cells, the role of Dok1, 2, 3 in ontogenesis and hemopoiesis. We have disrupted the Dok 1, 2, 3 genes and mice lacking their functions (-/-, null) have been generated. Ontogenesis and hemopoiesis will be studied in these mutants. 2) To define in double or triple knock-out mutants the role of Dok1, 2, 3 in ontogenesis and hemopoiesis. We will intercross the various Dok-/- mice among them in order to generate double or triple knock-out mutants. We will define the developmental role of these genes and their role in hemopoiesis by characterizing the embryonic and adult phenotype resulting from their concomitant inactivation. 3) To establish the role of Dok proteins in leukemia and cancer promotion/progression. We will examine spontaneous or physically/chemically induced tumorigenesis as well as leukemogenesis by p210bcr-abl in the various K.O. mutants and in double and triple Dok-/- mutants. We will cross Dok1-/- mutants with mice lacking Nf1 or Pten gone products to test whether Dok1 cooperates with these proteins in tumor suppression. 4) To identify genes critical for Dok1, 2 and 3 function and for CML pathogenesis. We will utilize purified cell populations from our single,
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Chronic Myelogenous Leukemia
double and triple K.O. mutants to identify, on a comparative basis, target genes relevant for their function. We will test whether these genes are also deregulated in CML blasts. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: FLAVOPIRIDOL AND IMATINIB IN BCR/ABL+ LEUKEMIA Principal Investigator & Institution: Grant, Steven; Professor of Medicine, Biochemistry, And; Internal Medicine; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2003; Project Start 11-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant): Recent evidence suggests that neoplastic cells are particularly susceptible to a strategy involving simultaneous interruption of survivalassociated signal transduction and cell cycle regulatory pathways. Consistent with this notion, we have observed in preclinical studies that the cyclin-dependent kinase inhibitor flavopiridol (NSC 649890) interacts synergistically with the Bcr/Abl kinase inhibitor imatinib (STI571; Gleevec) to induce mitochondrial injury, caspase activation and apoptosis in Bcr/Abl+ human leukemia cells, including those highly resistant to imatinib. These events are associated with multiple perturbations in survival signaling and cell cycle-related pathways, including down-regulation of Mcl-1 and Bcl-xL, reduced expression of cyclin D1, activation of JNK, and inactivation of CREB and Stat5. Based upon these findings, a multi-institutional Phase I trial has been developed in which patients with progressive CML (chronic and accelerated phase) or CML-BC or Philadelphia chromosome+ AML or ALL will be treated with escalating doses of daily imatinib in conjunction with flavopiridol administered as a 1-hr infusion weekly x 3 q month. The goals of this Phase I trial are to define the MTD for these agents, characterize dose-limiting toxicities, and gain preliminary information regarding activity of the regimen. Correlative laboratory studies will test the hypothesis that in vivo administration of imatinib in conjunction with flavopiridol will induce perturbations in apoptotic regulatory proteins in peripheral blood Bcr/Abl+ cells (e.g., diminished expression of Mcl-1, Bcl-xL, and cyclin D1, inactivation of Stat5 and CREB, activation of JNK) similar to those observed in Bcr/Abl+ cell lines exposed to these agents in vitro. Other studies will investigate a) effects of the imatinib/flavopiridol regimen on Stat5 phosphorylation of Bcr/Abl+ peripheral blood cells by flow cytometry; b) the pharmacokinetics of imatinib and flavopiridol when administered together; and c) the presence of Bcr/Abl mutations as well as increased Bcr/Abl expression/activity in cells from imatinib-resistant patients, and their possible relationship to imatinib/flavopiridol pharmacodynamics. Information derived from this trial will provide a foundation for a successor Phase II trial and correlative laboratory studies which will address issues of regimen activity and imatinib/flavopiridol molecular interactions more definitively. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: GENE EXPRESSION PROFILE OF PROGRESSION & RESPONSE IN CML Principal Investigator & Institution: Radich, Jerry P.; Full Member; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2002; Project Start 30-SEP-1999; Project End 31-MAR-2004 Summary: Chronic myeloid leukemia (CML) is a hematopoetic stem cell disease with distinct biological and clinical features, presenting as a relatively clinically benign state ( chronic phase ), which invariably evolves to an incurable aggressive disease ( blast crisis ). Treatment can range from low intensity chemotherapy to the curative yet potentially lethal therapy of bone marrow transplantation (BMT). Unfortunately little is known
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about the molecular events that trigger the evolution of chronic phase to blast crisis. Thus, tailoring therapy to individual patient s risk is impossible. This proposal aims to identify changes in gene expression that occur in the evolution of the chronic phase to blase crisis, as well as discovering gene expression patterns that are associated with good outcomes to conventional interferon-based therapy. Specifically, we will: 1) optimize and validate the expression array technology, then 2) use mRNA expression arrays to identify genes involved in the progression of chronic phase to blast phase CML; and 3) identify genes associated with good or poor outcome following conventional interferon-based therapy. These studies will allow us to begin to study the biology of CML transformation, and understand at a genetic level why some patients respond to conventional therapy, while other patients are refractory to therapy, and quickly transform to highly aggressive disease. The identification of low v high risk patients will allow theraphy to be appropriately tailored to each individual s disease. In addition, the application of large-scale expression analysis in this model system will be ideal to iron out unforeseen technical problems, and thus the experience gained may be very valuable in future investigations other more complex tumor systems. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GRAFT REJECTION Principal Investigator & Institution: Mcniece, Ian K.; Professor; Oncology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 08-APR-2003; Project End 31-MAR-2005 Summary: (provided by applicant): Non-myeloablative transplants are being used increasingly for a number of diseases, including Non Hodgkins lymphoma, Hodgkin's disease, myeloma, acute leukemia, chronic lymphoytic leukemia (CLL) and chronic myelogenous leukemia (CML). A reduction in toxicity compared to fully myeloabative allogeneic stem cell transplantation is stimulating the use of this strategy particularly for older patients. Donor engraftment is achieved in the majority of patients, however, a significant number of patients, particularly those with myelodisplastic syndrome (MDS) experience secondary loss of donor engraftment. This can be fatal for some patients due to the prolonged pancytopenia that follows. There are several possibilities for the loss of donor engraftment; 1) donor graft rejection by recipient T cells, 2) late donor graft failure due to insufficient stem cells in the graft, or 3) dominance of recipient stem cells due to competitive repopulation. In allogeneic transplants to support high dose chemotherapy, graft failure/graft rejection occurs early after transplant within the first month, however, for patients that achieve early donor engraftment secondary graft failure/graft rejection is rare and only occurs in less than 5% of patients [1,2]. In contrast, nearly a 100% of patients receiving mini-allogeneic transplants achieve donor engraftment within 2 months of transplant. Graft failure/graft rejection occurs at 2 to 4 months post transplant in approximately 15% of mini-allogeneic recipients. We hypothesize that loss of donor grafts in non-myeloablative stem cell transplant (NST) recipients can occur due to rejection of the donor cells by recipient T cells and/or low numbers of donor stem cells in the graft resulting in secondary graft failure. The aim of this proposal is to develop methods to evaluate graft rejection and determine the mechanisms responsible for late donor graft failure in recipients of NST. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: HEMATOPOIETIC TRANSFORMATION BY TYROSINE KINASE FUSIONS Principal Investigator & Institution: Gilliland, D Gary.; Associate Professor; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2007 Summary: (provided by applicant): The overall hypothesis of this proposal is that a detailed characterization of the signal transduction properties of constitutive activated tyrosine kinases associated with human leukemias will identify the critical targets that are required for transformation of hematopoietic cells. These targets can then be exploited for the development of novel therapeutic approaches to leukemia. During the previous funding period, we accomplished each of the goals that were set forward. In particular, we cloned and characterized the transforming properties of a spectrum of tyrosine kinase fusions associated with recurring chromosomal translocations in human leukemias, using both cell culture systems and murine models of leukemia. These include, in addition to the TEL/PDGFbetaR and TEL/ABL fusions, the HIP1/PDGFbetaR, H4/PDGFbetaR, TEL/JAK2 and TEL/TRKC fusion proteins. The availability of a spectrum of constitutively activated tyrosine kinases provides a unique opportunity to identify critically important pathways of transformation through comparative analysis of the signal transduction pathways and target genes activated by these fusion proteins, with validation in animal models. In Specific Aim 1, we will address the hypothesis that characterization of the signal transduction pathways and target genes activated by TEL/PDGFbetaR, TEL/JAK2, TEL/TRKC, and TEL/ABL, and BCR/ABL, will identify critical pathways and targets that are required for transformation. We will utilize standard approaches to analysis of signal transduction, as well as expression arrays. In Specific Aim 2, we will test the hypothesis that the putative critical effectors of transformation identified in Specific Aim 1 can be evaluated and validated in our model systems. We will utilize a combination of approaches that focus on inhibition of transformation in cell culture systems, as well as murine bone marrow transplant models of leukemia using hematopoietic progenitors from donor mice are that are genetically deficient in one or more of the putative targets. In Specific Aim 3, we will test the hypothesis that acute leukemia phenotypes are a collaboration between constitutively activated tyrosine kinases and transcription factor fusion genes such as AML1/ETO, AML1/EVI1 and NUP98/HOXA9. We hypothesize that coexpression of tyrosine kinase fusions and transcription factor fusions will cause an acute leukemia phenotype in murine models, and that these leukemias will retain sensitivity to specific tyrosine kinase inhibitors. This proposal will provide insights into signal transduction and target genes critical for transformation of hematopoietic cells, as well as novel therapies for leukemia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: IMMUNOTHERAPY AFTER TRANSPLANT TO PREVENT RELAPSE
AUTOLOGOUS
STEM
CELL
Principal Investigator & Institution: Miller, Jeffrey S.; Professor; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 01-DEC-2001; Project End 30-NOV-2002 Summary: This study proposes a series of clinical and related preclinical investigations to minimize peritransplant tumor burden and to reduce the chances of posttransplantation recurrence of certain lymphomas and of other cancers. Autologous IL-2 activated natural killer cells have been shown to fill a broad spectrum of tumor targets.
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Thus, autologous lymphocytes may have anti-tumor activity which may be most effective in a minimal residual disease setting indeced by autologous transplantation. In this study, we will test the safety and tolerance of subcutaneous, low dose IL-2 +/- GMCSF on an outpatient basis in subjects who have had an autologous transplant for lymphoma, breast cancer, chronic myelogenous leukemia, or multiple myeloma. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INDUCTION AND MANIPULATION OF HUMAN CML IN NOD/SCID Principal Investigator & Institution: Conrad, Patricia D.; Children's Research Institute 700 Children's Dr Columbus, Oh 432052664 Timing: Fiscal Year 2002; Project Start 20-SEP-1999; Project End 31-AUG-2003 Summary: This proposal describes an intensive, five-year training program designed to allow the principal investigator to successfully bridge the gap between clinical and basic science training. The ultimate goal of the performance of this training will be to achieve scientific independence in the fields of normal and malignant hematopoiesis. Dr. Conrad is board certified in pediatrics and is currently a third year pediatric hematology/oncology fellow at the Children's Hospital of Philadelphia. She has been working for the last 18 months in the laboratory of Stephen G. Emerson, M.D., Ph.D. During this time, Dr. Conrad has intensively pursued laboratory investigation and is ready for the next phase of training, progressively independent work. The candidate's research has focused on 1) investigating functional and biological properties of umbilical cord blood (UCB) hematopoietic stem cells (HSCs) and 2) establishing the NOD/SCID assay using cord blood as the source for stem cells. UCB stem cells are not identical to their bone marrow or peripheral blood counterparts, and seem to act as a more primitive population. Immunodeficient mice, including NOD/SCID, have become the preferred in vivo assay for HSCs. Chronic myelogenous leukemia (CML) is believed to be a myeloproliferative disorder of stem-cell origin. Therefore, experiments designed to investigate fundamental questions relating to pathogenesis of CML will be optimized utilizing a system of UCB HSCs and NOD/SCID mice. Dr. Conrad's sponsor, Dr. Emerson, is division chief of the hematology/oncology section at the University of Pennsylvania. He holds a Ph.D. in cell biology and immunology and was scientific director of the alloBMT program at the University of Michigan. He has significantly contributed to and remains committed to Dr. Conrad's growth into a physician scientist. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: LEUKEMIA ANTIGENS FOLLOWING DONOR LEUKOCYTE INFUSION Principal Investigator & Institution: Wu, Catherine J.; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-SEP-2000; Project End 31-AUG-2005 Summary: The infusion of donor lymphocytes (DLI) induces remission in approximately 75 percent of patients with relapsed chronic myelogenous leukemia (CML) after allogeneic bone marrow transplantation. The efficacy of DLI reveals that immune responses against leukemia cells can be mounted in the absence of complicating chemotherapy or radiation treatment, and is thus a unique model for studying tumor immunity. How DLI mediates this anti-leukemic effect is unclear. T cells are required for this response, but their antigenic targets are unknown. Recent reports have demonstrated the presence of autoantibodies reactive to various tumors and have
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utilized autologous sera to identify novel tumor-associated antigens, which were later shown to be recognized by T cells as well (for review, see Old et al., 1998). Our preliminary results reveal that an analogous approach may succeed in identifying CMLassociated antigens in patients who have responded to DLI. In our trial which used CD4+-DLI to treat relapsed CML, many patients were observed to develop marked elevations in their peripheral B cell number and frequent lymphocytosis and plasmacytosis on bone marrow biopsies, suggesting the presence of a potent B cell response. Immunoscreening of a CML cDNA expression library with high titer post-DLI sera identified eight gene products with antibody reactivity to patient sera collected after but not before DLI. Herein, we propose to characterize the humoral and cellular response to these DLI-associated targets. The CML cDNA expression library will be further screened with other patients' post-DLI sera in order to expand the panel of DLIassociated antigens. Our questions will focus on determining whether the identified antigens are shared among DLI-treated patients (in effort to understand whether leukemia-specific targets or host-donor differences explain the basis of anti-tumor immunity), on delineating the time course of antibody response; and on ascertaining whether the presence of antibody reactivity correlates with a clinical response to DLI, or to the development of graft-versus-host disease (GVHD). To gain insight into whether the identified genes play a role in leukemogenesis, the genes will be fully sequenced, and differential expression between normal and malignant cells will be examined by Northern analysis. Lastly, because T cells are critical to DLI, the gene products will be tested for their ability to induce an antigen- specific T cell response in CML patients' peripheral blood leukocytes in culture. The experiments described in this proposal will lead to a deeper understanding of the mechanisms underlying the antitleukemic effect of DLI and provide a basis for improved diagnosis and treatment of CML and potentially other hematological malignancies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: LEUKEMOGENESIS BY ABL AND OTHER ONCOGENES Principal Investigator & Institution: Baltimore, David; Institute Professor; None; California Institute of Technology Mail Code 201-15 Pasadena, Ca 91125 Timing: Fiscal Year 2002; Project Start 15-DEC-1989; Project End 31-DEC-2004 Summary: This proposal has 5 parts representing 5 on-going efforts by different groups of junior investigators in the laboratory. They are: 1. Conditional Abl knockout. Having knocked out both the Abl and Arg genes and found that one of the two genes is needed for development beyond embryonic day 10, we plan to construct a conditional knockout of Abl on an Arg-deficient background so that the roles of the genes in later stages of mouse development and function can be examined. 2. Abl in C. elegans. Abl function has been investigated in mice and Drosophila but the putative functions of the gene are so variable that examination of another organism is warranted. We have chosen C. elegans because its entire genome is known and it is possible to examine it genetically at very high resolution. 3. NF-kappaB control of transcription. While there is much fragmentary knowledge of the genes controlled by NF-kappaB, a global analysis of gene expression in cells with defined genetic lesions in the NF-kappaB-related proteins will give more precise knowledge of which genes are controlled and by which subunits. 4. NF-kappaB activation by TANK and TBK1. There are numerous pathways of NFkappaB activation but none are known in precise detail. We have found a new kinase, TBK1, that interacts with TANK and appears to act along with TRAF proteins and may phosphorylate them. A deeper knowledge of the details of the biochemistry of these events could help to understand the precise mechanisms of NFkappaB activation. 5.
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ATR kinase. This very large kinase has been implicated in checkpoint control of the cell cycle in mammalian cells. We have knocked out the gene for this protein and the mice die very early in gestation, in a manner similar to mice lacking the BRCA genes. We plan to construct a conditional allele of this gene to examine in more detail its function and, in particular, its relation to p53, BRCA1 and 2, and Chk1. These studies are all aimed at a deeper understanding of both the processes of oncogenic transformation and the normal development and function of mammals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MDS NORDIAN GAMMACELL-40 EXACTOR WHOLE ANIMAL IRRADIATOR Principal Investigator & Institution: Monroe, John G.; Professor; Pathology and Lab Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2003 Summary: Funds are requested for a MDS Nordian Inc. Gammacell-40 exactor selfcontained low dose rate research animal (rodent) irradiator to support the ongoing NIHfunded individual-initiated research programs in a new state of the art animal facility located within a recently erected research building (BRBII) on the campus of the University of Pennsylvania School of Medicine. Twelve core laboratories comprise the list of the major users of the requested instrument. Each have laboratories in the BRBII and will house their mice and perform ongoing experiments requiring whole animal irradiation and extended maintenance of irradiated animals in ongoing experiments in the animals in the basement of this building. These core laboratories will constitute the majority (>75%) of the usage of the irradiator. In addition, there is a group of over 25 additional users that will utilize this instrument on an infrequent (<25% basis. This latter group is comprised of NIH-funded faculty from University of Pennsylvania School of Medicine associated departments, institutes, and hospitals in addition to other faculty with laboratories in the BRBII. Although two other similar instrument are available on the campus, a specific need for this additional instrument arises because the new animal facility in which the animals of the core user group are housed is a closed facility in which the animals taken to other buildings for irradiation cannot be returned to the investigator's designated area. As a consequence, it is impossible to perform experiments that are either long-term requiring maintaining the animals beyond a single day after irradiation, or require comparison of irradiated and reconstituting models, bone marrow chimeras, induction of immunodeficiency, among others. The University of Pennsylvania School of Medicine has already made a significant financial commitment to support the procurement of this instrument. At a cost of over $33,000, the school has committed funds for an ongoing service contract to maintain and service the instrument, committed funds to compensate an individual to oversee the day to day operation of the instrument, and agree to pay for the moving and setup costs for the irradiator. Scientific oversight will be accomplished by a committee comprised of the PI of the proposal, the scientific director of the Abrahamson Family Cancer Research Institute, and two faculty representatives from the core user group. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MICROFLUIDIC POINT-OF-CARE CANCER CELL ANALYZER Principal Investigator & Institution: Battrell, C. F. Fred.; V.P. Operations; Micronics, Inc. 8463 154Th Ave Ne, Bldg F Redmond, Wa 98052 Timing: Fiscal Year 2004; Project Start 08-MAR-2004; Project End 31-AUG-2004
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Chronic Myelogenous Leukemia
Summary: (provided by applicant): Micronics, Inc., and Xtrana, lnc., will develop an inexpensive point of care cancer marker detection device. The device will integrate and automate blood sample preparation, cell sorting and enrichment by microcytometry, antigen (CD marker) analysis, and both DNA sequence and gene expression analysis. Micronics has developed a technology platform for performing microfluidic processes on laminate-based disposables. The technology comprises microfluidic cartridges assembled from plastic laminates, a computer-controlled fluid driver system, pneumatic and passive on-chip valving capability using accurate Iow-pulsatility pumps, and computer software to control fluid motion in the cartridge. Xtrana has developed a novel series of products and applications centered around unique capabilities in nucleic acid sample preparation. Key to the sample preparation is a family of materials, referred to as Xtra Bind, that bind nucleic acids essentially irreversibly, but still allow the bound DNA or RNA to be amplified using conventional methods like PCR. The project will require research and proof-of-principle experiments in the area of microfluidic cell marker identification and sorting, as well as in on-chip cell lysing and microfluidicsbased nucleic acid amplification and detection. Specifically, experiments involving fluorescence detection on micro-cytometer card, accurate counting and display of fluorescent beads of different sizes as well as beads conjugated with antigen, tagged by antibody and counted on micro-cytometer will be performed initially, followed by sorting/fluorescence gating on micro-cytometer. At the same time, Xtrana will develop the protocols for the Xtra BindTM BCR/ABL mRNA expression measurement and will experimentally determine limit of detection and linear range of detection of bcr/abl mRNA transcripts for control cell lines spiked into white blood cells or blood. In Phase II, an instrument capable of BCR/ABL gene translocation diagnostic of chronic myeloid leukemia (CML) and the associated chimeric mRNA expression will be developed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MIGRATION AND ADHESION OF CHRONIC MYELOGNEOUS LEUKEMIA C Principal Investigator & Institution: Verfaillie, Catherine M.; Professor; Medicine; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 01-AUG-1994; Project End 31-DEC-2003 Summary: Beta1-integrins in part support adhesion and migration of NL CD34+ cells to BM stroma and fibronectin (FN). NL CD34+ cell adhesion /migration is also influenced by chemokines, such as SDF-1alpha. The molecular mechanism(s) underlying integrin and chemokine dependent adhesion and migration of NL CD34+ cells are not known. Preliminary studies from our lab suggest involvement of PI3-kinase and the GTPase Cdc42 in these processes. CML is a stem cell leukemia characterized clinically by premature circulation of a massively expanded malignant CD34+ cell population in the blood. CML is caused by the Bcr/Abl oncogene. Although numerous studies have described alterations in signal pathways induced by Bcr/Abl in cell lines, the mechanism(s) underlying the features characteristic for chronic phase CML are not understood. Our lab has shown that (a) CML CD34+ cells adhere less and migrate more over FN than NL CD34+ cells which is not caused by decreased beta1-integrin expression. (b) In CML, the cell cytoskeleton is constitutively activated which decreases the mobility of integrins in the cell membrane. (c) CML CD34+ cell adhesion nor migration is affected by chemokines, such as SDF-1alpha. (d) GTPases and PI3-K, thought to play a role in NL CD34+ cell adhesion and migration, may be constitutively activated in CML and contribute to the aberrant adhesion and migration of CML CD34+ cells. (e) In CML CD34+ cells we have detected abnormally spliced and potentially
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dominant negative, isoforms of the focal adhesion kinase Pyk2. (f) Suppression of Bcr/Abl with antisense ODNs reverses these abnormalities and transfer of Bcr/Abl cDNA in cell lines induces these anomalies, strongly suggesting that Bcr/Abl is responsible for decreased integrin mobility and affinity, adhesion and increased migration. These observations support the following hypotheses (l) Engagement of beta1-integrins and stimulation of CXCR4 via SDF-1alpha activates Pyk2- H. This leads to the activation of signal pathways such as PI3-K, which activates the GTPases Cdc42 and Rac2 responsible for adhesion and migration of CD34+ cells. (2) Constitutive phosphorylation and activation of some of these signal molecules as a result of Bcr/Abl in CML HPC underlies the aberrant adhesion and migration seen in CML. We will test these hypotheses in the following specific aims: SA l. Characterize expression and function of Pyk2-H in CD34+ HPC. SA 2. Examine role of Cdc42 and Rac1/2, PI3-K, and Pyk2 in beta1-integrin- and SDF-1alpha mediated adhesion and migration of CD34+ HPC. SA 3. Examine effect of p210-Bcr/Abl on the function and interactions of GTPases, PI3-K, and Pyk2 leading to the decreased adhesion and enhanced migration characteristic of CML. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR AND CELLULAR ANAYLSIS OF T CELLS DURING DLI Principal Investigator & Institution: Margolis, David A.; Associate Professor; Pediatrics; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532260509 Timing: Fiscal Year 2002; Project Start 25-SEP-1998; Project End 31-AUG-2004 Summary: The potential of the graft versus leukemia (GVL) effect to cure leukemia is illustrated by the success of adoptive immunotherapy with donor leukocyte infusions (DLI) to treat patients who have relapsed with CML after an allogeneic bone marrow transplant. Understanding the immunologic mechanisms underlying this could lead to a significant advancement in the treatment of leukemia in both children and adults through adoptive immunotherapy. The following hypothesis will be tested in the proposed research project: The therapeutic effect of DLI is mediated by a distinguishable population of donor-derived, MHC- restricted T cells responding to both allogeneic and leukemia-specific stimuli. Three Specific Aims are proposed: 1) To characterize at cellular and molecular levels the T cell response to a leukemia-specific peptide (bcr-abl) in the absence (autologous) and presence (allogeneic) of various degrees of major and minor histoincompatibility; (2) To characterize at cellular and molecular levels the T cell response to intact CML cells, compare this response to that generated by the bcr-abl peptide, and evaluate how alloreactivity alters these responses; and (3) To assess the repertoire of T cells in the peripheral blood of patients given DLI for CML and compare the in vivo T cell repertoire to that identified in vitro in Specific Aims 1 and 2 to distinguish alloreactive and leukemia-reactive T-cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MOLECULAR DETECTION AND MONITORING OF LEUKEMIA Principal Investigator & Institution: Stock, Wendy; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2003; Project Start 13-MAY-2003; Project End 31-MAR-2009 Summary: (provided by applicant): The major translational goals of molecular diagnostic and minimal residual disease (MRD) studies in the CALGB Leukemia Correlative Science Committee (LCSC) are to identify new prognostic groups and to
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utilize this information to adapt therapy to improve treatment outcome. We propose to consolidate all molecular diagnostic and MRD monitoring studies into a comprehensive "Molecular Detection and Monitoring Core" that will provide high quality data to Leukemia Committee clinical trials and to other LCSC projects and cores. The work will be performed in three disease-specific laboratories: Dr. Stock's laboratory (University of Chicago) for ALL and CML; Dr. Slack's (Roswell Park) laboratory for APL; and Dr. Gribben's (Dana Farber) laboratory for CLL. Several goals are proposed for Project 5. First, we will continue to utilize Real-time PCR technology for the prospective molecular detection of specific disease subsets and evaluation of MRD, correlating these findings with response to novel therapies as they are tested in the next generation of CALGB leukemia trials in ALL, APL, CML, and CLL. We propose that assessment of response using quantitative MRD monitoring as a surrogate endpoint provides unique clinical insights that will be particularly relevant as we perform the first generation of molecularly targeted CALGB leukemia trials described below in detail. A second goal of Project 5 is to validate the use of quantitative MRD monitoring as an independent prognostic marker of outcome for patients with acute and chronic leukemia. Prospective MRD evaluation of large, uniformly treated patient cohorts is essential for identification and validation of a "threshold" level of MRD that may distinguish patients at high (or low) risk of relapse. We also propose, for the first time in CALGB Leukemia studies, to utilize MRD monitoring to adapt and individualize post-remission therapy. A fourth goal of this Project is closely linked to Project 3, Gene Profiling Studies in Leukemia. As new molecular "signatures" characterizing novel disease subsets are identified by gene profiling studies in Project 3, we will evaluate expression levels of new "molecular signature" genes in ALL, AML and CLL, using Real-time reverse transcriptase (RT)-PCR methodology. The correlation of gene expression using Real-time RT-PCR with microarray findings will be useful for validating these data and will provide important new diagnostic and prognostic information about new molecular genetic subsets that may be used to adapt therapy in future CALGB treatment trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOUSE MODEL FOR PH-POSTIVE CML AND ALL Principal Investigator & Institution: Heisterkamp, Nora C.; Professor; Children's Hospital Los Angeles 4650 Sunset Blvd Los Angeles, Ca 900276062 Timing: Fiscal Year 2002; Project Start 01-SEP-1991; Project End 31-MAR-2004 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NEUROFIBROMATOSIS TYPE 1 GENE REGULATES MYELOPOIESIS Principal Investigator & Institution: Clapp, David W.; Associate Professor; Pediatrics; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2002; Project Start 01-APR-1997; Project End 30-JUN-2007 Summary: (provided by applicant): Mutatons in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF-1). NF1 encodes a GTPase activating protein (GAP) for p21 ras (Ras) called neurofibromin. Neurofibromin converts p21 ras from its active GTP to its inactive GDP bound conformation. Individuals with NFl have a propensity to acquire benign and malignant tumors. Additionally, children with NFl are predisposed to juvenile myelomonocytic leukemia (JMML). A hallmark of myeloid progenitors (CFU-GM) from JMML bone marrow cells is their propensity to hyperproliferate in
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response to low doses of the growth factor granulocyte macrophage colony stimulating factor (GM-CSF). Homozygous disruption of Nfl is lethal in utero; however we found that murine Nf1 -deficient fetal hematopoletic cells show an abnormal pattern of CFUGM growth and hyperactivation of Ras effectors in response to multiple growth factors, including GM-CSF and stem cell factor (SCF), the ligand for the c-kit receptor tyrosine kinase. C-kit is encoded by the murine dominant white spotting locus, W). Since the W and Nfl loci appeared to function along a common developmental pathway, mice with mutations at both loci were generated. We found that haploinsufficiency of Nfl partially rescued the mast cell and coat color defects in W41 mice. These data offered genetic evidence that haploinsufficiency at Nfl modulates cell fates in vitro and in vivo in two lineages that are affected in individuals with NFl. The results support the emerging concept that heterozygous inactivation of tumor suppressor genes may have important biological effects.While loss of neurofibromin increases p21 ras activity in specific cell lineages, identification of alterations in distinct p21 ras effector pathways that control proliferation and survival in NF1-deficient cells is incomplete and critical for understanding disease pathogenesis. Most previous studies argue that loss of neurofibromin results in increased activation of the classical p21 ras-Raf-Mek-ERK pathway. However, we have preliminary data to support an alternative biochemical model where the growth advantage of Nfl1-deficient cells is mediated through increased signals from p21 ras to the small Rho GTPase, Rac2, a Rac isoform expressed only in hematopoietic cells. We propose studies to examine how activation of p21 ras and Rac isoforms cooperate to alter the biology of Nfl +/- mast cells and Nf 1 -/- stem and myeloid progenitor cells utilizing mice with genetic mutations in these loci. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NEW ENGLAND PEDIATRIC ONCOLOGY CONSORTIUM Principal Investigator & Institution: Ferguson, William S.; Rhode Island Hospital (Providence, Ri) Providence, Ri 029034923 Timing: Fiscal Year 2002; Project Start 01-JAN-1981; Project End 31-DEC-2002 Summary: The specific aims of the New England Pediatric Oncology Consortium (NEPOC) are: Development and enhanced productivity of a consortium of regional pediatric cancer centers (Brown University/Rhode Island Hospital; Dartmouth University/Dartmouth-Hitchcock Medical Center; Harvard University/Massachusetts General Hospital; SUNY at Stony Brook/Children's Medical Center at Stony Brook; University of Vermont/Medical Center Hospital-Vermont Regional Cancer Center) for the purposes of: A. Contributing to the understanding and treatment of children and adolescents with malignancies through: 1. Input into national cooperative studies through membership in the Pediatric Oncology Group (POG): a. Patient accrual: Achieve significant number and quality of patient entries on protocols; b. Study development and evaluation: Assist in the development of new protocols through committee memberships, institutional reviews of proposed protocol designs, analysis of study results, and proposal of new protocols for POG implementation based on NEPOC studies; c. Administration: Accept responsibilities for POG administrative functions. 2. Cooperative efforts within NEPOC (New England Pediatric Oncology Consortium) in studies of joint interest in the areas of childhood malignancies, particularly toward developing potential pilot studies for POG. B. Enhancement of the care of children and adolescents with cancer in the geographical areas served by the member institutions through: 1. Assuring comprehensive and modern management of children and adolescents with malignancies as a benefit of membership in POG; 2. Sharing staff expertise and investigative facilities at each of the member institutions; 3. Joint efforts in
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promotion of education of the local community in the area of cancer in children and adolescents. Through a centralized administration, this Consortium integrates the activities and resources (staff, facilities, patients) at each institution into a single program aimed at achieving these goals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NK RECEPTORS AND BONE MARROW TRANSPLANT OUTCOME Principal Investigator & Institution: Hsu, Katharine C.; Sloan-Kettering Institute for Cancer Res New York, Ny 100216007 Timing: Fiscal Year 2004; Project Start 27-JAN-2004; Project End 31-DEC-2008 Summary: (provided by applicant): Dr. Katherine C. Hsu is a junior faculty member at Memorial SIoan-Kettering Cancer Center, whose research interest is in the impact of killer immunoglobulin-like receptors (KIR) on allogeneic hematopoietic stem cell transplantation. AIIogeneic hematopoietic stem cell transplantation (AHSCT) is a valuable therapy for acute leukemias and chronic myelogenous leukemia. Natural killer (NK) cells may influence early and late post-transplant complications, such as graft-versus-host disease (GVHD), disease relapse, and viral infection. The overall objective of this study is to gain insight into the influence of NK killer Ig-like receptors (KIR) on AHSCT outcome. Typing for the 14 known genes encoding activating and inhibitory KIR will be performed for transplant donors and recipients from HLA-A, -B, and -DR-matched allogeneic transplants. Dr. Hsu hypothesizes that KIR genotypes can predict NK-mediated influence on AHSCT outcome: lack of donor activating KIR genes will predispose to post-transplant viral infection and to disease relapse for certain leukemias but not others; donor-recipient inhibitory KIR gene disparity will influence disease relapse/survival in patients receiving transplants from HLA-C disparate donors (KIR epitope mismatched); and donor-recipient KIR gene disparity may influence engraftment and GVHD in nonmyeloablative transplants. Dr. Hsu aims to address these hypotheses through: 1) determining the influence of donor KIR on overall survival and post-transplant complications in patients receiving T-cell depleted HLA-identical sibling AHSCT for CML and AML; 2) determining in a multi-center analysis, the influence of donor KIR genotype and donor-recipient KIR disparity in patients undergoing unrelated AHSCT; and 3) evaluating prospectively the influence of NK receptors, including both donor and host KIR, on engraftment, GVHD and overall survival in patients undergoing transplants with non-myeloablative conditioning. Dr. Hsu has two mentors, Dr. Bo Dupont and Dr. Richard O'Reilly who have previously served as mentors for both clinical research and basic research scientists. Dr. Glenn Heller is the biostatistician for the proposed studies. As her immediate goals, Dr. Hsu hopes to demonstrate conclusively the influence of the activating KIR on transplant outcome and to identify in which clinical setting the inhibitory KIR may play a role in affecting transplant outcome. In addition, she seeks to understand the interplay between donor and recipient NK cells in non-myeloablative transplants and to determine if KIR may direct their interaction and influence on transplant outcome. Eventually, she hopes to utilize this information to develop adoptive cell therapy using NK cells. Dr. Hsu intends to develop a career as an independent investigator in the field of NK cell immunogenetics and allogeneic hematopoietic stem cell transplantation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NONMYELOABLATIVE ALLOTRANSPLANTS
HEMATOPOIETIC
STEM
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CELL
Principal Investigator & Institution: Storb, Rainer F.; Member and Professor/ Program Head; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2002; Project Start 18-MAR-2002; Project End 30-NOV-2006 Summary: (provided by applicant): Traditional allogeneic hematopoietic stem cell transplantation (HSCT) for treatment of patients with hematological malignancies relies on maximally tolerated doses of systemic chemoradiation to both eradicate cancer and achieve host immunosuppression. The allografts then serve to rescue patients from treatment-induced marrow aplasia and contribute a graft-versus-tumor effect of uncertain magnitude. Associated toxicities have limited HSCT to younger, medically fit patients with therapy administered on specialized hospital wards. This age restriction has excluded most patients with myeloid leukemias and B cell malignancies from transplantation. To address this limitation, we have developed a nonmyeloablative transplant approach applicable to elderly or medically infirm patients in which the burden of tumor eradication has been shifted from cytotoxic agents to the graft-versustumor effect. Using a large randombred canine model, we have shown that the intense conditioning regimens customarily used for host immunosuppression in HSCT could be largely replaced by optimizing postgrafting immunosuppression with a combination of mycophenolate mofetil and cyclosporine, which not only served to control serious graftversus-host disease (GVHD) but, as importantly, reduced the magnitude of the hostversusgraft reaction. The current clinically used conditioning regimen consists of only 2 Gy of total body irradiation (TBI) and three doses of fludarabine. The preliminary clinical results have shown that this nonmyeloablative regimen was safe and minimally toxic in patients otherwise excluded from HSCT because of age or medical infirmity. In a majority of patients, transplants were carried out entirely in the outpatient setting. Importantly, impressive anti-tumor responses have been seen. Given the consistent allogeneic engraftment with minimal toxicity, we propose to extend the preliminary observations with two specific aims: 1) In patients with CML we will establish the efficacy of nonmyeloablative related HSCT for inducing long-term remissions through graftversus- leukemia effects without undue long-term complications from GVHD, and 2) we will extend the application of nonmyeloablative HSCT to include elderly recipients of unrelated grafts. We anticipate that, in later grant years, we shall carry out Phase II studies in younger patients followed by Phase III studies in which the nonmyeloablative HSCT approach is compared to standard HSCT. We anticipate that future graft-versus-tumor effects can be made more specific by the use of donor lymphocyte clones specific either for CML-specific antigens or host minor histocompatibility antigens associated with malignant cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NOVEL FUSION PROTEIN IN CMML Principal Investigator & Institution: Ross, Theodora S.; Internal Medicine; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 10-FEB-1998; Project End 31-JAN-2003 Summary: (Applicant's Description): The TEL-PDGFBR fusion protein was identified as the protein product of a t(5;12) translocation in a patient with chronic myelomonocytic leukemia (CMML). The protein fuses the amino portion of TEL with the transmembrane and cytoplasmic domains of the PDGFBR. TEL, a member of the ETS family of
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transcription factors, has subsequently been described as a common site of rearrangement in multiple forms of leukemia. This is not yet the case for the PDGFBR. The applicants find, however, in the Preliminary Results, that another patient with CMML has a novel t(5;7) translocation. Southern blotting analysis has identified a breakpoint in this patient at the same genomic localization in the PDGFBR as the t(5;12) translocation. Their hypothesis is, that in this patient, as for the t(5;12) TEL-PDGFR patients, PDGFBR is constitutively activated by fusion with a 7q24 partner. Although rare (as for identification of TEL), the PDGFBR fusion partner at 7q24 may identify a gene involved in a broader group of malignancies. Also, in light of the facts that other patients with CMML have PDGFR containing fusions and the region of 7q24 is frequently deleted in MDS, the cloning, characterization and manipulation of this fusion protein is paramount. Hence, in Specific Aim 1, they will use anchored PCR to clone the breakpoint. Their specific oligos will come from the known PDGFBR sequence. In Specific Aim 2, they will obtain a full length cDNA and determine the relevance of this by performing ribonuclease protection assays and mapping back to chromosome 7. Finally, for Specific Aim 3 they propose to characterize the fusion protein by determining its transforming, activity(s) and biological properties using mutational and biochemical analyses. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NOVEL PATHWAYS FOR BCR-ABL TRANSFORMATION Principal Investigator & Institution: Whitehead, Ian P.; Microbiol & Molecular Genetics; Univ of Med/Dent Nj Newark Newark, Nj 07107 Timing: Fiscal Year 2003; Project Start 03-APR-2003; Project End 31-MAR-2007 Summary: Chromosomal rearrangements that fuse amino terminal sequences of the Bcr protein to carboxyl terminal sequences of the Abl tyrosine kinase (p210 Bcr-Abl) are associated with virtually all cases of chronic myelogenous leukemia (CML). Whereas the contribution of Abl encoded sequences to Bcr-Abl-mediated leukemogenesis are relatively well understood, the contribution from the Bcr encoded sequences is unclear. For example, several in vitro studies have identified catalytic activities within the amino terminus of Bcr, yet the relationship of these activities to the in vivo functions of Bcr, and Bcr-Abl, are not known. We have recently completed two studies which suggest that Bcr may contribute to the transforming activity of Bcr-Abl in ways that were not previously realized. First, we have identified a functional interaction between Bcr and the oncogenic transcription factor c-Myc. The disruption of this interaction may account for the elevated levels of c-Myc expression that are observed in Bcr-Abl transformed cells. Consistent with this, we have observed that c-Myc protein levels are sensitive to the dosage of Bcr in a CML-derived leukemic cell line. Second, we have demonstrated that the central RhoGEF domain of Bcr (which is retained in Bcr-Abl) contains in vivo catalytic, signaling and transforming activity. Importantly, a similar catalytic activity is observed within the context of p210 Bcr-Abl. The objective of this proposal is to characterize these new activities, and determine their fates within the context of Bcr-Abl. Specifically, we propose to (1) determine if the association of Bcr with the c-Myc transcription factor has functional consequences that contribute to Bcr-Abl-mediated transformation, and (2) determine whether the transforming and catalytic activities that we have mapped to the RhoGEF domain of Bcr contribute to Bcr-Abl-mediated transformation. The results from these studies should contribute substantially to our knowledge of the molecular basis of Philadelphia chromosome positive leukemias. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: OVERCOMING TRANSPLANTATION
GENETIC
BARRIERS
IN
STEM
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CELL
Principal Investigator & Institution: Hansen, John A.; Professor and Member; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2002; Project Start 18-MAR-2002; Project End 30-NOV-2006 Summary: (provided by applicant): The goal of this project is to increase access to hematopoietic stem cell transplants (HSCT) from normal volunteer or partially matched family member donors for patients lacking an HLA identical sibling, and to improve the safety and efficacy of these alternative donor transplants for patients with hematological malignancy. HSCT from alternative donors are associated with greater risk of severe graft-versus-host disease (GVHD), morbidity, and non-relapse mortality than HSCT from HLA identical siblings. In the past, these differences have been partly due to inadequate methods for detecting HLA sequence polymorphisms capable of inducing allograft reactions causing graft failure and GVHD. Advances in DNA-based typing technology have provided powerful tools for detecting genetic differences between patients and donors, but the greater sensitivity achieved has created ambiguities in the definition of an acceptable match. Previous studies have demonstrated the advantages of better matching; however, the limits of safe mismatching are poorly defined. The studies proposed here will continue to examine this question and aim to determine the degree of mismatching for HLAA, B, C, DR and DQ that can be tolerated without significantly increasing the risk of severe GVHD or transplant-related mortality. Other genes encoding immune regulator molecules may also affect transplant outcome by modifying the severity of GVHD and regimen-related toxicity (RRT). Investigations will be undertaken to determine if genetic variation in these genes may explain the different degrees of toxicity seen in individual patients. The problems of RRT and transplantrelated mortality (TRM) will be addressed through two approaches, modifying the conditioning regimen and minimizing the severe neutropenia usually associated with myeloablative regimens. One phase I/II trial will evaluate the safety and efficacy of substituting fludarabine for cyclophosphamide in a regimen containing busulfan. A second phase I/II trial will evaluate the ability of growth factor mobilized peripheral blood stem cells (PBSC) to mitigate RRT and TRM by improving the speed and quality of donor cell engraftment. Clinical trials will also be undertaken to determine if modifications to the pretransplant conditioning regimen can mitigate the risk of graft failure associated with donor HLA incompatibility, and future trials will evaluate new approaches for controlling GVHD in the presence of recipient HLA disparity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PATHOGENESIS OF CHRONIC MYELOGENOUS LEUKEMIA Principal Investigator & Institution: Pear, Warren S.; Associate Professor; Pathology and Lab Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 18-JAN-1999; Project End 31-DEC-2003 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PATIENTS, CLINICS, AND SYSTEMS: SCREENING FOR ALCOHOL Principal Investigator & Institution: Chang, Grace; Associate Professor of Pyschiatry; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 24-SEP-1999; Project End 31-AUG-2004
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Summary: The majority of patients with alcohol problems present to general medical and other clinical settings, rather than directly to alcohol treatment. The consequences of untreated alcohol problems are well known, and include a whole range of medical and social complications. The identification and treatment of alcohol problems, when patients present for prenatal care, emergency services, or a medical appointment, has been a longstanding clinical research interest. A Midcareer Investigator Award in Clinical Research would allow the applicant to focus on patient-oriented research interests during a critical professional period. The purpose of the current project, "Alcohol Abuse in Bone Marrow Transplant," is to test the hypothesis that alcohol abuse or dependence has an adverse impact on survival after bone marrow transplant, the second most frequent major organ transplant in the United States and the transplant with the least limited donor organ supply. A prospective cohort study of 124 patients with Chronic Myeloid Leukemia undergoing allogeneic bone marrow transplant is underway. The purpose of the proposed project, "Alcohol Screening in Medicaid Managed Care," is to test the hypothesis that routine alcohol and substance abuse screening of Medicaid members at health plan (HMO) enrollment is less effective than alcohol and substance abuse screening at the HMO primary care site. A sample of 2,000 Medicaid enrollees screened at enrollment will compared with a sample of 715 patients who will be screened for alcohol and substance abuse as they initiate care at primary care HMO sites. Their utilization of alcohol and substance abuse treatment, psychiatric and medical treatment for 12 months subsequent to screening will be compared. A sample of 150 patients with positive primary care screens will be studied more intensively. Both of these studies will focus on patients, but will have important practice and policy implications, as transplant medicine and managed care are increasingly prevalent and underscore the need for alcohol and drug screening of patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Lauer, Stephen J.; Professor of Pediatrics; Pediatrics; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 01-JAN-1978; Project End 31-MAR-2003 Summary: The Pediatric Oncology Program at Emory University is the only comprehensive children's cancer center in Georgia and one of the largest of its kind in the Southeast. It serves a racially, ethnically, and socioeconomically diverse population from metropolitan Atlanta, the State of Georgia, and other states including Alabama, Arkansas, the Carolinas, Florida, and Mississippi. Since the inception of the Pediatric Oncology Group (POG), Emory is consistently one of the largest single-institution contributors to POG clinical and laboratory studies. Emory is a center for Phase I and pilot POG trials and has initiated numerous protocols that have subsequently been implemented by POG. The specific aims of the Emory POG Program are: l) to continue as a major source of patients for POG-sponsored Phase I, pilot, groupwide, and intergroup studies; 2) to provide leadership by its investigators as POG Study Coordinators, Co- coordinators, and Core Committee members; 3) to develop innovative institutional clinical trials on which to base future POG investigations; and 4) to maintain strong basic and translational research programs in pediatric oncology. To address these aims, Emory investigators are Coordinators for several major POG studies, including standard-risk new ALL (#9405), high-risk new ALL (#9006), salvage chemotherapy in relapsed neuroblastoma (#9140), and chemotherapy vs. autologous bone marrow transplantation (ABMT) in AML (#8821). Emory POG members actively participate in POG Core Committees, Subcommittees, and new protocol development.
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Institutional pilot studies include therapy of relapsed AML with idarubicin and chlordeoxyadenosine, treatment of relapsed solid tumors with high-dose busulfan/melphalan and ABMT, transplantation of haploidentical CD34+ cells for relapsed ALL or AML, and vincristine plus dose-escalated cyclophosphamide and infusions of peripheral blood-derived progenitor cells in refractory solid tumors. Complementary laboratory research activities include molecular biology of ALL (mechanisms of IL-6- mediated autocrine growth and aberrations in tumor-suppressor genes); in vitro sensitivity of leukemia cells to antineoplastic agents mid biological response modifiers; mechanisms of resistance of AML cells to alkylating agents; molecular neuro-oncology; and xenogeneic models to evaluate normal and neoplastic human hematopoiesis. Investigators at Emory are participating in the POG laboratory study of methotrexate metabolism by ALL cells (ALinC #16) and coordinate the study of alterations in p53 tumor-suppressor gene pathways in relapsed ALL (SIMAL #l0). Taken together, these activities of the Emory POG Program will continue to contribute to our knowledge of the biology, therapy, and prevention of neoplastic diseases in infancy, childhood and adolescence. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Grier, Holcombe E.; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 30-SEP-1986; Project End 31-DEC-2002 Summary: The principal activity of this grant is to improve the care and treatment of children with cancer by participating in the Pediatric Oncology Group (POG). The three specific goals of the participation of the Dana-Farber Cancer Institute/Children's Hospital (DFCI/CH) and Maine Children's Cancer Program (MCCP) are to 1) enter and follow children with malignancies on appropriate Pediatric Oncology Group (POG) protocols 2) provide leadership in planning and executing POG protocols and 3) provide pilot clinical studies and scientific leadership to POG. 1) Patient entry: the referral patterns at the two institutions has not changed and the commitment to POG protocols remains high. Therefore, patients accrual will continue at the high level previously noted over the last grant period. 2) Leadership within POG: Drs. Weinstein and Grier respectively are the disease chairs for the Myeloid and Sarcoma Committees. The disease committee chairs have primary responsibility for all scientific and clinical activities within POG. Investigators from these institutions are currently or were in the last cycle chairs for 7 separate POG protocols and co chairs of 35 more. They also have 18 positions on disease or discipline committees within POG. Enthusiasm remains strong, and involvement at the current level will continue. 3) Pilot POG protocols and scientific leadership: Scientific leadership is detailed in part above. Dr. Arceci provided scientific leadership for and analyzed the samples of the MEC protocol (#9222) that piloted the use of multidrug resistance reversal agents (cyclosporine) in relapsed AML. This protocol provided the background for the about to open group wide AML up-front protocol (#9394) that will randomize whether or not patients will receive cyclosporine during maintenance therapy. DFCI ALL protocols have provided the background for one of the arms of the proposed new T- cell protocol (#9404). In addition, the background for the current stereotactic protocol (#9373) was in part developed at the Joint Center for Radiation Therapy and the DFCI. Finally, POG has embarked on a major effort to study the autologous transplant protocols for ALL (#9421) developed at the DFCl. Finally Dr. Lipshultz ran at DFCI/CH the pilot studies of late cardiac toxicity
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from anthracyclines that provides the background data for the randomized trial of enalapril for patients with elevated after load. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Meyer, William H.; Pediatrics; University of Oklahoma Hlth Sciences Ctr Health Sciences Center Oklahoma City, Ok 73126 Timing: Fiscal Year 2002; Project Start 01-JAN-1978; Project End 31-DEC-2002 Summary: Children's Hospital of Oklahoma (CHO) at the University of Oklahoma is a member institution of the Pediatric Oncology Group. One of our primary goals is the enrollment of the majority of pediatric patients with cancer in the state of Oklahoma in a cooperative cancer program (POG). Participation in group studies guarantees optimal care for these patients and the opportunity to study in depth the natural history of childhood cancer, develop effective therapeutic regimens, and evaluate the toxicity. and effectiveness of new anti-cancer agents in the treatment of childhood cancer. In addition to the POG studies, institutional non- therapeutic protocols have been developed, i.e., evaluation of leukemic therapy on the central nervous system of newly diagnosed leukemic patients and longitudinal evaluation of coping mechanisms with stress among patients and parents of children with cancer. For all these programs, patient resources and scientific expertise are available in Children's Hospital of Oklahoma. The team at the University of Oklahoma is multidisciplinary. It consists of pediatric hematologistsoncologists, radiation therapists, radiologists, pediatric surgeons, immunologists, pathologists and psychologists. All protocols are reviewed by the Institutional Review Board and informed consent is obtained on all patients entered into these protocols. Protocol compliance remains a high priority. The evaluability rate for the last four years averaged 92.5%. St. Francis Hospital of Tulsa was previously considered a branch of CHO. At the request of the POG Operations Office, Tulsa has applied to become an affiliate institution. The University of New Mexico is also affiliated with the University of Oklahoma. It serves an economically disadvantaged population (native American Indians) which needs to be included in the population studied by cooperative cancer groups. The Pathology Department at the University of New Mexico has special expertise in molecular diagnostic hematopathology and in solid tumors which can benefit the research efforts of the Pediatric Oncology Group. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Steuber, C P.; Pediatrics; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 01-JAN-1978; Project End 31-DEC-2002 Summary: The concept of the pediatric cooperative cancer group was introduced over 30 years ago because of the rarity of pediatric malignant diseases and the vital importance of controlled trials to improve the outcome for such patients. For such a group to succeed, the collaborative contributions of individuals from a large variety of specialties and fields of research are absolutely essential. This multimodal organized approach to the treatment of childhood cancer through the cooperative group has welldemonstrated its value. The Section of Pediatric Hematology-Oncology at Baylor College of Medicine has been involved in the genesis of this kind of clinical research and has participated in the activities at even level. The current goals of the Section regarding cancer prevention, treatment, and research have lead to the recent development of the
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Texas Children's Cancer Center. The Center is a joint effort of Texas Children's Hospital and Baylor College of Medicine and is committed to providing the finest possible patient care, education and research in the areas of pediatric and adolescent cancer and hematological disorders. Major expansion of the clinic and research lab facility is underway. New faculty are being recruited to expand the current research program in the areas of gene therapy, bone marrow transplantation, molecular biology, clinical pharmacology, and experimental therapeutics. Additional personnel including data managers, pediatric nurse practitioners, and research personnel have been recruited to support the new faculty members and the expanded programs. In addition, outreach efforts are making the Center known to communities in Texas that would benefit from a service dedicated to the treatment of children with cancer. The development of the Texas Children's Cancer Center will enhance Baylor's contributions to the Pediatric Oncology Group (POG) by expanding the research and treatment programs that have so successfully contributed to POG throughout the years, by developing new and innovative treatment and research programs, and by increasing study populations for those programs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Breitfeld, Philip P.; Pediatrics; Duke University Durham, Nc 27710 Timing: Fiscal Year 2002; Project Start 01-JAN-1983; Project End 31-DEC-2002 Summary: The goal of the proposed research is to determine optimum care for children with all types of cancer. The research mechanism involves participation by pediatric investigators in a consortium of medical institutions in North Carolina and West Virginia in collaborative multidisciplinary clinical cancer research protocols generated through the Pediatric Oncology Group. The proposed research grant will allow for the continued participation of Duke University Medical Center, Charlotte Memorial Hospital, East Carolina University School of Medicine and West Virginia University School of Medicine in Pediatric Oncology Group activities. These activities involve studies of the epidemiology and tumor biology of selected neoplasms and the natural history and optimum multimodal therapy of all childhood malignancies. Cooperative studies among physicians from a group of medical centers allow for rapid accrual of a statistically significant number of children with cancer in order to define quickly both those avenues of biologic research which have immediate clinical relevance and those therapeutic approaches which provide prolonged disease-free survival. Through participation in cooperative studies, the entire medical community engaged in the care of children with cancer has a focal point to provide not only improved patient care but also improved multidisciplinary teaching and research. Our objectives for the coming years are: 1) to develop new protocols for the immunologic stratification and chemotherapeutic management of patients with malignant lymphoproliferative and myeloproliferative disorders; 2) to develop protocols for specific brain tumor therapy which take advantage of our expanding knowledge of the biology and pharmacologic sensitivity of human brain tumors in vitro and in vivo; 3) to expand our studies of the pharmacologic agents which influence intermediary metabolism, using our in vitro data as the basis for drug scheduling in clinical trials; 4) to expand our innovative groupwide epidemiology studies to include studies of neuroblastoma and T-cell malignancies which include laboratory investigation (immunologic, biochemical and cytogenetic) where relevant; 5) to expand our multidisciplinary therapeutic research efforts in other
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pediatric malignancies; and 6) to expand our outreach programs for patient care and education through our regional consortium. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Kung, Faith H.; Associate Professor; Pediatrics; University of California San Diego La Jolla, Ca 920930934 Timing: Fiscal Year 2002; Project Start 01-JUL-1980; Project End 31-DEC-2002 Summary: This proposal represents a request to support continued participation in the pediatric Oncology Group (POG). This cooperative research is devoted to the investigation of chemotherapeutic, immunological and molecular biological approaches to the treatment of acute leukemia and other neoplastic diseases of childhood. Significant disease free survival has been achieved and contributions have been made in clinical pharmacology, tumor immunology and biology of cancer. However the real objective of these studies is the eradication of neoplastic diseases by treatment. Studies are being designed to reflect an increasing intensity of attack on the neoplastic cell. The cooperative group technique permits prompt evaluation in series of reasonable size of promising leads in chemotherapy. These leads or new approaches are often suggested by the results of the group's own work in clinical oncology. Thus, a completed protocol often suggests new avenues to be explored in new protocols. POG led in the investigation in the immunophenotyping of acute lymphoblastic leukemia, NTX polyglutamates accumulation in leukemic cells, and N-myc gene amplication in neuroblastoma, correlated the findings with patient outcome, and then incorporated them in new treatment protocols designed to improve the survival of children with cancer. The Division of pediatric Hematology/Oncology at the University of California, San Diego has 24 years experience (10 years in CALGB and 14 in POG) in cooperative clinical trials. In the past 5 years the 4 consortium member institutions had entered 332 patients on both therapeutic and non- therapeutic studies and the satellites, 211 patients. Our investigators served on 12 committees, designed/coordinated 16 group protocol studies. We also contributed to 15 group publications/presentations. Our investigators will continue to design and chair therapeutic protocols,and serve on committees. Dr. Yu's laboratory will continue to explore new immunotherapeutic agents for Group use, and serve as the Group Reference Laboratory. We plan to continue our active participation in all phases of POG activities. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Link, Michael P.; Professor; Pediatrics; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 01-JAN-1983; Project End 31-DEC-2002 Summary: The overall goal of this research proposal is for Stanford University, the University of Arizona, and the Kaiser Permanente Medical Centers of the South San Francisco Bay Area to continue their active involvement in Pediatric Oncology Group research activities. Stanford faculty and the University of Arizona faculty have already assumed key leadership positions in POG and have or have had major roles in the scientific and administrative aspects of the Group. Further, Stanford, the University of Arizona, and Kaiser have maintained excellent performance ratings in their participation in POG studies and have received commendations for the large numbers of evaluable patients placed on therapeutic protocols. Specifically: l) We plan to
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continue to enter patients on appropriate POG studies where they exist. The number of patient entries from Stanford has increased each year as appropriate POG studies become available. We anticipate that between 65 and 80 patients will be entered on front-line therapeutic studies each year from Stanford in addition to patients who will be entered from the affiliates; in addition, 40-50 patients or more will be entered on POG non-therapeutic studies. 2) We anticipate that the activities of individual investigators from Stanford and the University of Arizona will continue and increase during the period of this research proposal. Currently, our faculty serve as study coordinators for front- line therapeutic studies in lymphoma and leukemia, and they have coordinated and analyzed data from recently closed protocols in osteosarcoma, lymphoma, leukemia, and Ewing's sarcoma. Our faculty also serve key scientific and administrative roles as Group Vice Chair, Disease and Discipline Committee Chairmen and CoChairmen, as members of Disease and Discipline Core Committees, and as members of the Executive Committee. Thus, our faculty are in position to influence the future direction of the scientific activities of POG. 3) We anticipate that involvement of Stanford faculty in the laboratory scientific activities of POG will continue. The laboratories of Drs. Link and Cleary have served as immunology reference laboratories and molecular biologic reference laboratories for leukemia studies of POG. 4) We anticipate that non-POG related laboratory and clinical research conducted at Stanford University and its affiliates will become increasingly relevant to POG activities. Some of these activities have already been incorporated into POG laboratory and therapeutic studies and others are targeted for incorporation into future POG studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Kavan, Petr; Montreal Children's Hospital 2300 Tupper St Montreal, Pq Timing: Fiscal Year 2002; Project Start 01-JAN-1983; Project End 31-DEC-2002 Summary: The Pediatric Oncology Group (POG) is a multi-disciplinary, multiinstitutional research community which collaborates to increase knowledge of and improve treatment for cancer and leukemia in children and adolescents. The Montreal Children's Hospital/McGill University (MCH), a founding member, requests funding for itself and its two affiliates, the Children's Hospital of Eastern Ontario (CHEO) and the University of Sherbrooke Medical Center (USMC) to continue to participate fully in administrative and scientific activities of the POG during the next 5 years. We expect to enroll a total of 70 patients a year on therapeutic protocols for childhood leukemias, lymphomas, solid tumors and brain tumors, with continued emphasis on Phase I and II studies of new agents and coordination or co-coordination of a minimum of 13 protocols. We expect to enroll 110 patients per year on non-therapeutic studies of cancer etiology, epidemiology, biology, psychologic impact and late effects of therapy with particular emphasis on the pharmacology and molecular pharmacology of methotrexate in acute lymphoblastic leukemia (ALL). We will comply with all requirements of the POG constitution, with MR regulations governing ethical conduct of clinical research and with OPRR and IRB requirements for informed consent and protection of subjects from research risks. In addition to an anticipated doubling of patient accruals since 5 years ago, our major contributions to POG research will include: confirmation that the extent of accumulation of methotrexate polyglutamates by lymphoblasts in B-progenitor cell ALL correlates with event-free survival (EFS) and characterization of the mechanisms regulating this metabolism (Whitehead); promotion of new agent drug development through New Agents and Pharmacology Committee leadership
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(Whitehead and Bernstein) and protocol coordination (Bernstein, Baruchel); introduction of stereotactic and fractionated stereotactic radiation therapy in brain tumors (Freeman); coordination of treatment protocols of newly-diagnosed and relapsed B-progenitor cell ALL (Abish, Bernstein); introduction of new agents and combinations in recurrent lymphoid disease as Sub-committee Chair, Lymphoid Relapse (Bernstein); chemotherapy and surgery of brain tumors (Baruchel, Ventureyra); and study of the biology, including p53 gene mutations, and treatment of HIV-related lymphomas (Baruchel, Whitehead). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Castleberry, Robert P.; Professor of Pediatrics; Pediatrics; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-MAR-1979; Project End 31-DEC-2002 Summary: The University of Alabama at Birmingham (UAB) is a leading contributor to the ongoing clinical and basic research activities of the Pediatric Oncology Group (POG) which are focused upon improving the care and cure for children with cancer. Current results of these trials are in some cases already published and are available in the Progress Report. The leadership from UAB in POG is evident in several areas: l) through enrollment of substantial numbers of assessable patients on Phase I, II and III therapeutic trials, including multidiscipline (surgery, chemotherapy, and radiotherapy) management studies; through participation in and development of Group-wide biological studies of selected hematopoietic and solid malignancies; through evolving, coordinating and reporting data from POG therapeutic trials; and by providing discipline and disease committee, and administrative leadership within the group. UAB will continue to enroll all eligible patients on active POG therapeutic and biological studies, including phase I investigations, and maintain high evaluability. UAB investigators will continue to coordinate clinical trials for children with neuroblastoma, bone tumors, and juvenile chronic myelogenous leukemia (JCML) and to assess the therapeutic utility of IL6. Further, UAB investigators will be principal to the development of new studies in neuroblastoma, brain tumors, JCML and acute myelogenous leukemia. UAB will continue to supervise laboratories for POG in the following areas: 1) Banded chromosomal analysis in newly diagnosed patients with lymphoid leukemia; 2) A required reference laboratory for children with JCML (POG #9265) studying the pathogenesis of myeloproliferation; 3) A required serum/plasma repository (POG #9047) with clinical and demographic data referenced on a computer data base; and 4) A non- mandatory reference laboratory to evaluate the biological and clinical significance of rnicrotubular associated protein (MAP) and tubulin isotype expression in neuroblastoma. UAB investigators will continue their scientific and administrative leadership roles on the Neuroblastoma and Other Embryonal Tumors, Myeloid Disease Core, Biologic Response Modifier Core, Executive, Principal Investigator Core, Clinical Research Associate Core, and Diagnostic Imaging Core Committees. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Luchtman-Jones, Lori; Pediatrics; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-JAN-1978; Project End 31-DEC-2002
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Summary: The Washington University Medical Center in St. Louis is one of the 39 full member institutions, 48 affiliate, 12 consortia and 9 CCOP institutions of the Pediatric Oncology Group who has pooled their patient resources and scientific expertise to study the natural history of childhood cancer, develop and compare effective therapeutic regimens and investigate the toxicity and effectiveness of new anticancer agents in the treatment of children with cancer. Additionally tumor specimens and occasionally normal tissue and blood samples are collected to determine more about the basic cancer biology and pathology of the disease. Group studies are ongoing in epidemiology, cancer control, pharmacology and pharmacokinetics. The investigators at the Washington University Medical Center include pediatric oncologists, radiologists, radiation oncologists, cytogenetists, neurologists, surgeons, and pathologists. All children with malignant disease are placed on cooperative group protocols if they are eligible and if informed consent is obtained. Data accessioned at the time the patient is placed on study protocol, during the study, and when off therapy is submitted to the Group Statistical Office for data analysis, interpretation and eventual publication. The investigators at Washington University Medical Center serve in multiple administrative and research capacities for the Group. The diagnostic studies, pathological findings, surgical procedure and therapeutic plan for all new patients and patients who relapse are discussed at the weekly Tumor Board Conference. The Principal Investigator has a phase I contract and works with 16 other POG institutions to establish the maximum tolerated dose of a new agent along with the pharmacology and, if indicated, the biologic response of the agent. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Ravindranath, Yaddanapudi; Pediatrics; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2002; Project Start 01-JUN-1981; Project End 31-DEC-2002 Summary: This proposal is a request for funding for our continued involvement in the Pediatric Oncology Group (POG). The aims and objectives are to find better means of management for malignant diseases in children and adolescents, and thus increase disease-free survival rates. The Children's Hospital of Michigan (CHM) provides diagnostic evaluation and multimodal therapy for children throughout the State of Michigan. While there is one other Pediatric Oncology facility in the State, the Hematology/Oncology service sees almost all children and adolescents with malignant disease who live in the greater metropolitan Detroit area, and also sees large numbers of such children referred from other parts of the State (and from Canada) regardless of their ability to pay. Until 1979, the oncology service at CHM remained "independent". In September 1979, the CHM oncology team joined the pediatric division of the Southwest Oncology Group and in January 1981 joined the Pediatric Oncology Group, which appears to have even a greater potential for development of better treatment regimens for childhood malignant disease. At the time of referral and/or admission to CHM for possible malignancy, each child is seen and evaluated by the appropriate oncology team members. Following appropriate diagnostic evaluation, each child is presented and discussed at the Tumor Board, which meets weekly and is attended by pediatric oncologists, pathologists, radiologists, surgeons, surgical subspecialities, and radiotherapists. A plan of action is outlined for each child's management. All such children are registered with POG, and whenever judged appropriate, children are entered on POG treatment protocols. By our participation in such a cooperative children's cancer group, our investigators are able to share new information and ideas
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and gain access to new multimodal therapy regimens and investigational drugs which hopefully provide the best available care to these children. Our objectives in the coming years are: 1) increased participation in POG cancer biology and epidemiology studies; 2) to continue our leukemia biology studies particularly pharmacology studies in AML/T ALL, and 3) to develop new strategies for treatment of brain tumors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Cohn, Susan L.; Associate Professor of Pediatrics; Children's Memorial Hospital (Chicago) Chicago, Il 606143394 Timing: Fiscal Year 2002; Project Start 01-DEC-1978; Project End 31-DEC-2002 Summary: The objectives of this project are to enroll children with cancer in clinical trials, to develop clinical trials and study the biologic behaviors of childhood cancer, and to improve and evaluate the disease- free survival of patients enrolled in these clinical trials. In order to achieve these goals, the member institutions of the Pediatric Oncology Group (POG) meet biannually to discuss, develop, and implement clinical trials for the most common childhood malignancies and to supply the reference research laboratories of the proper material or tissue necessary for the research. Since 1989, CMH has been one of the member institutions of POG who is actually involved in the accrual of children with cancer to clinical trials. CMH's faculty is also involved in the coordination of studies either as the Principal Investigator or co-Investigator. These protocols are POG 9443, POG 9240/41/42, POG 9135/6, POG 9410, NTWS #5. Participation in administrative activities within POG include the POG Chairperson, the POG Executive Officer, the Head of the Neuroblastoma Biology Committee, the Head of the Neuroblastoma Bone Marrow Transplant Working Group, along with members of the following committees: Non- Hodgkin's Lymphoma, Neuroblastoma, Bone Marrow Transplantation, Hodgkin's Disease, New ALL, Wilms' Tumor, Nursing, and Surgery, Radiotherapy, and Pathology Disciplines. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PEDIATRIC ONCOLOGY GROUP ACTIVITIES Principal Investigator & Institution: Winick, Naomi J.; Professor of Pediatrics; Pediatrics; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2002; Project Start 01-JAN-1983; Project End 31-DEC-2002 Summary: This grant application seeks continued support for the Pediatric Oncology Group (POG) activities of The University of Texas Southwestern Medical Center (UT Southwestern) Consortium, which consists of UT Southwestern (Dallas), Cook-Ft. Worth Children's Medical Center (Ft. Worth), and Scott & White Clinic (Temple). Since joining POG in 1981, this partnership of children's cancer treatment and research centers in North Texas has grown to become POG's largest contributing member with regard to patients enrolled on therapeutic studies (over 100 annually). During the current grant cycle, consortium investigators have held administrative and scientific leadership positions on major Group committees, including Executive Committee, Principal Investigator's Committee, New ALL Committee, T-cell Committee, and Lymphoid Relapse Committee. UT Southwestern Consortium investigators have also served or are serving as study coordinators on multiple POG treatment protocols studying ALL (newly diagnosed patients with B-lineage and T-cell disease as well as following relapse), non-Hodgkin's lymphoma, bone marrow transplantation and new agents being explored in Phase I-II trials. UT Southwestern Consortium investigators have also had
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prominent roles in the arenas of data management, protocol development, molecular and pharmacologic monitoring in authorized POG reference laboratories, and supportive care. Results of pilot projects conducted at UT Southwestern have been instrumental in the construct of group-wide treatment strategies, especially involving use of methotrexate for B-lineage ALL. To support the UT Southwestern Consortium's continued commitment to POG research during the next 5 years, this new grant proposal describes personnel and facilities in the 3 consortium centers. Specifically, during 1996-2000 the Consortium aims to advance POG research by: (l) enrolling as many patients as possible on POG treatment, biological classification, and epidemiology protocols; (2) collecting, recording, and submitting research data in an accurate and timely fashion; (3) providing administrative and scientific expertise to the Group through continued active participation on major committees, including service as disease committee chairs and protocol coordinators; and (4) continuing to conduct innovative in-house pilot studies for subsequent use by the Group. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PEDIATRIC ONCOLOGY GROUP MEMBERSHIP Principal Investigator & Institution: Schwartz, Cindy L.; Associate Professor; Oncology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 01-JUL-1980; Project End 31-DEC-2002 Summary: The aim of this research is to improve the treatment of childhood cancer through participation in organized clinical trials with fellow members of the Pediatric Oncology Group. In addition, we intend to expand our understanding of these diseases by collaborative laboratory investigations. Multiple projects are described which reflect the intense commitment of our faculty to work within the Pediatric Oncology Group. Our faculty are leaders of the POG commitments in ALL phenotyping, Neuropathology, Bone Tumors, Hodgkins disease, Rhabdomyosarcoma, Radiation Oncology, Bone Marrow Transplantation, Myeloid disease, Germ Cell Tumors, Late Effects of Childhood Cancer Therapy, and Multiple Drug Resistance. Pediatrics is the program that describes patient accrual and protocol activity within the division of Pediatric Oncology at Johns Hopkins under the supervision of Dr. Cindy Schwartz as POG PI. The disciplines of Radiation Oncology, Pathology, Pediatric Surgery, Orthopedic Surgery, Neurosurgery and Nursing also play a major role in patient accrual and protocol activity. In addition, Fairfax Hospital under the direction of Dr. Jay Greenberg is an active affiliate of our institution. With the limited numbers of children admitted with any single oncologic diagnosis to an individual institution, it is clear that cooperative clinical research is required if significant advances are to be made. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PEDIATRIC ONCOLOGY GROUP PARTICIPATION Principal Investigator & Institution: Pui, Ching-Hon; Acting Chairman; St. Jude Children's Research Hospital Memphis, Tn 381052794 Timing: Fiscal Year 2002; Project Start 01-JAN-1982; Project End 31-DEC-2002 Summary: We propose continued participation in the Pediatric Oncology Group (POG). Our goals are as follows: (1) to improve cure rates for children with cancer through participation in Phase I, II, and III clinical trials designed to test new agents or concepts; and (2) to participate in laboratory-based research aimed at clarifying the basis of drug resistance and pathogenetic mechanisms of childhood cancers. We are committed to Group participation because we believe: (1) that collaborative efforts are both desirable
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and necessary for study of childhood cancers, since all are relatively rare; and (2) that well-designed randomized clinical trials provide the most definitive test of efficacy and general applicability of new therapies and that pooled intellectual resources are advantageous as well. Our contribution to the Group can be categorized as follows: (1) contribution of selected patients (those with rare tumors or less common stages of other cancers, n approximately 80-100/year) to Group studies; (2) administrative and scientific leadership (e.g., disease or discipline committee chairs, and protocol coordinators); (3) provision of multiple reference laboratories (flow cytometry analyses of leukemia and solid tumors, cell bank, AML cytogenetics, pharmacokinetics/pharmacodynamics, molecular genetics of leukemia and solid tumor); (4) regular presentation of results of in-house research to the group. Since our center has an unusually large number of patients and staff (both clinical and basic), the latter contribution assumes unusual importance. We have an extensive in-house developmental therapeutics program which is independent of, but complementary to, the Group's clinical research programs. We also have extensive programs in basic research. The aim of these programs, to determine the pathogenesis of pediatric neoplasia, is expected to positively influence the Group's central goal -- curing children with cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PEDIATRIC ONCOLOGY GROUP STUDIES Principal Investigator & Institution: Mclean, Thomas W.; Pediatrics; Wake Forest University Health Sciences Winston-Salem, Nc 27157 Timing: Fiscal Year 2002; Project Start 01-APR-1991; Project End 31-DEC-2002 Summary: The overall objective of the proposed research effort is to continue work towards determining the optimum care for children with all types of cancer. The research mechanism involves participation by pediatric investigators at the Bowman Gray School of Medicine in the development and execution of collaborative multidisciplinary clinical protocols of the pediatric Oncology Group. The proposed research grant will support the continued participation of the Bowman Gray School of Medicine as a full member of the pediatric Oncology Group. Our accomplishments in the past grant period are described in detail in the proposal. Our institutional goals for the five year period of this grant include: (1) continuing our high level of patient accrual and excellent clinical contributions to the POG including our outstanding patient evaluability and protocol compliance which has merited a letter of commendation from the operations office at every 6-month analysis in the past (2) maintaining our institutional involvement in POG leukemia studies and our representation on the new ALL core committee (3) continuation and further development of our multi-disciplinary institutional commitment to POG Hodgkin's disease activities (4) a major role on the POG cytogenetics committee including optimal use of our new reference laboratory status (5) increased institutional development of late effects studies in collaboration with the POG late effects efforts (6) expansion of our efforts in neuro-oncology including increased enrollment on brain tumor studies and investigator roles on the POG brain tumor committee (7) use of in situ studies of tumor cell ploidy in collaboration with POG and other investigators (8) continued contributions to the administrative aspects of the POG. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CANCER CTR
PEDIATRIC
ONCOLOGY
GROUP--MIDWEST
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CHILDREN'S
Principal Investigator & Institution: Camitta, Bruce M.; Pediatrics; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532260509 Timing: Fiscal Year 2002; Project Start 01-JAN-1983; Project End 31-DEC-2002 Summary: The primary objective of the Midwest Children's Cancer Center is to reduce the incidence of and mortality from childhood cancers. This is approached by: 1) providing the best possible patient care (diagnostic and therapeutic; 2) education of medical and nonmedical groups as to the types of, treatments for, and availability of care for different childhood cancers; and 3) clinical and laboratory research. Investigators at the Cancer Center include specialists in pediatric oncology, surgery, orthopedic surgery, neurosurgery, radiology, radiation therapy, pathology, neurology, psychology and nursing. All new patients are discussed at a multidisciplinary Tumor Board. The children are then treated on Pediatric Oncology Group (POG) or institutional protocols. Results are analyzed and reported regularly. The purpose for the Midwest Children's Cancer Center's participation in POG are: l) to enhance the probability of achieving the above objectives by collaboration with other institutions in the design and execution of clinical protocols; and 2) to evaluate, through laboratory investigations, aspects of tumor biology which result in successful and unsuccessful therapy. Pediatric tumors are relatively rare. The POG is composed of more than 50 member institutions. By pooling resources, biologic and therapeutic studies on these uncommon tumors are facilitated. Similar collaboration permits more rapid development of new drugs. In addition, participation in a common milieu promotes dissemination of information between institutions and investigators. If all children with cancer receive the best possible care, morbidity and mortality will be minimized. The Midwest Children's Cancer Center has been a major contributor to POG by: 1) patient accrual; 2) coordination of POG protocols; 3) institutional pilot studies that were advanced to POG studies; and 4) participation in POG disease and administrative committees. In the next grant period we will continue each of these activities. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PEDIATRIC ONCOLOGY GROUP--THE CAROLINAS CONSORTIUM Principal Investigator & Institution: Barredo, Julio C.; Professor; Pediatrics; Medical University of South Carolina P O Box 250854 Charleston, Sc 29425 Timing: Fiscal Year 2002; Project Start 15-JUN-1996; Project End 31-DEC-2002 Summary: (Adapted from the applicant's description): The institutions included in this proposal have been part of the Pediatric Oncology Group (POG) and received good performance scores during the past five years. There are two primary goals of this proposed research; the first is to accrue patients to the Group clinical trials in order to determine the optimal care of children with all types of cancers. The second is to contribute scientific expertise to the Group in areas of both patient care and tumor biology. This proposed research will allow participation in POG activities through a consortium effort of East Carolina University (ECU) School of Medicine, Carolinas Medical Center, Medical University of South Carolina (MUSC), Greenville Hospital, Presbyterian Hospital, and Memorial Mission Hospital (The Carolinas' Consortium). In addition to these clinical activities, their scientific efforts in next five years will include: (1) development of new protocols for the treatment of children with cancer focusing mainly on pediatric lymphomas; (2) expansion of studies of minimal marrow residual disease (using RT-PCR analysis) and assessment of new purging techniques in
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Chronic Myelogenous Leukemia
neuroblastoma; (3) participation in the laboratory evaluation of folylpolyglutamate synthetase (FPGS) in lymphoblasts of newly diagnosed patients; and (4) evaluation of the role hematopoietic growth factors in the treatment of pediatric malignancies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: POSTTRANSCRIPTIONAL MESSENGER RNA
REGULATION
OF
ONCOGENE
Principal Investigator & Institution: Brewer, Gary A.; Professor; Molecular Genetics & Microbiol; Univ of Med/Dent Nj-R W Johnson Med Sch Robert Wood Johnson Medical Sch Piscataway, Nj 088545635 Timing: Fiscal Year 2002; Project Start 01-JUL-1990; Project End 30-NOV-2006 Summary: (provided by applicant): Our major goal is to understand how the levels of mRNAs encoding cytokines and oncoproteins are regulated, because sustained synthesis of these gene products can favor cell growth rather than differentiation, a hallmark of the neoplastic phenotype. Many cytokine and proto-oncogene mRNAs exhibit extremely short half-lives which limits their use as templates for translation. Moreover, the half-lives of their mRNAs are frequently subject to regulatory control. Their decay is controlled in part by A+U-rich elements (AREs) located in the 3'-UTR. AREs target mRNAs for rapid degradation usually via a sequential, 3'-to-5' pathway involving rapid removal of the poly(A) tract followed by degradation of the mRNA body. Candidate 3'-5' activities include a deadenylase, such as PARN; the exosome, which is a large complex of exoribonucleases; and the proteasome, which appears to possess an ARE-specific ribonuclease activity. We are interested in why and how AREs target mRNAs for rapid degradation and what factors are involved in this process. Toward these ends, we utilized a previously described cell-free mRNA decay system, which reconstitutes cellular decay processes, to biochemically dissect the degradation machinery. We identified and purified the ARE-binding factor AUF1 from K562 cells, a human chronic myeloid leukemia cell line Ectopic expression of AUF1 reverses the inactivation of ARE-directed mRNA decay in hemin-treated K562 cells, supporting an in vivo role for AUF1 in mRNA destabilization. In cells AUF1 exists in complexes with other cellular proteins, such as the translation initiation factor eIF4G, the hspfhsc7O heat shock proteins, and poly(A)binding protein. AUF1 is also ubiquitinated. Under the stress of cell culture at elevated temperatures, heat shock proteins like hsp7O may prevent AUF1 from recruiting the mRNP to both the ubiquitin-proteasome pathway and ribonucleolytic degradation activities resulting in stabilization of ARE-mRNAs. Thus, our central hypothesis is that binding of AUF1 to an ARE promotes the assembly of an mRNA-protein complex that recruits the proteasome and ribonucleolytic activities to the mRNA for its destruction. We plan to utilize our cell-free mRNA decay system along with the reagents and expertise gained from our studies of AUF1 so far to further test, validate, refine, and if necessary, modify our central hypothesis of AUF1 function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PRESENILINS IN TUMORIGENESIS AND NEURODEGENERATION Principal Investigator & Institution: Zheng, Hui; Associate Professor; Center on Aging; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2004; Project Start 20-APR-2000; Project End 31-JAN-2008 Summary: (provided by applicant): Mammalian presenilins consist of two homologous proteins: PS1 and PS2. They are indispensable for the proteolytic processing of a variety of substrates including Notch and the amyloid precursor protein (APP), molecules that
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play critical roles in cell fate determination and Alzheimer's disease (AD) pathogenesis, respectively. In addition, PS1 associates with beta-catenin---a multi-functional protein involved in cell adhesion, Wnt signaling and tumorigenesis. The original application was aimed at investigating the role of PS 1-beta-catenin pathway in skin tumorigenesis and dissecting the PSI-mediated activities in vivo. We have achieved all of our objectives within the grant-funding period. We reported that PS 1 facilitates beta-catenin turnover. As such, loss of PS 1 is associated with enhanced beta-catenin signaling, activation of its downstream target cyclin D1, accelerated cell proliferation and skin tumorigenesis in mice. Using our novel human PS1 "rescue" system in which expression of wild-type PSI could rescue the mouse PS1 null lethal phenotype, we established that a) PS 1 in Notch processing and beta-catenin interaction can be genetically and functionally uncoupled; and b) Aspartate 257 of PS 1 is critical for Notch and APP proteolysis, thus providing strong support that these two pathways are mediated through the same mechanisms. Two important findings emerged during the course of the study: a) We discovered a widespread role of presenilins in regulating cell proliferation and tumorigenesis: Presenilin deficiency leads to age-dependent myeloproliferative defect indicative of human chronic myelogenous leukemia (CML). Investigating the nature of the defect and determining the molecular mechanisms of presenilins in hematopoiesis is one of the research topics of the current application; b) We established a potent and specific regulation of cyclin D1 by presenilins in both mitotic cells and developing neurons. This observation, combined with the fact that activation of cyclin D1 is an early marker in degenerating neurons of AD patients, leads to an appealing hypothesis that compromised presenilin function, by genetic or environmental insults could result in deregulation of cyclin D1 and unscheduled cell cycle re-entry, with the outcome of neoplasia in peripheral tissues and neurodegeneration in the central nervous system. This competitive renewal is aimed at experimental approaches to test this hypothesis using our powerful mouse genetic systems. The studies combined will significantly advance our understanding of the molecular mechanisms underlying presenilin activities in tumorigenesis, neurodegeneration and AD pathogenesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PROGRESSION OF CHRONIC MYELOGENOUS LEUKEMIA Principal Investigator & Institution: Dessain, Scott K.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 01-JUL-2000; Project End 31-AUG-2002 Summary: (Applicant's Description): A career development award will provide the opportunity to obtain in depth training and experience in the essentials of cancer and hematology research. The proposed training involves didactic study, professional meetings, and collaborations with leaders in the fields of cancer and leukemia research. The goal of the research plan is to provide an opportunity to learn basic techniques in the study of cancer and malignant hematologic diseases, to learn to think creatively and analytically, and to develop the skills necessary to develop a successful independent research program. The combination of Dr. Robert A. Weinberg as a primary sponsor and Dr. George Q. Daley as a co-sponsor will provide outstanding mentorship. Dr. Weinberg has an established record of training outstanding investigators. Dr. Daley has a strong background in the study of human leukemias and as a clinical hematologist he provides an excellent role model of a physician-scientist. The educational opportunities and the resources that the Whitehead Institute for Biomedical Research provides are outstanding, and will complement the strong mentorship of Dr. Weinberg and Dr. Daley. The proposed research seeks to explain the clinical course of chronic
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Chronic Myelogenous Leukemia
myelogenous leukemia (CML). CML initially manifests as a clinically manageable chronic phase disease, characterized by a hyperproliferation of relatively normal cells. CML inevitably progresses to blast phase, a virtually u n t reatable acute leukemia. The genetic changes responsible for the progression to blast are unknown. The Weinberg laboratory has recently developed a model for cooperating oncogenes in human cells, demonstrating that primary human cells can be transformed by the combination of a viral oncogene, a ras oncogene, and the t e l o merase gene. This experimental system yields a model of human carcinogenesis that can be used to formulate a number of specific, testable hypotheses that may explain the progression of chronic phase CML to blast phase. Building on the observation that human chronic phase and blast phase cells engraft differently in the immunocompromised NOD/SCID mouse, hypotheses regarding the progression of chronic phase CML can be tested in vivo. The first two parts of the research address the role of telomerase in the natural history of CML. The second two parts explore the role of oncogenes in the pathogenesis of blast phase CML and attempt to build a multi-step model to explain the progression of chronic phase CML to blast phase. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: RESISTANCE OF CML STEM CELLS TO STI571 (GLEEVEC) Principal Investigator & Institution: Bhatia, Ravi; City of Hope/Beckman Research Institute Helford Building Duarte, Ca 910103000 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2007 Summary: (provided by applicant): Chronic myelogenous leukemia (CML) results from malignant transformation of a hematopoietic stem cell. Malignant cells in CML are characterized by the t (9; 22) translocation resulting in the BCR/ABL gene rearrangement. The BCR/ABL protein has constitutively activated protein-tyrosine kinase activity, which is essential for transformation in CML. STI571 (STI, Gleevec), an inhibitor of the BCR/ABL tyrosine kinase, has shown a high degree of activity in all stages of CML in early clinical studies. However, a significant proportion of patients treated with STI do not achieve cytogenetic responses. Moreover, for patients who achieve cytogenetic responses following STI therapy, it is not known whether responses to STI will be durable and result in prolongation of survival. Our preliminary studies indicate that persistent BCR/ABL positive progenitor cells can be detected even in responsive patients in complete cytogenetic remission, indicating that they may be at risk for relapse. We hypothesize that lack of cytogenetic response to STI treatment will correlate with in vitro observations of reduced inhibition of leukemic progenitor growth and reduced suppression of BCR/ABL activated signaling mechanisms by STI. We further hypothesize that the burden of persistent malignant progenitors in patients in cytogenetic response following STI treatment will predict for durability of response. We will determine the relationship between cytogenetic response or lack of response to STI treatment and laboratory assessments of STI-induced inhibition of leukemic progenitor growth and BCR/ABL signaling activities (Specific Aim 1). Development of predictors of non-responsiveness may allow upfront identification of patients requiring alternative treatment approaches. We will also determine the relationship between persistent malignant progenitors in patients with cytogenetic responses to STI and durability of response and risk of relapse, and investigate mechanisms underlying persistence of malignant progenitors (Specific Aim 2). These studies will determine the efficacy of STI in targeting malignant primitive hematopoietic progenitors and may lead to the development of surrogate markers for long-term response. The long-term goal of these
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studies is to allow optimal use of STI, alone or in combination, in the treatment of CML and improve overall outcomes of treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ROLE LEUKEMOGENESIS
OF
RNA-BINDING
PROTEINS
IN
BCR/ABL
Principal Investigator & Institution: Perrotti, Danilo; Comprehensive Cancer Center; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2003; Project Start 15-AUG-2003; Project End 31-JUL-2007 Summary: (provided by applicant): Shuttling hnRNPs control the fate of eukaryotic mRNAs throughout their journey from the active site of transcription to that of translation; thus, gain or loss of their function in hematopoietic cells might result in altered hematopoiesis and/or emergence of leukemia. In BCR/ABL-expressing cells, there is a marked increase in the levels of different RNA binding proteins including FUS, hnRNP A1, hnRNP E2 and hnRNP K, four shuttling hnRNPs involved in the regulation of mRNA biogenesis, processing, nuclear export, and translation. Ectopic expression and/or inhibition of the activity of FUS, hnRNP A1 and hnRNP E2 affects the proliferation, survival, and differentiation of normal and BCR/ABL-expressing cells, suggesting that enhanced expression/activity of certain RNA-binding proteins plays an important but as yet unrecognized role in BCR/ABL leukemogenesis. Thus, the objective of this proposal is: 1) To investigate the mechanisms regulating hnRNP E2 and hnRNP A1 expression/function in BCR/ABL-expressing cells. 2) To identify hnRNP A1 and hnRNP E2-associated mRNAs encoding proteins differentially expressed in CMLblast crisis and CML-chronic phase cells. 3) To determine the BCR/ABL-dependent mechanisms regulating the expression/function of hnRNP K and determine whether hnRNP K function(s) is(are) required for BCR/ABL-induced leukemogenesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SEQUENCE CHROMOSOMES
BASED
FISH
ANALYSIS
OF
PHILADELPHIA
Principal Investigator & Institution: Knoll, Joan H.; Children's Mercy Hosp (Kansas City, Mo) 2401 Gillham Rd Kansas City, Mo 64108 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2004 Summary: (provided by applicant) One of the most prevalent abnormalities in leukemia patients, the Philadelphia chromosome, a translocation of the ABL1 oncogene on chromosome 9 to the BCR gene on chromosome 22, occurs in adult chronic myelogenous leukemia and childhood acute chronic leukemia. In addition to the translocation, the commercial ES-probe used in clinical cytogenetics laboratories sometimes detects deletions of DNA sequences upstream of the ABL1 gene on the derivative 9 chromosome (in 1/10 to 1/3 of patients). These deletions appear to be prognostic for early blast crisis. We hypothesize that these deletions result in hemizygosity of additional genes adjacent to ABLI. These deletion breakpoints can be refined with high- resolution fluorescence in situ studies (scFISH), which uses short single copy (sc) DNA probes designed from the draft genome sequence. Chromosomal preparations of patient specimens diagnosed with Philadelphia chromosomes in clinical cytogenetic laboratories will be analyzed with these probes. ScFISH, which has been developed in our laboratories, provides an unprecedented level of resolution for delineating sequences associated with inherited chromosomal rearrangements by FISH (Rogan, Cazcarro, Knoll, 2001; Knoll, Cazcarro, Rogan, 2000). We have developed and
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Chronic Myelogenous Leukemia
validated single copy DNA probes (quickly and without cloning) for FISH analysis of more than 20 distinct chromosomal regions. We aim (1) to develop scFISH probes for ABL1 oncogene, BCR and their adjacent regions from the draft genome sequence and verify their locations by FISH; (2) to compare results with scFISH probes to those obtained using the commercially available ES-probes for t(9;22) on the same patient specimens; and (3a) to categorize cytogenetically positive t(9;22) into molecular subgroups based on the sizes of deletion centromeric to ABL1 and the breakpoints within the BCR gene, (3b) to determine if there are preferential sites of breakage on chromosome 9 adjacent to ABL1, and to localize these sites. In contrast with scFISH probes, commercial reagents detecting this translocation routinely used in clinical laboratories comprise large multigenic segments. We anticipate that both the commercial and scFISH probes will detect the chromosomal translocation in some patients, however, only the scFISH probes are expected to delineate deletions in sequences immediately adjacent to ABL 1, and to distinguish the major and minor sites of breakage in the BCR gene that correspond to chronic myelogenous leukemia and acute lymphocytic leukemia, respectively. The proposed study will delineate the chromosomal regions that undergo breakage in these types of leukemia and will establish whether there are common deletion breakage intervals on the translocated chromosome 9. Our long range goal is to classify patients based on the sites of translocation and deletion size, and then to determine if the disease complications can be attributed to the loss of specific genes adjacent to ABL1. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SIGNALING PATHWAYS UTILIZED BY V-ABL AND BCR-ABL Principal Investigator & Institution: Calame, Kathryn L.; Professor; Microbiology; Columbia University Health Sciences Po Box 49 New York, Ny 10032 Timing: Fiscal Year 2002; Project Start 20-JAN-1999; Project End 31-DEC-2003 Summary: Mutant forms of the Abelson tyrosine kinase, v-Abl and BCR-ABL, cause malignant transformation in many mammalian species including humans. Understanding the signaling paths utilized by v-Abl and BCR-ABL is key to understanding the mechanisms by which they cause malignancy. The goal of this Program Project is to study three particular aspects of signaling by v-Abl and BCR-ABL. Project #1, led by Dr. Stephen Goff, will study the role of a newly discovered Ablbinding protein, Abi-l is probably important in early signaling events which link Abl tyrosine kinase activity to downstream effectors which link Abl tyrosine activity to downstream effectors, particularly Ras. Project #2 led by Dr. Paul Rothman, will determine the role of the recently discovered activation of Janus kinases (Jaks) by v-Abl. Jaks represent an alternative signaling path, utilized by normal cytokines, which may be important for Abl transformation. Project #3, led by Dr. Kathryn Calame will study recently discovered connections between regulation of cell cycle and V- Abl including vAbl dependent induction of cyclin D mRNA, v-Abl-dependent decrease in p27 protein and p53-dependent inhibition of v-Abl transformation. In each of these projects the molecular mechanisms and functional importance for Abl-dependent transformation of different signaling pathways will be determined. The projects will be supported by three scientific cores and one administrative core. The first Core will provide standardized virus stocks, monoclonal antibodies and Abelson transformed cell lines to all projects. The second Core will provide care and breeding of mice nullizygous for genes involved in the pathways under study. The third Core will supply primary cells from patients with Chronic Myelogenous Leukemia to individual projects, supported by the Cores, will be shared among the projects so that collaborative experiments can be performed to
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determine how signaling by each of the pathways under study is related to the others. The knowledge gained by this Program Project will not improve our understanding of Abelson-dependent transformation but will also help us understand general mechanisms of oncogenesis and signal transduction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SPAN-XB AS AN IMMUNOLOGIC TARGET FOR CML Principal Investigator & Institution: Lim, Seah H.; Internal Medicine; Texas Tech University Health Scis Center Health Sciences Center Lubbock, Tx 79430 Timing: Fiscal Year 2004; Project Start 01-JUN-2004; Project End 31-MAY-2008 Summary: (provided by applicant): There is abundant of evidence to suggest that chronic myeloid leukemia (CML) can be modulated by the effector cells in the immune system, suggesting the potential for the use of immunotherapy for patients with CML, either as a therapy following standard treatment to maintain disease remission or as part of leukemia-specific donor lymphocyte infusion to reduce the risk of leukemia relapse after allogeneic stem cell transplant. Unfortunately the antigens suitable for this purpose are yet to be defined. We have recently found that the testicular-specific antigen, SPAN-Xb, is aberrantly expressed by leukemia cells from CML patients. We have also found that in these patients, high IgG directing at SPAN-Xb protein could be detected in the serum. We have generated a recombinant SPAN-Xb protein and murine MoAbs against the protein. We have also demonstrated that SPAN-Xb recombinant protein could be used to induce HLA-A2-restricted CTLs from a healthy donor. These CTLs are not only SPAN-Xb-specific; they also killed fresh HLA-A2+ CML cells, providing the rationale for the present proposal. In this application, we hypothesize that SPAN-Xb is a target for immunotherapy of CML. To test this hypothesis, we will: 1. Use a combination of real time PCR and immunocytochemistry to determine the frequency and levels of SPAN-Xb gene and protein expression in CML. We will determine if there is any correlation between gene and protein expression in the CML population and also between the levels of gene and protein expression within individual patients. 2. We will serially determine any correlation between the de novo SPAN-Xb immunity and disease status of the patients. We will study HLA-A2+ SPAN-Xb+ CML patients and correlate the intensity of B- and T-cell immunity to the response to treatment. 3. We will determine the feasibility of generating SPAN-Xb-specific CTLs from healthy donors and SPAN-Xb+ CML patients with common HLA-class I phenotypes. We will characterize these CTLs in types of their phenotypes, cytokine profiles, activities against CML cells and inhibitory effect on CML colony formation. Successful completion of the proposal will therefore provide the basis for the clinical translation of SPAN-Xb. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SPECIFIC ADOPTIVE IMMUNOTHERAPY OF MALIGNANT DISEASES Principal Investigator & Institution: Greenberg, Philip D.; Professor of Medicine; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2002; Project Start 18-MAR-2002; Project End 30-NOV-2006 Summary: (provided by applicant): The antitumor activity of human T cells, as definitively demonstrated by donor lymphocyte infusions following allogeneic hematopoietic stem cell transplantation (HSCT), has provided impetus for developing T cell therapy as a modality to treat leukemia. However, identifying immunogenic antigens expressed by leukemic cells has been a major obstacle. Self-proteins
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Chronic Myelogenous Leukemia
overexpressed by cancer cells have been shown in some settings to induce T cell responses with avidity sufficient to recognize transformed cells but not normal cells which express lower levels of the protein. The best candidate self-proteins are the subset which are oncogenic and/or associated with maintenance of the malignant phenotype, as these may be indispensable to the leukemia. Two proteins, WT1 and Proteinase 3/myeloblastin (PR3/MBN), expressed by acute leukemias and CML respectively, have recently been demonstrated in animal models, and preclinical and clinical studies, to potentially fulfill criteria for oncogenicity, immunogenicity, and safety as targets. Our laboratory has extensive experience with adoptive transfer of cloned T cells, which can facilitate analysis of candidate antigens by establishing in vivo qualitative and quantitative responses not readily achieved by other means. This approach can not only help define the therapeutic potential of specifically targeting a selected antigen, but determine the possible risks and toxicities to normal tissues, and the magnitude of response that would need to be achieved by alternative approaches such as vaccination. The proposed experiments are designed to evaluate the immunogenicity of the WT1 and PR3/MBN proteins, and to determine if adoptive transfer of CD8+ CTL clones specific for these antigens can mediate an antileukemic effect without toxicity to the recipient. The specific aims are to: 1. Determine if CD8+ T cells specific for WT1 and PR3/MBN and capable of selectively recognizing leukemic cells can be isolated from an MHC diverse population of normal individuals and patients with leukemia. 2. Determine if expanded numbers of CD8+ CTL specific for immunogenic epitopes from WT1 and PR3/MBN are present in leukemic patients prior to and following HSCT. 3. Determine if the transfer of donor-derived CD8+ CTL specific for PR3/MBN into patients with CMLAP or CML-BP that has relapsed post-allogeneic HSCT is safe and can mediate an antitumor effect. 4. Determine if the transfer of donor-derived CD8+ CTL specific for WT1 into patients with AML or ALL that has relapsed post-allogeneic HSCT is safe and can mediate an antitumor effect. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SRC FAMILY TYROSINE KINASES IN TUMOR CELL SIGNALING Principal Investigator & Institution: Smithgall, Thomas E.; Associate Professor; Molecular Genetics & Biochem; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2004; Project Start 01-JUL-2004; Project End 30-JUN-2008 Summary: (provided by applicant): Bcr-Abl is the oncogenic tyrosine kinase expressed as a result of the Philadelphia translocation in chronic myelogenous leukemia (CML). Src family kinase inhibitors and dominant-negative mutants block Bcr- Abl-induced transformation of myeloid progenitor cells, strongly suggesting that Bcr-Abl cooperates with Src in CML pathogenesis. Experiments proposed here will investigate the molecular mechanisms that regulate the interaction of Bcr-Abl with Src kinases, determine whether Src kinases affect Bcr-Abl kinase activity and sensitivity to the antiCML drug STI-571 (Gleevec), and look at the genetic requirement for Src kinases in a model system for CML: Aim 1: Test the hypothesis that association with Bcr-Abl is sufficient to induce Src kinase activation. Recent data from our laboratory show that interaction with Bcr-Abl involves Src family kinase SH2 and SH3 domains, suggesting that association with Bcr-Abl may be sufficient to induce sustained Src kinase activation in vivo. Using fibroblast and myeloid cell transformation assays, we will test this idea by co-expressing Hck and Lyn with regions of Bcr-Abl previously shown to bind to these myeloid Src family members in vitro. Identification of the Bcr-Abl regions essential for Src family kinase activation will define a novel molecular surface for anti-CML drug
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design. Aim 2: Test the hypothesis that Src kinases phosphorylate Bcr-Abl in vivo and modulate its kinase activity and sensitivity to inhibition by STI-571. Preliminary data show that Src kinases directly phosphorylate the c-Abl kinase domain on the activation loop tyrosine in vitro. Bcr-Abl mutants lacking Src family kinase phosphorylation sites and selective inhibitors will be used to determine whether Src family kinases affect BcrAbl activity and sensitivity to STI-571, which selectively inhibits the inactive conformer of Abl. Aim 3: Test the genetic requirement for Src family kinases in Bcr-Abl signal transduction and STI-571 sensitivity. The transforming activity of Bcr-Abl will be assessed in hematopoietic colony-forming assays of bone marrow cells from mice lacking the three major myeloid Src family members (Hck/Lyn/Fgr), all of which interact with Bcr-Abl. Triple-knockout cells will also be used to address the requirement for Src family members in coupling Bcr-Abl to Stats and other downstream effectors as well as sensitivity to STI-571. Successful completion of these studies will provide strong validation of myeloid-specific Src kinases as targets for second-generation anti-CML drug development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: STAT ACTIVATION IN LEUKEMIAS Principal Investigator & Institution: Zuckerman, Kenneth S.; Professor; Internal Medicine; University of South Florida 4202 E Fowler Ave Tampa, Fl 33620 Timing: Fiscal Year 2002; Project Start 01-FEB-2001; Project End 31-JAN-2006 Summary: (Applicant's Abstract) The first purpose of this project is to understand the molecular mechanisms responsible for the constitutive activation of the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signal transduction pathways in some cases of acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myelogenous leukemia (CML). The second purpose of this project is to determine the importance of constitutive JAK2/STAT5 activation in development and maintenance of the leukemic phenotype, both in vitro and in vivo. The primary hypotheses being tested are that specific activating mutations that lead to constitutive activation of JAK/STAT signal transduction pathways are responsible for the development and/or maintenance of leukemic cell survival and proliferation, and that, in leukemic cells expressing constitutively activated STAT5, inhibition of STAT5 activation or function. Three specific aims are proposed to test these hypotheses. Specific Aim 1 is to determine the mechanism(s) of constitutive activation in the HEL/Dami and Meg-01 human leukemic cell lines. Specific Aim 2 is to determine whether constitutive JAK/STAT signaling pathway activation plays an important role in maintenance of the leukemic phenotype of primary human AML cells. Specific Aim 3 is to determine the ability of double-stranded "decoy" oligonucleotides containing the STAT5 binding domain to inhibit the unregulated survival and proliferation of leukemic cells in vivo. The models to be tested include: (1) human HEL/Dami and Meg-01 cell lines implanted in sublethally irradiated NOD/SCID mice; (2) tet-off bcr/abl transgenic mice, which develop leukemia when mice are deprived of tetracycline in their drinking water (obtained from Dan Tenen); and (3) mice transplanted with bone marrow cells transfected with TEL/JAK2 or TEL/ABL retroviruses, which result in development of leukemias that have constitutively activated STAT5. These studies should lead to new understanding approaches for treatment of leukemias in which STAT activation plays a role in maintenance of the leukemic phenotype. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Chronic Myelogenous Leukemia
Project Title: STUDIES OF BCR/ABL LEUKEMOGENESIS IN MICE Principal Investigator & Institution: Van Etten, Richard A.; Director, Hematologic Malignancies; Cbr Institute for Biomedical Research 800 Huntington Ave Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2006 Summary: (Adapted from the investigator's abstract) The human Philadelphia (Ph) chromosome-positive leukemias, including chronic myeloid leukemia (CML) and B-cell acute lymphoblastic leukemia, are among the most common hematological malignancies, and current therapy for these diseases is inadequate. Expression of the product of the t(9;22) Ph chromosome, the BCR!ABL fusion gene, in the hematopoietic system of mice by generation of transgenic mice or through retroviral transduction and transplantation of bone marrow has demonstrated that BCR/ABL is a leukemia specific oncogene and the direct cause of CML. The long term objective of this application is a more complete molecular and genetic understanding of the pathophysiology of human Ph-positive leukemias, particularly the myeloproliferative disease CML. These goals will be accomplished by the use of a retroviral bone marrow infection/transplantation mouse model system that accurately and quantitatively models both human CML and Ph-positive B-lymphoid leukemia, and will have two Specific Aims. In the first Aim, the signaling pathways important for leukemogenesis by BCR/ABL will be identified by testing BCR/ABL mutants, by further analysis of the requirement for direct binding of the Grb2 adapter protein by the Bcr/Abl fusion protein, and through the use of mice with germline mutations in signaling molecules. In the second Aim, the bone marrow target cells that initiate the CML-like disease and B-lymphoid leukemia induced by BCR/ABL will be characterized and isolated by physical and immunological methods. These investigations will add important new information to our understanding of these leukemias, that would be difficult if not impossible to obtain from studies in vitro, in cultured cells, or in primary human CML cells. This knowledge will be valuable for improving the diagnosis and treatment of the Ph-positive leukemias. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TARGETED TREATMENT OF LEUKEMIA WITH SPECIFIC CTL CLONES Principal Investigator & Institution: Ho, William Y.; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2002; Project Start 06-SEP-2002; Project End 30-JUN-2007 Summary: (provided by applicant): Standard therapies for leukemia such as chemotherapy and hematopoietic stem cell transplantation (HSCT) have significant toxicities due their lack of specificity. Adoptive T cell immunotherapy targeting leukemia-associated antigens has the potential to selectively eliminate leukemic cells with minimal toxicity to normal tissues. Two candidate target antigens, WT1 and Proteinase 3 (PR3 or Myeloblastin), are selectively over expressed in many types of leukemias. Aims of this project include (1) to determine whether the number and function of WT1 or PR3-specific CD8+ cytotoxic T cells (CTL) in the blood of leukemia patients receiving HSCT correlate with disease remission, (2) to develop reliable and efficient methods for generating WT1 and PR3-specific CTL clones from normal donors using autologous peptide-loaded dendritic cells (DC), (3) to determine whether these clones are able to selectively inhibit the growth of leukemic but not normal cells in both in vivo and in vitro systems, (4) to initiate a Phase I clinical trial in patients with acute leukemia that has relapsed after HSCT to determine whether the transfer of donor-
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derived WT1-specific CTL clones is safe and can mediate an anti-leukemia effect, and (5) to initiate a similar Phase I trial in relapsed CML patients using PR3-specific clones. Using both WT1 and PR3-derived MHC-peptide tetramers, this proposal seeks to identify specific CTL in the blood of leukemia, patients undergoing HSCT, to isolate and expand high-avidity CTL clones from donor-derived, DC-stimulated cell lines for use in adoptive immunotherapy, and to track WT1 and PR3-specific CTL clones in the blood of patients after infusion. Clones will be assayed for safety and efficacy prior to clinical trials using in vitro colony forming assays and the NOD/SCID mouse model of leukemic engraftment. The long-term goal of this project is to determine whether the adoptive transfer of WT1 or PR3-specific CTL clones is a safe and effective treatment for leukemia. As a Research Associate at the Fred Hutchinson Cancer Research Center and Acting Instructor in the University of Washington Department of Medicine, the candidate is in an ideal environment in which to receive both didactic and practical training related to clinical investigation. In order to develop an independent career in patient-oriented translational research, the candidate will pursue ongoing coursework in clinical trial design, biostatistics, epidemiology, ethics, and the responsible conduct of research, in addition to continuing his preclinical studies and designing and implementing the Phase I clinical trials outlined in this proposal. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: THERAPY OF CML Principal Investigator & Institution: Champlin, Richard E.; Professor and Director, Bone Marrow Tran; Hematology; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 01-DEC-1989; Project End 31-MAY-2003 Summary: Eight projects and eight cores are proposed forming a translational research program with the goal of advancing the treatment of chronic myelogenous leukemia. Projects 1-3 involve 1) clinical investigation of novel chemo- and biologic therapies, 2) allogeneic blood and marrow transplantation focusing on enhancement of graft-versusleukemia and improving the therapeutic index of preparative regimen, and 3) Use of "leukemic" dendritic cells to generate autologous anti-leukemic T-cells for adoptive immunotherapy. Projects 4 and 5 are designed to improve the safety and effectiveness of allogeneic transplants for CML. The allogeneic graft-versus-leukemia effect can independently produce prolonged remissions in CML patients,b ut its efficacy is limited by the development of graft-versus-host disease. Project 4 studies the induction of GVL using lymphocytes transduced with Herpes virus thymidine kinase which renders them sensitive to the antiviral drug ganciclovir; if GVHD occurs the effectors cells can be ablated by ganciclovir treatment. In a preclinical murine model, the hypothesis that this strategy can abrogate GVHD while retaining GVL will be tested and strategies for optimally employing TK transduced donor lymphocyte infusions will be developed. Project 5 focuses on development of less toxic preparative regimens to achieve engraftment of allogeneic stem cell grafts and strategies to induce GVL without GVHD in histoincompatible recipients. Projects 6 and 7 examine the function of the bcr-abl tyrosine kinase and molecular strategies to block its transforming effects. Project 8 examines abnormalities in DNA methylation which occur in the course of CML and their significance for therapeutic intervention. Core A is for administration. Core B provides biostatistical support for the program. Core C is for minimal disease detection using fluorescence in situ hybridization (C1) or quantitative polymerase chain reaction (C2). Core D is for cell culture assays, in vitro (D1) and in a NOD-SCID murine model
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(D2). Core E provides flow cytometry support and Core F is the sample collection, processing and distribution core. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TRANSCRIPTION FACTOR REGULATION BY THE BCR/ABL ONCOGENE Principal Investigator & Institution: Calabretta, Bruno; Professor; Microbiology and Immunology; Thomas Jefferson University Office of Research Administration Philadelphia, Pa 191075587 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2007 Summary: Transcription factor regulation by the BCR/ABL oncogene Human hematological malignancies are characterized by well- defined genetic abnormalities responsible for the generation of autonomous growth signals or the aberrant transduction of these signals from the cytoplasm to the nucleus. The BCR/ABL oncoproteins, the leukemia-specific gene products of the Philadelphia chromosome (Ph1) translocation, induce and maintain the leukemic phenotype through their deregulated tyrosine kinase activity; such activity is essential for recruitment and activation of multiple pathways that transduce signals leading to growth factorindependent proliferation, inhibition of apoptosis, and altered differentiation of myeloid precursor cells. The mechanisms of activation of the cytoplasmic downstream effectors of BCR/ABL are understood in some detail, but much less is known on the pathways leading to transcription factor regulation. This application focuses on investigating the BCR/ABL-dependent pathways leading to changes in the expression of c-Myb and C/EBPalpha, two transcription factors involved in the regulation of proliferation, survival, and differentiation of hematopoietic cells. Specifically, we will: 1) Investigate mechanisms of the enhanced expression/activity of c-Myb by: a. determining sequence requirements and enzymatic pathways that regulate ubiquitination and/or proteasomedependent degradation of c-Myb in normal and BCR/ABL-expressing hematopoietic cells. b. identifying the interacting proteins promoting the ubiquitin/proteasomedependent degradation of c-Myb. c. determining whether the activity of proteins promoting c-Myb degradation is modulated in BCR/ABL-expressing cells. 2) Assessing the effects of degradation-resistant c-Myb mutants on proliferation, survival, and differentiation of hematopoietic cells. 3) Assessing leukemic samples for the presence of c-myb mutations within domains involved in protein degradation. 4) Investigating the mechanisms whereby BCR/ABL suppresses the expression of the granulocytic differentiation regulator C/EBPalpha. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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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
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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, 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
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 “chronic myelogenous leukemia” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for chronic myelogenous leukemia in the PubMed Central database: •
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A phosphatase activity present in peripheral blood myeloid cells of chronic myelogenous leukemia patients but not normal individuals alters nuclear protein binding to transcriptional enhancers of interferon-inducible genes. by Seong DC, Sims S, Johnson E, Howard OM, Reiter B, Hester J, Talpaz M, Kantarjian H, Deisseroth A.; 1990 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=296917
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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Abnormal integrin-mediated regulation of chronic myelogenous leukemia CD34 + cell proliferation: BCR /ABL up-regulates the cyclin-dependent kinase inhibitor, p27Kip, which is relocated to the cell cytoplasm and incapable of regulating cdk2 activity. by Jiang Y, Zhao RC, Verfaillie CM.; 2000 Sep 12; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=27060
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Calcium signaling induces acquisition of dendritic cell characteristics in chronic myelogenous leukemia myeloid progenitor cells. by Engels FH, Koski GK, Bedrosian I, Xu S, Luger S, Nowell PC, Cohen PA, Czerniecki BJ.; 1999 Aug 31; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=17888
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Cell lines and clinical isolates derived from Ph1-positive chronic myelogenous leukemia patients express c-abl proteins with a common structural alteration. by Konopka JB, Watanabe SM, Singer JW, Collins SJ, Witte ON.; 1985 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=397362
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Cell lines and peripheral blood leukocytes derived from individuals with chronic myelogenous leukemia display virtually identical proteins phosphorylated on tyrosine residues. by Huhn RD, Posner MR, Rayter SI, Foulkes JG, Frackelton AR Jr.; 1987 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=305098
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Clinical resistance to the kinase inhibitor STI-571 in chronic myeloid leukemia by mutation of Tyr-253 in the Abl kinase domain P-loop. by Roumiantsev S, Shah NP, Gorre ME, Nicoll J, Brasher BB, Sawyers CL, Van Etten RA.; 2002 Aug 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=125018
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Disruption of the estrogen receptor [beta] gene in mice causes myeloproliferative disease resembling chronic myeloid leukemia with lymphoid blast crisis. by Shim GJ, Wang L, Andersson S, Nagy N, Kis LL, Zhang Q, Makela S, Warner M, Gustafsson JA.; 2003 May 27; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=164509
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Interferon-alpha restores the deficient expression of the cytoadhesion molecule lymphocyte function antigen-3 by chronic myelogenous leukemia progenitor cells. by Upadhyaya G, Guba SC, Sih SA, Feinberg AP, Talpaz M, Kantarjian HM, Deisseroth AB, Emerson SG.; 1991 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=295821
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Mapping of four distinct BCR-related loci to chromosome region 22q11: order of BCR loci relative to chronic myelogenous leukemia and acute lymphoblastic leukemia breakpoints. by Croce CM, Huebner K, Isobe M, Fainstain E, Lifshitz B, Shtivelman E, Canaani E.; 1987 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=299252
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Molecular relapse in chronic myelogenous leukemia patients after bone marrow transplantation detected by polymerase chain reaction. by Sawyers CL, Timson L, Kawasaki ES, Clark SS, Witte ON, Champlin R.; 1990 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=53305
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Overlapping cDNA clones define the complete coding region for the P210c-abl gene product associated with chronic myelogenous leukemia cells containing the
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Philadelphia chromosome. by Mes-Masson AM, McLaughlin J, Daley GQ, Paskind M, Witte ON.; 1986 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=387222 •
p53 in chronic myelogenous leukemia in acute phase. by Feinstein E, Cimino G, Gale RP, Alimena G, Berthier R, Kishi K, Goldman J, Zaccaria A, Berrebi A, Canaani E.; 1991 Jul 15; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=52069
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Phosphotyrosine antibodies identify the p210c-abl tyrosine kinase and proteins phosphorylated on tyrosine in human chronic myelogenous leukemia cells. by Naldini L, Stacchini A, Cirillo DM, Aglietta M, Gavosto F, Comoglio PM.; 1986 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=367710
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Quantification of Bcr-Abl transcripts in chronic myelogenous leukemia (CML) using standardized, internally controlled, competitive differential PCR (CD-PCR). by Nagel S, Schmidt M, Thiede C, Huhn D, Neubauer A.; 1996 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=146207
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Rearrangement and amplification of c-abl sequences in the human chronic myelogenous leukemia cell line K-562. by Collins SJ, Groudine MT.; 1983 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=384135
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T cells recognizing leukemic CD34 + progenitor cells mediate the antileukemic effect of donor lymphocyte infusions for relapsed chronic myeloid leukemia after allogeneic stem cell transplantation. by Smit WM, Rijnbeek M, van Bergen CA, Fibbe WE, Willemze R, Falkenburg JH.; 1998 Aug 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=21477
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Treatment of marrow stroma with interferon-alpha restores normal beta 1 integrindependent adhesion of chronic myelogenous leukemia hematopoietic progenitors. Role of MIP-1 alpha. by Bhatia R, McGlave PB, Verfaillie CM.; 1995 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=185281
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Unresponsiveness of Primitive Chronic Myeloid Leukemia Cells to Macrophage Inflammatory Protein 1[alpha], an Inhibitor of Primitive Normal Hematopoietic Cells. by Eaves CJ, Cashman JD, Wolpe SD, Eaves AC.; 1993 Dec 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=48116
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Variable expression of the translocated c-abl oncogene in Philadelphia-chromosomepositive B-lymphoid cell lines from chronic myelogenous leukemia patients. by Konopka JB, Clark S, McLaughlin J, Nitta M, Kato Y, Strife A, Clarkson B, Witte ON.; 1986 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=323663
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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 chronic myelogenous leukemia, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “chronic myelogenous leukemia” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for chronic myelogenous leukemia (hyperlinks lead to article summaries): •
A 41-year-old woman with chronic myelogenous leukemia. Author(s): Antin JH. Source: Jama : the Journal of the American Medical Association. 2003 August 27; 290(8): 1083-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12941682
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A case of acute myeloid leukemia with t(7;11)(p15;p15) mimicking myeloid crisis of chronic myelogenous leukemia. Author(s): Kawakami K, Miyanishi S, Nishii K, Usui E, Murata T, Shinsato I, Shiku H. Source: International Journal of Hematology. 2002 July; 76(1): 80-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12138901
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A case of hypoplastic chronic myelogenous leukemia initiating with pancytopenia. Author(s): Matsuda M, Miyazato H, Ueda S, Morita Y, Sakaguchi M, Tatsumi Y, Maeda Y, Kanamaru A. Source: International Journal of Hematology. 2002 April; 75(3): 335-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11999367
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A case of myelodysplastic syndrome developed blastic crisis of chronic myelogenous leukemia with acquisition of major BCR/ABL. Author(s): Onozawa M, Fukuhara T, Takahata M, Yamamoto Y, Miyake T, Maekawa I. Source: Annals of Hematology. 2003 September; 82(9): 593-5. Epub 2003 July 24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12898186
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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 mathematical model for chronic myelogenous leukemia (CML) and T cell interaction. Author(s): Moore H, Li NK. Source: Journal of Theoretical Biology. 2004 April 21; 227(4): 513-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15038986
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A mutation conferring resistance to imatinib at the time of diagnosis of chronic myelogenous leukemia. Author(s): Roche-Lestienne C, Lai JL, Darre S, Facon T, Preudhomme C. Source: The New England Journal of Medicine. 2003 May 29; 348(22): 2265-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12773665
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A study on the incidence of ABL gene deletion on derivative chromosome 9 in chronic myelogenous leukemia by interphase fluorescence in situ hybridization and its association with disease progression. Author(s): Lee DS, Lee YS, Yun YS, Kim YR, Jeong SS, Lee YK, She CJ, Yoon SS, Shin HR, Kim Y, Cho HI. Source: Genes, Chromosomes & Cancer. 2003 July; 37(3): 291-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12759927
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A unique, complex variant philadelphia chromosome translocation in a patient with typical chronic myelogenous leukemia. Author(s): Oudat R, Khan Z, Glassman AB. Source: Archives of Pathology & Laboratory Medicine. 2001 March; 125(3): 437-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11231500
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Aberrant expression of the LHX4 LIM-homeobox gene caused by t(1;14)(q25;q32) in chronic myelogenous leukemia in biphenotypic blast crisis. Author(s): Yamaguchi M, Yamamoto K, Miura O. Source: Genes, Chromosomes & Cancer. 2003 November; 38(3): 269-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14506703
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Abnormality of c-kit oncoprotein in certain patients with chronic myelogenous leukemia--potential clinical significance. Author(s): Inokuchi K, Yamaguchi H, Tarusawa M, Futaki M, Hanawa H, Tanosaki S, Dan K. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2002 February; 16(2): 170-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11840282
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Activation of the c-Jun N-terminal kinase (JNK) signaling pathway is essential during PBOX-6-induced apoptosis in chronic myelogenous leukemia (CML) cells. Author(s): Mc Gee MM, Campiani G, Ramunno A, Nacci V, Lawler M, Williams DC, Zisterer DM. Source: The Journal of Biological Chemistry. 2002 May 24; 277(21): 18383-9. Epub 2002 February 20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11856743
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Acute lymphoblastic leukemia without the Philadelphia chromosome occurring in chronic myelogenous leukemia with the Philadelphia chromosome. Author(s): Jin Huh H, Won Huh J, Myong Seong C, Lee M, Soon Chung W. Source: American Journal of Hematology. 2003 November; 74(3): 218-20. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14587058
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Allogeneic bone marrow transplantation for chronic myelogenous leukemia: comparative analysis of unrelated versus matched sibling donor transplantation. Author(s): Weisdorf DJ, Anasetti C, Antin JH, Kernan NA, Kollman C, Snyder D, Petersdorf E, Nelson G, McGlave P. Source: Blood. 2002 March 15; 99(6): 1971-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11877268
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Allogeneic bone marrow transplantation in children with chronic myelogenous leukemia. Author(s): Sharathkumar A, Thornley I, Saunders EF, Calderwood S, Freedman MH, Doyle J. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 2002 March-April; 24(3): 215-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11990309
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Analysis of the impact of imatinib mesylate therapy on the prognosis of patients with Philadelphia chromosome-positive chronic myelogenous leukemia treated with interferon-alpha regimens for early chronic phase. Author(s): Kantarjian H, O'Brien S, Cortes J, Shan J, Giles F, Garcia-Manero G, Verstovsek S, Faderl S, Rios MB, Talpaz M. Source: Cancer. 2003 October 1; 98(7): 1430-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14508830
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Approval summary: imatinib mesylate capsules for treatment of adult patients with newly diagnosed philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase. Author(s): Johnson JR, Bross P, Cohen M, Rothmann M, Chen G, Zajicek A, Gobburu J, Rahman A, Staten A, Pazdur R. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2003 June; 9(6): 1972-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12796358
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Arsenic trioxide induces apoptosis in chronic myelogenous leukemia K562 cells: possible involvement of p38 MAP kinase. Author(s): Shim MJ, Kim HJ, Yang SJ, Lee IS, Choi HI, Kim T. Source: J Biochem Mol Biol. 2002 July 31; 35(4): 377-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12296996
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Aseptic necrosis of both femoral heads as first symptom of chronic myelogenous leukemia. Author(s): Kraemer M, Weissinger F, Kraus R, Beer M, Kunzmann V, Wilhelm M. Source: Annals of Hematology. 2003 January; 82(1): 44-6. Epub 2002 December 14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12574965
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Asymptomatic pericardial effusion in chronic myelogenous leukemia. Author(s): Kadikoylu G, Onbasili A, Barutca S, Tekten T, Bolaman Z. Source: Leukemia & Lymphoma. 2003 April; 44(4): 723-5. Erratum In: Leuk Lymphoma. 2003 July; 44(7): 1265. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12769352
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ATG as part of the conditioning regimen reduces transplant-related mortality (TRM) and improves overall survival after unrelated stem cell transplantation in patients with chronic myelogenous leukemia (CML). Author(s): Zander AR, Kroger N, Schleuning M, Finke J, Zabelina T, Beelen D, Schwerdtfeger R, Baurmann H, Bornhauser M, Ehninger G, Fauser AA, Kiehl M, Trenschel R, Ottinger HD, Bertz H, Berger J, Kolb HJ, Schaefer UW. Source: Bone Marrow Transplantation. 2003 August; 32(4): 355-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12900771
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BCR rearrangement-negative chronic myelogenous leukemia revisited. Author(s): Kurzrock R, Bueso-Ramos CE, Kantarjian H, Freireich E, Tucker SL, Siciliano M, Pilat S, Talpaz M. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2001 June 1; 19(11): 2915-26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11387365
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BCR/ABL kinase inhibition by imatinib mesylate enhances MAP kinase activity in chronic myelogenous leukemia CD34+ cells. Author(s): Chu S, Holtz M, Gupta M, Bhatia R. Source: Blood. 2004 April 15; 103(8): 3167-74. Epub 2003 December 11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15070699
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BCR/ABL: from molecular mechanisms of leukemia induction to treatment of chronic myelogenous leukemia. Author(s): Salesse S, Verfaillie CM. Source: Oncogene. 2002 December 9; 21(56): 8547-59. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12476301
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BCR/ABL-mediated increased expression of multiple known and novel genes that may contribute to the pathogenesis of chronic myelogenous leukemia. Author(s): Salesse S, Verfaillie CM. Source: Molecular Cancer Therapeutics. 2003 February; 2(2): 173-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12589034
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Bcr-Abl and inhibition of apoptosis in chronic myelogenous leukemia cells. Author(s): Fernandez-Luna JL. Source: Apoptosis : an International Journal on Programmed Cell Death. 2000 October; 5(4): 315-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11227211
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BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Author(s): Donato NJ, Wu JY, Stapley J, Gallick G, Lin H, Arlinghaus R, Talpaz M. Source: Blood. 2003 January 15; 101(2): 690-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12509383
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Bcr-Abl kinase modulates the translation regulators ribosomal protein S6 and 4E-BP1 in chronic myelogenous leukemia cells via the mammalian target of rapamycin. Author(s): Ly C, Arechiga AF, Melo JV, Walsh CM, Ong ST. Source: Cancer Research. 2003 September 15; 63(18): 5716-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14522890
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Behcet's disease in a patient with chronic myelogenous leukemia under hydroxyurea treatment: a case report and review of the literature. Author(s): Vaiopoulos G, Terpos E, Viniou N, Nodaros K, Rombos J, Loukopoulos D. Source: American Journal of Hematology. 2001 January; 66(1): 57-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11426495
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Beyond chronic myelogenous leukemia: potential role for imatinib in Philadelphianegative myeloproliferative disorders. Author(s): Cortes J, Kantarjian H. Source: Cancer. 2004 May 15; 100(10): 2064-78. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15139047
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Bilateral alveolar infiltrates in a 29-year-old man with chronic myelogenous leukemia. Author(s): Cheng SL, Kuo PH, Yang PC, Luh KT. Source: Chest. 2002 December; 122(6): 2238-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12475870
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Bilateral sensorineural hearing loss as a first symptom of chronic myelogenous leukemia. Author(s): Genden EM, Bahadori RS. Source: Otolaryngology and Head and Neck Surgery. 1995 October; 113(4): 499-501. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7567031
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Biologic and clinical aspects of autologous stem cell transplantation with mobilized peripheral blood cells in chronic myelogenous leukemia. Author(s): Frassoni F. Source: Current Oncology Reports. 2000 March; 2(2): 144-51. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11122836
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Biphenotypic blast crisis of chronic myelogenous leukemia: abnormalities of p53 and retinoblastoma genes. Author(s): Ishikura H, Yufu Y, Yamashita S, Abe Y, Okamura T, Motomura S, Nishimura J, Nawata H. Source: Leukemia & Lymphoma. 1997 May; 25(5-6): 573-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9250829
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Blastic mantle cell lymphoma developing concurrently in a patient with chronic myelogenous leukemia and a review of the literature. Author(s): Rodler E, Welborn J, Hatcher S, Unger K, Larkin E, Gumerlock PH, Wun T, Richman C. Source: American Journal of Hematology. 2004 April; 75(4): 231-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15054816
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Bone marrow cytogenetic complete remission achieved by interferon-alpha plus cytarabine ocfosfate therapy in a patient with chronic myelogenous leukemia during extramedullary blast crisis. Author(s): Gotoh A, Miyazawa K, Uchida Y, Sashida G, Kawakubo K, Kuriyama Y, Ohyashiki K. Source: International Journal of Hematology. 2002 February; 75(2): 191-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11939268
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Bone marrow features improve prognostic efficiency in multivariate risk classification of chronic-phase Ph(1+) chronic myelogenous leukemia: a multicenter trial. Author(s): Kvasnicka HM, Thiele J, Schmitt-Graeff A, Diehl V, Zankovich R, Niederle N, Leder LD, Schaefer HE. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2001 June 15; 19(12): 2994-3009. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11408494
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Bone marrow reconstitution with normal autologous cells demonstrated by VNTR analysis after allogeneic bone marrow transplantation for chronic myelogenous leukemia. Author(s): del Rosario Uriarte M, Bonomi R, Azambuja C, Seuanez HN. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1997 December; 11(12): 2213-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9447845
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Bronchiolitis obliterans organizing pneumonia in a patient with chronic myelogenous leukemia developing after initiation of interferon and cytosine arabinoside. Author(s): Patel M, Ezzat W, Pauw KL, Lowsky R. Source: European Journal of Haematology. 2001 November-December; 67(5-6): 318-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11872080
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Busulfan alone as cytoreduction before autografting for chronic myelogenous leukemia. Author(s): O'Brien SG, Goldman JM. Source: Blood. 1998 February 1; 91(3): 1091-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9446673
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Busulfan systemic exposure relative to regimen-related toxicity and acute graftversus-host disease: defining a therapeutic window for i.v. BuCy2 in chronic myelogenous leukemia. Author(s): Andersson BS, Thall PF, Madden T, Couriel D, Wang X, Tran HT, Anderlini P, de Lima M, Gajewski J, Champlin RE. Source: Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. 2002; 8(9): 477-85. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12374452
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Candida arthritis in a patient with chronic myelogenous leukemia (CML) in blastic transformation, unresponsive to fluconazole, but treated effectively with liposomal amphotericin B. Author(s): Turgut B, Vural O, Demir M, Kaldir M. Source: Annals of Hematology. 2002 September; 81(9): 529-31. Epub 2002 August 16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12373355
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Characteristics and outcome of patients with Philadelphia chromosome negative, bcr/abl negative chronic myelogenous leukemia. Author(s): Onida F, Ball G, Kantarjian HM, Smith TL, Glassman A, Albitar M, Scappini B, Rios MB, Keating MJ, Beran M. Source: Cancer. 2002 October 15; 95(8): 1673-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12365015
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Chromosomal abnormalities in Philadelphia chromosome-negative metaphases appearing during imatinib mesylate therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase. Author(s): Medina J, Kantarjian H, Talpaz M, O'Brien S, Garcia-Manero G, Giles F, Rios MB, Hayes K, Cortes J. Source: Cancer. 2003 November 1; 98(9): 1905-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14584073
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Chronic myelogenous leukemia as a paradigm of early cancer and possible curative strategies. Author(s): Clarkson B, Strife A, Wisniewski D, Lambek CL, Liu C. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2003 July; 17(7): 1211-62. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12835715
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Chronic myelogenous leukemia molecular signature. Author(s): Nowicki MO, Pawlowski P, Fischer T, Hess G, Pawlowski T, Skorski T. Source: Oncogene. 2003 June 19; 22(25): 3952-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12813469
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Chronic myelogenous leukemia shapes host immunity by selective deletion of highavidity leukemia-specific T cells. Author(s): Molldrem JJ, Lee PP, Kant S, Wieder E, Jiang W, Lu S, Wang C, Davis MM. Source: The Journal of Clinical Investigation. 2003 March; 111(5): 639-47. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12618518
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Chronic myelogenous leukemia with e13a3 (b2a3) type of BCR-ABL transcript having a DNA breakpoint between ABL exons a2 and a3. Author(s): Liu LG, Tanaka H, Ito K, Kyo T, Ito T, Kimura A. Source: American Journal of Hematology. 2003 December; 74(4): 268-72. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14635208
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Chronic myelogenous leukemia with p190BCR-ABL expression: the missing link with monocytosis. Author(s): Ohtake S. Source: Intern Med. 2002 December; 41(12): 1092-3. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12521192
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Chronic myelogenous leukemia. Author(s): O'Dwyer ME. Source: Current Opinion in Oncology. 2003 January; 15(1): 10-5. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12490756
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Chronic myelogenous leukemia. Author(s): Druker BJ, O'Brien SG, Cortes J, Radich J. Source: Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program. 2002; : 111-35. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12446421
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Chronic myelogenous leukemia: a review and update of therapeutic strategies. Author(s): Garcia-Manero G, Faderl S, O'Brien S, Cortes J, Talpaz M, Kantarjian HM. Source: Cancer. 2003 August 1; 98(3): 437-57. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12879460
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Chronic myelogenous leukemia: elements of conventional chemotherapy and an overview of autografting in the treatment of the chronic phase. Author(s): Lauta VM. Source: Medical Oncology (Northwood, London, England). 2003; 20(2): 95-116. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12835513
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Clinical course of thrombocytopenia in patients treated with imatinib mesylate for accelerated phase chronic myelogenous leukemia. Author(s): van Deventer HW, Hall MD, Orlowski RZ, Mitchell BS, Berkowitz LR, Hogan C, Dunphy CH, Koehler J, Shea TC. Source: American Journal of Hematology. 2002 November; 71(3): 184-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12410573
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Clinical relevance of VEGF receptors 1 and 2 in patients with chronic myelogenous leukemia. Author(s): Verstovsek S, Lunin S, Kantarjian H, Manshouri T, Faderl S, Cortes J, Giles F, Albitar M. Source: Leukemia Research. 2003 July; 27(7): 661-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12681367
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Clonal dominance of chronic myelogenous leukemia is associated with diminished sensitivity to the antiproliferative effects of neutrophil elastase. Author(s): El-Ouriaghli F, Sloand E, Mainwaring L, Fujiwara H, Keyvanfar K, Melenhorst JJ, Rezvani K, Sconocchia G, Solomon S, Hensel N, Barrett AJ. Source: Blood. 2003 November 15; 102(10): 3786-92. Epub 2003 July 31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12893759
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Complete cytogenetic and molecular responses to interferon-alpha-based therapy for chronic myelogenous leukemia are associated with excellent long-term prognosis. Author(s): Kantarjian HM, O'Brien S, Cortes JE, Shan J, Giles FJ, Rios MB, Faderl SH, Wierda WG, Ferrajoli A, Verstovsek S, Keating MJ, Freireich EJ, Talpaz M. Source: Cancer. 2003 February 15; 97(4): 1033-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12569603
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Complete remission from chronic myelogenous leukemia--blastic crisis caused by reduced intensity stem cell transplantation following partial remission due to imatinib. Author(s): Myojo T, Hino N. Source: Intern Med. 2004 February; 43(2): 126-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15005255
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Constitutively activated phosphatidylinositol 3-kinase primes platelets from patients with chronic myelogenous leukemia for thrombopoietin-induced aggregation. Author(s): Kubota Y, Tanaka T, Ohnishi H, Kitanaka A, Okutani Y, Taminato T, Ishida T, Kamano H. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2004 June; 18(6): 1127-37. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15085152
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Contribution to the study of periodic chronic myelogenous leukemia. Author(s): Pujo-Menjouet L, Mackey MC. Source: Comptes Rendus Biologies. 2004 March; 327(3): 235-44. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15127894
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Cutaneous sclerosing extramedullary hematopoietic tumor in chronic myelogenous leukemia. Author(s): Lane JE, Walker AN, Kulharya A, Marzec T. Source: Journal of Cutaneous Pathology. 2002 November; 29(10): 608-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12453299
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Decreases in Ikaros activity correlate with blast crisis in patients with chronic myelogenous leukemia. Author(s): Nakayama H, Ishimaru F, Avitahl N, Sezaki N, Fujii N, Nakase K, Ninomiya Y, Harashima A, Minowada J, Tsuchiyama J, Imajoh K, Tsubota T, Fukuda S, Sezaki T, Kojima K, Hara M, Takimoto H, Yorimitsu S, Takahashi I, Miyata A, Taniguchi S, Tokunaga Y, Gondo H, Niho Y, Harada M, et al. Source: Cancer Research. 1999 August 15; 59(16): 3931-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10463586
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Deletion of BCR region 3' in chronic myelogenous leukemia. Author(s): Gonzalez FA, Anguita E, Mora A, Asenjo S, Lopez I, Polo M, Villegas A. Source: Cancer Genetics and Cytogenetics. 2001 October 1; 130(1): 68-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11672777
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Delphi-panel analysis of appropriateness of high-dose therapy and bone marrow transplants in chronic myelogenous leukemia in chronic phase. Author(s): Gale RP, Park RE, Dubois RW, Herzig GP, Hocking WG, Horowitz MM, Keating A, Kempin S, Linker CA, Schiffer CA, Wiernik PH, Weisdorf DJ, Rai KR. Source: Leukemia Research. 1999 September; 23(9): 817-26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10475621
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Demonstration of Philadelphia chromosome negative abnormal clones in patients with chronic myelogenous leukemia during major cytogenetic responses induced by imatinib mesylate. Author(s): O'Dwyer ME, Gatter KM, Loriaux M, Druker BJ, Olson SB, Magenis RE, Lawce H, Mauro MJ, Maziarz RT, Braziel RM. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2003 March; 17(3): 481-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12646934
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Dendritic cell vaccination for patients with chronic myelogenous leukemia. Author(s): Takahashi T, Tanaka Y, Nieda M, Azuma T, Chiba S, Juji T, Shibata Y, Hirai H. Source: Leukemia Research. 2003 September; 27(9): 795-802. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12804637
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Detection and quantification of residual disease in chronic myelogenous leukemia. Author(s): Hochhaus A, Weisser A, La Rosee P, Emig M, Muller MC, Saussele S, Reiter A, Kuhn C, Berger U, Hehlmann R, Cross NC. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2000 June; 14(6): 998-1005. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10865964
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Detection of a potent humoral response associated with immune-induced remission of chronic myelogenous leukemia. Author(s): Wu CJ, Yang XF, McLaughlin S, Neuberg D, Canning C, Stein B, Alyea EP, Soiffer RJ, Dranoff G, Ritz J. Source: The Journal of Clinical Investigation. 2000 September; 106(5): 705-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10974024
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Detection of the BCR-ABL fusion gene in natural killer cells in patients with chronic myelogenous leukemia. Author(s): Min CK, Yang IH, Kim DW, Lee JW, Han CW, Min WS, Kim CC. Source: Acta Haematologica. 2000; 104(2-3): 135-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11154991
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Detection of the BCR-ABL gene by interphase fluorescence in situ hybridization (iFISH) in chronic myelogenous leukemia patients after hemopoietic stem cell transplantation: the feasibility of iFISH monitoring of therapeutic response in peripheral blood. Author(s): Lee YK, Lee DW, Kim YL, Lee S, Min CK, Kim YJ, Oh IH, Kim TG, Kim CC, Kim DW. Source: International Journal of Hematology. 2002 August; 76(2): 180-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12215018
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Development of hyperthyroidism during long term interferon therapy in a patient with chronic myelogenous leukemia: case report. Author(s): Ozet A, Ozet G, Caliskaner Z, Komurcu S, Ozturk B. Source: Endocrine Journal. 1997 October; 44(5): 715-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9466328
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Development of interferon-alpha resistant subline from human chronic myelogenous leukemia cell line KT-1. Author(s): Yamauchi H, Sakai I, Narumi H, Takeuchi K, Soga S, Fujita S. Source: Intern Med. 2001 July; 40(7): 607-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11506301
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Development of Varicella-Zoster virus infection in patients with chronic myelogenous leukemia treated with imatinib mesylate. Author(s): Mattiuzzi GN, Cortes JE, Talpaz M, Reuben J, Rios MB, Shan J, Kontoyiannis D, Giles FJ, Raad I, Verstovsek S, Ferrajoli A, Kantarjian HM. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2003 March; 9(3): 976-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12631595
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Differentiation in chronic myelogenous leukemia cell K562 by spongean sesterterpene. Author(s): Aoki S, Higuchi K, Isozumi N, Matsui K, Miyamoto Y, Itoh N, Tanaka K, Kobayashi M. Source: Biochemical and Biophysical Research Communications. 2001 March 30; 282(2): 426-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11401476
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Dissecting the molecular mechanism of chronic myelogenous leukemia using murine models. Author(s): Ren R. Source: Leukemia & Lymphoma. 2002 August; 43(8): 1549-61. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12400597
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Disseminated granuloma annulare associated with chronic myelogenous leukemia. Author(s): Jee MS, Kim ES, Chang SE, Lee MW, Koh JK. Source: The Journal of Dermatology. 2003 August; 30(8): 631-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12928535
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Disseminated Mycobacterium kansasii infection with pulmonary alveolar proteinosis in a patient with chronic myelogenous leukemia. Author(s): Goldschmidt N, Nusair S, Gural A, Amir G, Izhar U, Laxer U. Source: American Journal of Hematology. 2003 November; 74(3): 221-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14587059
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Donor lymphocyte infusion followed by interferon-alpha plus low dose cyclosporine A for modulation of donor CD3 cells activity with monitoring of minimal residual disease and cellular chimerism in a patient with first hematologic relapse of chronic myelogenous leukemia after allogeneic bone marrow transplantation. Author(s): Leda M, Ladon D, Pieczonka A, Boruczkowski D, Jolkowska J, Witt M, Wachowiak J. Source: Leukemia Research. 2001 April; 25(4): 353-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11248334
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Donor lymphocyte infusion for relapsed chronic myelogenous leukemia: prognostic relevance of the initial cell dose. Author(s): Guglielmi C, Arcese W, Dazzi F, Brand R, Bunjes D, Verdonck LF, Schattenberg A, Kolb HJ, Ljungman P, Devergie A, Bacigalupo A, Gomez M, Michallet M, Elmaagacli A, Gratwohl A, Apperley J, Niederwieser D. Source: Blood. 2002 July 15; 100(2): 397-405. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12091328
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Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Author(s): Kantarjian HM, Talpaz M, O'Brien S, Giles F, Garcia-Manero G, Faderl S, Thomas D, Shan J, Rios MB, Cortes J. Source: Blood. 2003 January 15; 101(2): 473-5. Epub 2002 September 12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12393385
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Dynamics of BCR-ABL mRNA expression in first-line therapy of chronic myelogenous leukemia patients with imatinib or interferon alpha/ara-C. Author(s): Muller MC, Gattermann N, Lahaye T, Deininger MW, Berndt A, Fruehauf S, Neubauer A, Fischer T, Hossfeld DK, Schneller F, Krause SW, Nerl C, Sayer HG, Ottmann OG, Waller C, Aulitzky W, le Coutre P, Freund M, Merx K, Paschka P, Konig H, Kreil S, Berger U, Gschaidmeier H, Hehlmann R, Hochhaus A. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2003 December; 17(12): 2392-400. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14523462
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Early treatment decisions with interferon-alfa therapy in early chronic-phase chronic myelogenous leukemia. Author(s): Sacchi S, Kantarjian HM, Smith TL, O'Brien S, Pierce S, Kornblau S, Beran M, Keating MJ, Talpaz M. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 1998 March; 16(3): 882-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9508169
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Effect of interferon-alpha therapy on bone marrow fibrosis in chronic myelogenous leukemia. Author(s): Wilhelm M, Bueso-Ramos C, O'Brien S, Pierce S, Keating M, Talpaz M, Kantarjian HM. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1998 January; 12(1): 65-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9436922
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Effect of short-term interferon therapy on the outcome of subsequent HLA-identical sibling bone marrow transplantation for chronic myelogenous leukemia: an analysis from the international bone marrow transplant registry. Author(s): Giralt S, Szydlo R, Goldman JM, Veum-Stone J, Biggs JC, Herzig RH, Klein JP, McGlave PB, Schiller G, Gale RP, Rowlings PA, Horowitz MM. Source: Blood. 2000 January 15; 95(2): 410-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10627443
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Effective and safe interferon treatment for Japanese patients with chronic myelogenous leukemia relapse after bone marrow transplantation. The Nagoya Blood and Marrow Transplantation Group. Author(s): Sao H, Kato C, Kitaori K, Adachi T, Yano K, Kobayashi M, Kojima H, Tanimoto M, Hirabayashi N, Minami S, Yamada H, Morishita GY, Morishima Y, Kodera Y. Source: International Journal of Hematology. 2000 August; 72(2): 237-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11039675
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Effects of age on prognosis with imatinib mesylate therapy for patients with Philadelphia chromosome-positive chronic myelogenous leukemia. Author(s): Cortes J, Talpaz M, O'Brien S, Giles F, Beth Rios M, Shan J, Faderl S, GarciaManero G, Ferrajoli A, Wierda W, Kantarjian H. Source: Cancer. 2003 September 15; 98(6): 1105-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12973833
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Effects of chemotherapy (busulfan-hydroxyurea) and interferon-alfa on bone marrow morphologic features in chronic myelogenous leukemia. Histochemical and morphometric study on sequential trephine biopsy specimens with special emphasis on dynamic features. Author(s): Thiele J, Kvasnicka HM, Schmitt-Graeff A, Bundschuh S, Biermann T, Roessler G, Wasmus M, Diehl V, Zankovich R, Schaefer HE. Source: American Journal of Clinical Pathology. 2000 July; 114(1): 57-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10884800
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Effects of the bcr/abl kinase inhibitors AG957 and NSC 680410 on chronic myelogenous leukemia cells in vitro. Author(s): Svingen PA, Tefferi A, Kottke TJ, Kaur G, Narayanan VL, Sausville EA, Kaufmann SH. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2000 January; 6(1): 237-49. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10656455
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Efficacy of imatinib mesylate (STI571) treatment for a patient with rheumatoid arthritis developing chronic myelogenous leukemia. Author(s): Miyachi K, Ihara A, Hankins RW, Murai R, Maehiro S, Miyashita H. Source: Clinical Rheumatology. 2003 October; 22(4-5): 329-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14576993
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Engineering dendritic cell grafts for clinical trials in cellular immunotherapy of cancer: example of chronic myelogenous leukemia. Author(s): Dietz AB, Litzow MR, Gastineau DA, Vuk-Pavlovic S. Source: Croatian Medical Journal. 2001 August; 42(4): 428-35. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11471194
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Equivalent outcomes in patients with chronic myelogenous leukemia after early transplantation of phenotypically matched bone marrow from related or unrelated donors. Author(s): Davies SM, DeFor TE, McGlave PB, Miller JS, Verfaillie CM, Wagner JE, Weisdorf DJ. Source: The American Journal of Medicine. 2001 April 1; 110(5): 339-46. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11286947
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Establishment and characterization of a novel cell line, TK-6, derived from T cell blast crisis of chronic myelogenous leukemia, with the secretion of parathyroid hormonerelated protein. Author(s): Watanabe T, Kataoka T, Mizuta S, Kobayashi M, Uchida T, Imai K, Wada H, Kinoshita T, Murate T, Mizutani S, et al. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1995 November; 9(11): 1926-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7475285
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Evidence that specific T lymphocytes may participate in the elimination of chronic myelogenous leukemia. Author(s): Molldrem JJ, Lee PP, Wang C, Felio K, Kantarjian HM, Champlin RE, Davis MM. Source: Nature Medicine. 2000 September; 6(9): 1018-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10973322
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Expression of a truncated first exon BCR sequence in chronic myelogenous leukemia cells blocks cell growth and induces cell death. Author(s): Wang Y, Liu J, Wu Y, Luo W, Lin SH, Lin H, Hawk N, Sun T, Guo JQ, Estrov Z, Talpaz M, Champlin R, Arlinghaus RB. Source: Cancer Research. 2001 January 1; 61(1): 138-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11196151
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Expression of apoptosis proteins in chronic myelogenous leukemia: associations and significance. Author(s): Ravandi F, Kantarjian HM, Talpaz M, O'Brien S, Faderl S, Giles FJ, Thomas D, Cortes J, Andreeff M, Estrov Z, Rios MB, Albitar M. Source: Cancer. 2001 June 1; 91(11): 1964-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11391574
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Expression of DNA methyltransferases DNMT1, 3A, and 3B in normal hematopoiesis and in acute and chronic myelogenous leukemia. Author(s): Mizuno S, Chijiwa T, Okamura T, Akashi K, Fukumaki Y, Niho Y, Sasaki H. Source: Blood. 2001 March 1; 97(5): 1172-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11222358
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Expression of interferon consensus sequence binding protein (ICSBP) is downregulated in Bcr-Abl-induced murine chronic myelogenous leukemia-like disease, and forced coexpression of ICSBP inhibits Bcr-Abl-induced myeloproliferative disorder. Author(s): Hao SX, Ren R. Source: Molecular and Cellular Biology. 2000 February; 20(4): 1149-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10648600
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Expression of the TEL/EVI1 fusion transcript in a patient with chronic myelogenous leukemia with t(3;12)(q26;p13). Author(s): Nakamura Y, Nakazato H, Sato Y, Furusawa S, Mitani K. Source: American Journal of Hematology. 2002 January; 69(1): 80-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11835339
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Expression of thrombopoietin and its receptor (c-mpl) in chronic myelogenous leukemia: correlation with disease progression and response to therapy. Author(s): Kaban K, Kantarjian H, Talpaz M, O'Brien S, Cortes J, Giles FJ, Pierce S, Albitar M. Source: Cancer. 2000 February 1; 88(3): 570-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10649249
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Extramedullary blast crisis in a patient with chronic myelogenous leukemia in complete cytogenetic and molecular remission on interferon-alpha therapy. Author(s): Beedassy A, Topolsky D, Styler M, Crilley P. Source: Leukemia Research. 2000 August; 24(8): 733-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10936425
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Fas-mediated modulation of Bcr/Abl in chronic myelogenous leukemia results in differential effects on apoptosis. Author(s): Selleri C, Maciejewski JP, Pane F, Luciano L, Raiola AM, Mostarda I, Salvatore F, Rotoli B. Source: Blood. 1998 August 1; 92(3): 981-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9680367
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Fatal bone marrow aplasia during interferon-a treatment in chronic myelogenous leukemia. Author(s): Chiusolo P, Sica S, Laurenti L, Piccirillo N, Giordano G, Leone G. Source: Haematologica. 2000 February; 85(2): 212. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10681733
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Favorable therapeutic index of a p210(BCR-ABL)-specific tyrosine kinase inhibitor; activity on lineage-committed and primitive chronic myelogenous leukemia progenitors. Author(s): Kasper B, Fruehauf S, Schiedlmeier B, Buchdunger E, Ho AD, Zeller WJ. Source: Cancer Chemotherapy and Pharmacology. 1999; 44(5): 433-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10501919
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Female predominance in megakaryoblastic transformation of chronic myelogenous leukemia. Author(s): Linares M, Miguel-Garcia A, Miguel-Sosa A, Garcia S, Navarro M. Source: European Journal of Haematology. 1988 April; 40(4): 375. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3163303
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Fine needle aspiration cytology of extramedullary chronic myelogenous leukemia. Author(s): Mourad WA, Sneige N, Huh YO, Katz RL, Caraway NP, Corck A, Wojcik E. Source: Acta Cytol. 1995 July-August; 39(4): 706-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7631544
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First case in Tunisia of PH1 positive chronic myelogenous leukemia in a 3 year old child. Author(s): Toumi NH, Ben Abid H, Meddeb B, Ben Othman T, Trabelsi C, Boukef K, Hafsia A. Source: Nouv Rev Fr Hematol. 1991; 33(3): 275-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1956767
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Fludarabine-mediated repair inhibition of cisplatin-induced DNA lesions in human chronic myelogenous leukemia-blast crisis K562 cells: induction of synergistic cytotoxicity independent of reversal of apoptosis resistance. Author(s): Li L, Keating MJ, Plunkett W, Yang LY. Source: Molecular Pharmacology. 1997 November; 52(5): 798-806. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9351970
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Fluorescence in situ hybridization analysis of complex translocations in two newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia patients. Author(s): Rajcan-Separovic E, Bence-Bruckler I, Wells P, Wang H. Source: Cancer Genetics and Cytogenetics. 1999 October 1; 114(1): 71-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10526539
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Fluorescence in situ hybridization for the detection and monitoring of the Ph-positive clone in chronic myelogenous leukemia: comparison with metaphase banding analysis. Author(s): Cuneo A, Bigoni R, Emmanuel B, Smit E, Rigolin GM, Roberti MG, Bardi A, Piva N, Scapoli G, Castoldi G, Van Den Berghe H, Hagemeijer A. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1998 November; 12(11): 1718-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9823946
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Fractionation of chronic myelogenous leukemia marrow cells by stroma adherence: implications for marrow purging. Author(s): Rizzoli V, Mangoni L, Piovani G, Garau D, Caramatti C, Almici C, CarloStella C. Source: Leukemia & Lymphoma. 1993; 11 Suppl 1: 109-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8251884
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Frequency of clonal B lymphocytes in chronic myelogenous leukemia evaluated by fluorescence in situ hybridization. Author(s): al-Amin A, Lennartz K, Runde V, Seeber S, Opalka B, Kloke O. Source: Cancer Genetics and Cytogenetics. 1998 July 1; 104(1): 45-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9648557
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Frequency of molecular elimination of Ph1 clone in chronic myelogenous leukemia (CML) with interferon alpha. Author(s): Henic N, Preudhomme C, Noel M, Lai J, Wetterwald M, Simon M, Fenaux P. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1996 January; 10(1): 185-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8558928
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Frequent p53 gene mutations in blast crisis of chronic myelogenous leukemia, especially in myeloid crisis harboring loss of a chromosome 17p. Author(s): Nakai H, Misawa S, Toguchida J, Yandell DW, Ishizaki K. Source: Cancer Research. 1992 December 1; 52(23): 6588-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1423304
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Functional leukemia-associated antigen-specific memory CD8+ T cells exist in healthy individuals and in patients with chronic myelogenous leukemia before and after stem cell transplantation. Author(s): Rezvani K, Grube M, Brenchley JM, Sconocchia G, Fujiwara H, Price DA, Gostick E, Yamada K, Melenhorst J, Childs R, Hensel N, Douek DC, Barrett AJ. Source: Blood. 2003 October 15; 102(8): 2892-900. Epub 2003 June 26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12829610
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Further evidence of the involvement of the c-abl oncogene in chronic myelogenous leukemia and acute lymphocytic leukemia. Author(s): Szabo P, Macera MJ, Verma RS. Source: Mol Biol Med. 1988 December; 5(3): 139-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3072467
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Gamma-IFN induced cell adhesion in chronic myelogenous leukemia cells. Author(s): Grander D, Xu B, Wang P, Einhorn S. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1994 February; 8(2): 299-304. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7905942
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Gancyclovir-induced megakaryocyte loss in chronic myelogenous leukemia post bone-marrow transplant. Author(s): Gardner L, Grosso LE. Source: American Journal of Hematology. 1996 November; 53(3): 204-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8895696
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Gangrene of the toes in a patient with chronic myelogenous leukemia after long-term hydroxyurea therapy. Author(s): Leo E, Kramer A, Hochhaus A, Krasniqi F, Hehlmann R, Ho AD. Source: Annals of Hematology. 2002 August; 81(8): 467-9. Epub 2002 August 15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12224005
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Gene therapy for chronic myelogenous leukemia (CML): a retroviral vector that renders hematopoietic progenitors methotrexate-resistant and CML progenitors functionally normal and nontumorigenic in vivo. Author(s): Zhao RC, McIvor RS, Griffin JD, Verfaillie CM. Source: Blood. 1997 December 15; 90(12): 4687-98. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9389683
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Gene therapy for chronic myelogenous leukemia. Author(s): Verfaillie CM, McIvor RS, Zhao RC. Source: Molecular Medicine Today. 1999 August; 5(8): 359-66. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10431169
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Generation of chronic myelogenous leukemia-specific T cells in cytokine-modified autologous mixed lymphocyte/tumor cell cultures. Author(s): Muller L, Provenzani C, Pawelec G. Source: Journal of Immunotherapy (Hagerstown, Md. : 1997). 2001 NovemberDecember; 24(6): 482-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11759071
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Generation of dendritic cells from patients with chronic myelogenous leukemia. Author(s): Heinzinger M, Waller CF, von den Berg A, Rosenstiel A, Lange W. Source: Annals of Hematology. 1999 April; 78(4): 181-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10348149
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Genetic alterations in the p53 gene in the blast crisis of chronic myelogenous leukemia: analysis by polymerase chain reaction based techniques. Author(s): Neubauer A, He M, Schmidt CA, Huhn D, Liu ET. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1993 April; 7(4): 593-600. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8464238
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Genetic marking shows that Ph+ cells present in autologous transplants of chronic myelogenous leukemia (CML) contribute to relapse after autologous bone marrow in CML. Author(s): Deisseroth AB, Zu Z, Claxton D, Hanania EG, Fu S, Ellerson D, Goldberg L, Thomas M, Janicek K, Anderson WF, et al. Source: Blood. 1994 May 15; 83(10): 3068-76. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7514051
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Genomic instability of microsatellite repeats and its association with the evolution of chronic myelogenous leukemia. Author(s): Wada C, Shionoya S, Fujino Y, Tokuhiro H, Akahoshi T, Uchida T, Ohtani H. Source: Blood. 1994 June 15; 83(12): 3449-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8204873
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Gleevec for the treatment of chronic myelogenous leukemia: US. Food and Drug Administration regulatory mechanisms, accelerated approval, and orphan drug status. Author(s): Cohen MH, Moses ML, Pazdur R. Source: The Oncologist. 2002; 7(5): 390-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12401900
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Glutathione depletion restores the susceptibility of cisplatin-resistant chronic myelogenous leukemia cell lines to Natural Killer cell-mediated cell death via necrosis rather than apoptosis. Author(s): Dedoussis GV, Andrikopoulos NK. Source: European Journal of Cell Biology. 2001 September; 80(9): 608-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11675936
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GM-CSF can improve the cytogenetic response obtained with interferon-alpha therapy in patients with chronic myelogenous leukemia. Author(s): Cortes J, Kantarjian H, O'Brien S, Kurzrock R, Keating M, Talpaz M. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1998 June; 12(6): 860-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9639411
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Good predictive value of combined cytogenetic and molecular follow up in chronic myelogenous leukemia after non T-cell depleted allogeneic bone marrow transplantation: a report on 38 consecutive cases. Author(s): Preudhomme C, Wattel E, Lai JL, Henic N, Meyer L, Noel MP, Cosson A, Jouet JP, Fenaux P. Source: Leukemia & Lymphoma. 1995 July; 18(3-4): 265-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8535192
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Graft vs autoimmunity following allogeneic non-myeloablative blood stem cell transplantation in a patient with chronic myelogenous leukemia and severe systemic psoriasis and psoriatic polyarthritis. Author(s): Slavin S, Nagler A, Varadi G, Or R. Source: Experimental Hematology. 2000 July; 28(7): 853-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10907647
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Graft-versus-host reaction spares normal stem cells in chronic myelogenous leukemia. Author(s): Kolb HJ, Mittermuller J, Holler E, Thalmeier K, Bartram CR. Source: Bone Marrow Transplantation. 1996 March; 17(3): 449-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8704705
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Granulocyte-colony-stimulating factor (filgrastim) may overcome imatinib-induced neutropenia in patients with chronic-phase chronic myelogenous leukemia. Author(s): Quintas-Cardama A, Kantarjian H, O'Brien S, Garcia-Manero G, Rios MB, Talpaz M, Cortes J. Source: Cancer. 2004 June 15; 100(12): 2592-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15197801
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Granulocyte-macrophage colony stimulating factor and interleukin-6 enhanced white blood cell synthesis of leukotrienes in chronic myelogenous leukemia. Author(s): el-Ahmady O, Mansour M, Kamel H, Baker A. Source: Anticancer Res. 1997 July-August; 17(4B): 3179-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9329631
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Growth inhibition of chronic myelogenous leukemia cells by ODN-1, an aptameric inhibitor of p210bcr-abl tyrosine kinase activity. Author(s): Schwartz GN, Liu YQ, Tisdale J, Walshe K, Fowler D, Gress R, Bergan RC. Source: Antisense & Nucleic Acid Drug Development. 1998 August; 8(4): 329-39. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9743470
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Growth of erythroid colonies in chronic myelogenous leukemia is independent of erythropoietin only in the presence of steel factor. Author(s): Issaad C, Vainchenker W. Source: Blood. 1994 November 15; 84(10): 3447-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7524739
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Hematologic and cytogenetic findings in eleven chronic myelogenous leukemia patients treated with imatinib mesylate at a tertiary care hospital. Author(s): Usman M, Kakepoto GN, Adil SN, Sajid R, Arain S, Khurshid M. Source: J Pak Med Assoc. 2004 January; 54(1): 17-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15058636
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Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. Author(s): Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, GambacortiPasserini C, Niederwieser D, Resta D, Capdeville R, Zoellner U, Talpaz M, Druker B, Goldman J, O'Brien SG, Russell N, Fischer T, Ottmann O, Cony-Makhoul P, Facon T, Stone R, Miller C, Tallman M, Brown R, Schuster M, Loughran T, Gratwohl A, Mandelli F, Saglio G, Lazzarino M, Russo D, Baccarani M, Morra E; International STI571 CML Study Group. Source: The New England Journal of Medicine. 2002 February 28; 346(9): 645-52. Erratum In: N Engl J Med 2002 June 13; 346(24): 1923. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11870241
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Hematopathologic and cytogenetic findings in imatinib mesylate-treated chronic myelogenous leukemia patients: 14 months' experience. Author(s): Braziel RM, Launder TM, Druker BJ, Olson SB, Magenis RE, Mauro MJ, Sawyers CL, Paquette RL, O'Dwyer ME. Source: Blood. 2002 July 15; 100(2): 435-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12091333
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Hemolytic-uremic syndrome in a patient with chronic myelogenous leukemia treated with interferon alpha. Author(s): Schlaifer D, Dumazer P, Spenatto N, Mignon-Conte M, Brousset P, Lumbroso C, Cooper M, Muller C, Huguet F, Attal M, et al. Source: American Journal of Hematology. 1994 November; 47(3): 254-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7942805
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Hepatocellular carcinoma with splenic metastasis developing after 16 years of chemotherapy for chronic myelogenous leukemia: a case report. Author(s): Katoh M, Takeuchi K, Murashima N, Nakajima M, Yamaguchi H, Endo Y, Hara M. Source: Japanese Journal of Clinical Oncology. 1994 April; 24(2): 111-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8158858
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High expression of UDP-N-acetylglucosamine: beta-D mannoside beta-1,4-Nacetylglucosaminyltransferase III (GnT-III) in chronic myelogenous leukemia in blast crisis. Author(s): Yoshimura M, Nishikawa A, Ihara Y, Nishiura T, Nakao H, Kanayama Y, Matuzawa Y, Taniguchi N. Source: International Journal of Cancer. Journal International Du Cancer. 1995 February 8; 60(4): 443-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7829256
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High-dose cladribine therapy for chronic myelogenous leukemia in the accelerated or blast phase. Author(s): Dann EJ, Anastasi J, Larson RA. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 1998 April; 16(4): 1498-504. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9552058
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Histamine excess symptoms in basophilic crisis of chronic myelogenous leukemia. Author(s): Ishii N, Murakami H, Matsushima T, Tamura J, Sawamura M, Morita K, Karasawa M, Naruse T, Kubota K, Tsuchiya J, et al. Source: J Med. 1995; 26(5-6): 235-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8721900
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Histone deacetylase inhibitor LAQ824 both lowers expression and promotes proteasomal degradation of Bcr-Abl and induces apoptosis of imatinib mesylatesensitive or -refractory chronic myelogenous leukemia-blast crisis cells. Author(s): Nimmanapalli R, Fuino L, Bali P, Gasparetto M, Glozak M, Tao J, Moscinski L, Smith C, Wu J, Jove R, Atadja P, Bhalla K. Source: Cancer Research. 2003 August 15; 63(16): 5126-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12941844
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How do antisense oligodeoxynucleotides inhibit the growth of chronic myelogenous leukemia cells? Author(s): Bergan R, Neckers L. Source: Blood. 1996 May 1; 87(9): 4019-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8611740
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Hydroxyurea-induced fever in a patient with chronic myelogenous leukemia. Author(s): Tsurumi H, Goto H, Hara T, Moriwaki H. Source: International Journal of Hematology. 2000 October; 72(3): 386-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11186000
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Hydroxyurea-induced gangrene of the toes in a patient with chronic myelogenous leukemia. Author(s): Yasuda N, Ohmori S, Usui T. Source: American Journal of Hematology. 2000 February; 63(2): 103-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10629580
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Hydroxyurea-related leg ulcers in a patient with chronic myelogenous leukemia: a case report and review of the literature. Author(s): Kato N, Kimura K, Yasukawa K, Yoshida K. Source: The Journal of Dermatology. 1999 January; 26(1): 56-62. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10063214
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Imatinib (STI571) resistance in chronic myelogenous leukemia: molecular basis of the underlying mechanisms and potential strategies for treatment. Author(s): Cowan-Jacob SW, Guez V, Fendrich G, Griffin JD, Fabbro D, Furet P, Liebetanz J, Mestan J, Manley PW. Source: Mini Reviews in Medicinal Chemistry. 2004 March; 4(3): 285-99. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15032675
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Imatinib mesylate (Glivec, Gleevec) in the treatment of chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GIST). Author(s): Hochhaus A. Source: Annals of Hematology. 2004; 83 Suppl 1: S65-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15124676
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Imatinib mesylate (STI-571) reduces Bcr-Abl-mediated vascular endothelial growth factor secretion in chronic myelogenous leukemia. Author(s): Ebos JM, Tran J, Master Z, Dumont D, Melo JV, Buchdunger E, Kerbel RS. Source: Molecular Cancer Research : Mcr. 2002 December; 1(2): 89-95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12496355
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Imatinib mesylate as treatment for blastic transformation of Philadelphia chromosome positive chronic myelogenous leukemia. Author(s): Sureda A, Carrasco M, de Miguel M, Martinez JA, Conde E, Sanz MA, DiazMediavilla J, Sierra J. Source: Haematologica. 2003 November; 88(11): 1213-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14607749
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Imatinib mesylate resistance through BCR-ABL independence in chronic myelogenous leukemia. Author(s): Donato NJ, Wu JY, Stapley J, Lin H, Arlinghaus R, Aggarwal BB, Shishodia S, Albitar M, Hayes K, Kantarjian H, Talpaz M. Source: Cancer Research. 2004 January 15; 64(2): 672-7. Erratum In: Cancer Res. 2004 March 15; 64(6): 2306. Shishodin, Shishir [corrected to Shishodia, Shishir]. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14744784
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Imatinib mesylate therapy for relapse after allogeneic stem cell transplantation for chronic myelogenous leukemia. Author(s): Kantarjian HM, O'Brien S, Cortes JE, Giralt SA, Rios MB, Shan J, Giles FJ, Thomas DA, Faderl S, De Lima M, Garcia-Manero G, Champlin R, Arlinghaus R, Talpaz M. Source: Blood. 2002 September 1; 100(5): 1590-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12176876
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Imatinib mesylate therapy improves survival in patients with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia in the chronic phase: comparison with historic data. Author(s): Kantarjian HM, O'Brien S, Cortes J, Giles FJ, Rios MB, Shan J, Faderl S, Garcia-Manero G, Ferrajoli A, Verstovsek S, Wierda W, Keating M, Talpaz M. Source: Cancer. 2003 December 15; 98(12): 2636-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14669283
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Imatinib mesylate therapy in newly diagnosed patients with Philadelphia chromosome-positive chronic myelogenous leukemia: high incidence of early complete and major cytogenetic responses. Author(s): Kantarjian HM, Cortes JE, O'Brien S, Giles F, Garcia-Manero G, Faderl S, Thomas D, Jeha S, Rios MB, Letvak L, Bochinski K, Arlinghaus R, Talpaz M. Source: Blood. 2003 January 1; 101(1): 97-100. Epub 2002 August 29. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12393600
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Immunophenotypic and genotypic characteristics of chronic myelogenous leukemia in blast crisis. Author(s): Yen CC, Liu JH, Wang WS, Fan FS, Chiou TJ, Tai CJ, Yang MH, Chao TC, Hsiao LT, Chen PM. Source: Zhonghua Yi Xue Za Zhi (Taipei). 2000 November; 63(11): 785-91. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11155753
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Impact of bone marrow morphology on multivariate risk classification in chronic myelogenous leukemia. Author(s): Kvasnicka HM, Thiele J, Schmitt-Graeff A, Diehl V, Niederle N, Schaefer HE. Source: Acta Haematologica. 2003; 109(1): 53-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12486326
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In vitro studies of the combination of imatinib mesylate (Gleevec) and arsenic trioxide (Trisenox) in chronic myelogenous leukemia. Author(s): La Rosee P, Johnson K, O'Dwyer ME, Druker BJ. Source: Experimental Hematology. 2002 July; 30(7): 729-37. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12135670
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Indirubin and meisoindigo in the treatment of chronic myelogenous leukemia in China. Author(s): Xiao Z, Hao Y, Liu B, Qian L. Source: Leukemia & Lymphoma. 2002 September; 43(9): 1763-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12685829
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Induction of apoptosis in chronic myelogenous leukemia cells through nuclear entrapment of BCR-ABL tyrosine kinase. Author(s): Vigneri P, Wang JY. Source: Nature Medicine. 2001 February; 7(2): 228-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11175855
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Insights from pre-clinical studies for new combination treatment regimens with the Bcr-Abl kinase inhibitor imatinib mesylate (Gleevec/Glivec) in chronic myelogenous leukemia: a translational perspective. Author(s): La Rosee P, O'Dwyer ME, Druker BJ. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2002 July; 16(7): 1213-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12094245
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Interferon-alpha-induced focal segmental glomerulosclerosis in chronic myelogenous leukemia: a case report and review of the literature. Author(s): Bremer CT, Lastrapes A, Alper AB Jr, Mudad R. Source: American Journal of Clinical Oncology : the Official Publication of the American Radium Society. 2003 June; 26(3): 262-4. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12796597
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Interleukin 11 May improve thrombocytopenia associated with imatinib mesylate therapy in chronic Myelogenous leukemia. Author(s): Ault P, Kantarjian H, Welch MA, Giles F, Rios MB, Cortes J. Source: Leukemia Research. 2004 June; 28(6): 613-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15120938
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Involvement of Akt kinase in the action of STI571 on chronic myelogenous leukemia cells. Author(s): Kawauchi K, Ogasawara T, Yasuyama M, Ohkawa S. Source: Blood Cells, Molecules & Diseases. 2003 July-August; 31(1): 11-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12850478
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Is another bcr-abl inhibitor needed for chronic myelogenous leukemia? Author(s): Sausville EA. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2003 April; 9(4): 1233-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12684388
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Juvenile chronic myelogenous leukemia and cytomegalovirus infection. Author(s): Ozsoylu S. Source: Am J Pediatr Hematol Oncol. 1991 Winter; 13(4): 487. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1664663
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Juvenile chronic myelogenous leukemia and neurofibromatosis in infancy presenting as ocular hemorrhage. Author(s): Shaw NJ, Eden OB. Source: Pediatric Hematology and Oncology. 1989; 6(1): 23-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2641696
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Juvenile chronic myelogenous leukemia with abnormalities of chromosomes 4 and 5. Author(s): Berg SL, Phebus CK, Wenger SL. Source: Cancer Genetics and Cytogenetics. 1990 January; 44(1): 55-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2293880
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Juvenile chronic myelogenous leukemia, neurofibromatosis 1, and xanthoma. Author(s): Jang KA, Choi JH, Sung KJ, Moon KC, Koh JK, Im DJ. Source: The Journal of Dermatology. 1999 January; 26(1): 33-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10063210
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Juvenile chronic myelogenous leukemia. Author(s): Hess JL, Zutter MM, Castleberry RP, Emanuel PD. Source: American Journal of Clinical Pathology. 1996 February; 105(2): 238-48. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8607451
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Juvenile chronic myelogenous leukemia. Author(s): Freedman MH, Estrov Z, Chan HS. Source: Am J Pediatr Hematol Oncol. 1988 Fall; 10(3): 261-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3052147
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Juvenile chronic myelogenous leukemia: differentiation from infantile cytomegalovirus infection. Author(s): Kirby MA, Weitzman S, Freedman MH. Source: Am J Pediatr Hematol Oncol. 1990 Fall; 12(3): 292-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2173439
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Juvenile chronic myelogenous leukemia: in vitro characterization before and after allogeneic bone marrow transplantation. Author(s): Zecca M, Rosti V, Pinto L, Comoli P, Carra AM, Prete L, Bonetti F, Pedrazzoli P, Locatelli F, Cazzola M. Source: Medical and Pediatric Oncology. 1995 March; 24(3): 166-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7838038
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Juvenile chronic myelogenous leukemia: report of the Italian Registry. Associazione Italiana di Ematologia Oncologia Pediatrica (AIEOP). Author(s): Arico M, Bossi G, Schiro R, Galimberti M, Longoni D, Macchia P, Miniero R, Natale D, Pession A, Pillon M, et al. Source: Haematologica. 1993 September-October; 78(5): 264-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8314153
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Juvenile chronic myelogenous leukemia: therapeutic trial with interferon alpha 2B. Author(s): Agarwal BR, Gulvady A, Joshi K, Khemani S, Currimbhoy ZE. Source: Indian Pediatrics. 1995 September; 32(9): 1002-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8935266
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Juvenile xanthogranuloma, neurofibromatosis, and juvenile chronic myelogenous leukemia. Author(s): Zvulunov A. Source: Archives of Dermatology. 1996 June; 132(6): 712-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8651728
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Juvenile xanthogranuloma, neurofibromatosis, and juvenile chronic myelogenous leukemia. World statistical analysis. Author(s): Zvulunov A, Barak Y, Metzker A. Source: Archives of Dermatology. 1995 August; 131(8): 904-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7632061
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Kaposi's sarcoma following allogeneic hematopoietic stem cell transplantation for chronic myelogenous leukemia. Author(s): de Medeiros BC, Rezuke WN, Ricci A Jr, Tsongalis G, Shen PU, Bona RD, Feingold JM, Edwards RL, Tutschka PJ, Bilgrami S. Source: Acta Haematologica. 2000; 104(2-3): 115-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11154986
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Karyotype analysis in chronic myelogenous leukemia. A three-year experience at the American University of Beirut Medical Center (AUBMC). Author(s): el-Assaad W, al-Oreibi G, Zahed L. Source: J Med Liban. 1998 January-February; 46(1): 16-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9795517
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Karyotype at relapse following allogeneic bone marrow transplantation for chronic myelogenous leukemia. Author(s): Shah NK, Wagner J, Santos G, Griffin CA. Source: Cancer Genetics and Cytogenetics. 1992 July 15; 61(2): 183-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1638501
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Karyotype evolution of Ph positive chronic myelogenous leukemia patients relapsed in advanced phases of the disease after allogeneic bone marrow transplantation. Author(s): Sessarego M, Frassoni F, Defferrari R, Bacigalupo A, Fugazza G, Mareni C, Bruzzone R, Dejana A, Ajmar F. Source: Cancer Genetics and Cytogenetics. 1991 November; 57(1): 69-78. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1756487
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Karyotypic and clinical progression in chronic myelogenous leukemia after 30 years. Author(s): Nowell PC, Finan JB, Weiss A. Source: Cancer Genetics and Cytogenetics. 1992 May; 60(1): 96-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1591715
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Karyotypic changes during the course of blastic crisis of chronic myelogenous leukemia. Author(s): Mitani K, Miyazono K, Urabe A, Takaku F. Source: Cancer Genetics and Cytogenetics. 1989 June; 39(2): 299-300. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2752380
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Kinetics of relapse of leukemia after bone marrow transplantation: cytogenetic follow up of patients with chronic myelogenous leukemia. Author(s): Heinze B, Arnold R, Kratt E, Bunjes D, Reess K, Plecity P, Heimpel H, Fliedner TM. Source: Bone Marrow Transplantation. 1991; 7 Suppl 2: 16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1878692
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Klinefelter syndrome patient with chronic myelogenous leukemia. Author(s): Adhvaryu SG, Jani KH, Balar DB, Shah PM. Source: Cancer Genetics and Cytogenetics. 1990 August 1; 48(1): 135-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2372782
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Lack of efficacy of a double autograft program to prolong survival of chronic myelogenous leukemia patients in blastic transformation. Author(s): Capria S, Vignetti M, Montefusco E, Cardillo AM, Simone F, Meloni G. Source: Haematologica. 1996 July-August; 81(4): 349-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8870382
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Late autologous transplantation in chronic myelogenous leukemia with peripheral blood progenitor cells mobilized by G-CSF and interferon-alpha. Author(s): Michallet M, Thiebaut A, Philip I, Charrin C, Vigouroux C, Thomas X, Bilger K, Belhabri A, Guyotat D, Corront B, Salles B, Dumontet C, Peaud PY, Vilque JP, Devidas A, Fiere D. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2000 December; 14(12): 2064-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11187894
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Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myelogenous leukemia. Author(s): Druker BJ, Lydon NB. Source: The Journal of Clinical Investigation. 2000 January; 105(1): 3-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10619854
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Lineage involvement by BCR/ABL in Ph+ lymphoblastic leukemias: chronic myelogenous leukemia presenting in lymphoid blast vs Ph+ acute lymphoblastic leukemia. Author(s): Anastasi J, Feng J, Dickstein JI, Le Beau MM, Rubin CM, Larson RA, Rowley JD, Vardiman JW. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1996 May; 10(5): 795-802. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8656674
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Localized lymphoid relapse in the pancreas following allogeneic hematopoietic stem cell transplant for chronic myelogenous leukemia. Author(s): Rossetti JM, Lister J, Shadduck RK, Bloom E, Geyer SJ, Caushaj PF, Homann J, Papasavas P, Cedar M. Source: Leukemia & Lymphoma. 2003 June; 44(6): 1071-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12854913
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Long term follow up after allogeneic stem cell transplantation for chronic myelogenous leukemia. Author(s): Reiter E, Greinix HT, Brugger S, Keil F, Rabitsch W, Mannhalter C, Schwarzinger I, Hocker P, Fischer G, Dieckmann K, Hinterberger W, Linkesch W, Schneider B, Lechner K, Kalhs P. Source: Bone Marrow Transplantation. 1998 December; 22 Suppl 4: S86-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9916646
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Long-template DNA polymerase chain reaction for the detection of the bcr/abl translocation in patients with chronic myelogenous leukemia. Author(s): Waller CF, Dennebaum G, Feldmann C, Lange W. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 1999 December; 5(12): 4146-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10632353
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Long-term follow-up of allogeneic bone marrow transplantation after reducedintensity conditioning in patients with chronic myelogenous leukemia in the chronic phase. Author(s): Okamoto S, Watanabe R, Takahashi S, Mori T, Izeki T, Nagayama H, Ishida A, Takayama N, Yokoyama K, Tojo A, Asano S, Ikeda Y. Source: International Journal of Hematology. 2002 June; 75(5): 493-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12095149
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Long-term survival in advanced chronic myelogenous leukemia following bone marrow transplantation from haploidentical related donors. Author(s): Bishop MR, Henslee-Downey PJ, Anderson JR, Romond EH, Marciniak E, Yankey R, Reeves M, Thompson JS. Source: Bone Marrow Transplantation. 1996 October; 18(4): 747-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8899190
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Loss of heterozygosity of NF1 gene in juvenile chronic myelogenous leukemia with neurofibromatosis type 1. Author(s): Kai S, Sumita H, Fujioka K, Takahashi H, Hanzawa N, Funabiki T, Ikuta K, Sasaki H. Source: International Journal of Hematology. 1998 July; 68(1): 53-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9713168
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Loss of imprinting in disease progression in chronic myelogenous leukemia. Author(s): Randhawa GS, Cui H, Barletta JA, Strichman-Almashanu LZ, Talpaz M, Kantarjian H, Deisseroth AB, Champlin RC, Feinberg AP. Source: Blood. 1998 May 1; 91(9): 3144-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9558368
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Low megakaryocyte ploidy in Ph-positive chronic myelogenous leukemia measured by flow cytometry. Author(s): Jacobsson S, Wadenvik H, Kutti J, Swolin B. Source: American Journal of Clinical Pathology. 1999 February; 111(2): 185-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9930139
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Lymphoid blast crisis during interferon-alpha therapy in a patient with chronic myelogenous leukemia in myeloid blast crisis. Author(s): Goto H, Tsurumi H, Hara T, Moriwaki H. Source: International Journal of Hematology. 2000 December; 72(4): 474-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11197215
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Lymphoid blast crisis of chronic myelogenous leukemia occurring more than 11 years after receiving an allogeneic bone marrow transplant for chronic myelogenous leukemia in myeloid blast crisis at onset. Author(s): Fukuno K, Tsurumi H, Yamada T, Oyama M, Matsuyama T, Terakura S, Kodera Y, Moriwaki H. Source: Bone Marrow Transplantation. 2003 February; 31(3): 211-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12621483
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Lymphoid preponderance and the absence of basophilia and splenomegaly are frequent in m-bcr-positive chronic myelogenous leukemia. Author(s): Hur M, Song EY, Kang SH, Shin DH, Kim JY, Park SS, Cho HI. Source: Annals of Hematology. 2002 April; 81(4): 219-23. Epub 2002 February 28. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11976825
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Management of molecular-targeted therapy for chronic myelogenous leukemia. Author(s): Ault P, Kaled S, Rios MB. Source: Journal of the American Academy of Nurse Practitioners. 2003 July; 15(7): 292-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12929249
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Mixed chimerism of bone marrow CD34+ progenitor cells (genotyping, bcr/abl analysis) after allogeneic transplantation for chronic myelogenous leukemia. Author(s): Thiele J, Wickenhauser C, Kvasnicka HM, Varus E, Kleppe S, Beelen DW, Schaefer UW. Source: Transplantation. 2002 October 15; 74(7): 982-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12394842
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Mixed chimerism of bone marrow vessels (endothelial cells, myofibroblasts) following allogeneic transplantation for chronic myelogenous leukemia. Author(s): Kvasnicka HM, Wickenhauser C, Thiele J, Varus E, Hamm K, Beelen DW, Schaefer UW. Source: Leukemia & Lymphoma. 2003 February; 44(2): 321-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12688352
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Molecular cytogenetic analyses of HIG, a novel human cell line carrying t(1;3)(p36.3;q25.3) established from a patient with chronic myelogenous leukemia in blastic crisis. Author(s): Hosoya N, Ogawa S, Motokura T, Hangaishi A, Wang L, Qiao Y, Nannya Y, Kogi M, Hirai H. Source: International Journal of Hematology. 2003 December; 78(5): 432-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14704036
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Molecular monitoring of the treatment of patients with BCR/ABL (+) chronic myelogenous leukemia. Author(s): Ruiz-Arguelles GJ, Lopez-Martinez B, Ramirez-Cabrera JM, Reyes-Nunez V, Rodriguez-Cedeno HM, Garces-Eisele J. Source: Revista De Investigacion Clinica; Organo Del Hospital De Enfermedades De La Nutricion. 2001 May-June; 53(3): 235-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11496711
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Monitoring the course of chronic myelogenous leukemia by fluorescence in situ hybridization. Author(s): Seong CM. Source: International Journal of Hematology. 2002 August; 76 Suppl 2: 53-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12430901
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Multicenter prospective study of interferon-alpha versus bone marrow transplantation for newly diagnosed patients with chronic myelogenous leukemia: a preliminary analysis. Author(s): Ohnishi K, Ino T, Kishimoto Y, Usui N, Shimazaki C, Ohtake S, Taguchi H, Kusumoto S, Kuriyama K, Hotta T, Ohno R. Source: Cancer Chemotherapy and Pharmacology. 2001 August; 48 Suppl 1: S59-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11587369
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Multiple sclerosis associated with interferon-alpha therapy for chronic myelogenous leukemia. Author(s): Kataoka I, Shinagawa K, Shiro Y, Okamoto S, Watanabe R, Mori T, Ito D, Harada M. Source: American Journal of Hematology. 2002 June; 70(2): 149-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12111789
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Myeloid/natural killer cell precursor blast crisis of chronic myelogenous leukemia with two Philadelphia (Ph-1) chromosomes. Author(s): Kahl C, Pelz AF, Bartsch R, Jentsch-Ullrich K, Bruckner R, Fostitsch HP, Franke A. Source: Annals of Hematology. 2001 January; 80(1): 58-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11233779
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Natural killer cell dysfunction and apoptosis induced by chronic myelogenous leukemia cells: role of reactive oxygen species and regulation by histamine. Author(s): Mellqvist UH, Hansson M, Brune M, Dahlgren C, Hermodsson S, Hellstrand K. Source: Blood. 2000 September 1; 96(5): 1961-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10961901
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NCCN Practice Guidelines for Chronic Myelogenous Leukemia. Author(s): Berman E, Clift RA, Copelan EA, Emanuel PD, Erba HP, Glenn MJ, Greenberg PL, Jones RJ, O'Brien S, Saba HI, Schilder R, Snyder DS, Soiffer RJ, Tallman MS, Wetzler M, Ravandi-Kashani F, Kantarjian H, Talpaz M; National Comprehensive Cancer Network. Source: Oncology (Huntingt). 2000 November; 14(11A): 229-40. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11195415
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Neutrophil 5-nucleotidase reaction in chronic myelogenous leukemia, myelofibrosis with myeloid metaplasia, and polycythemia vera. Author(s): Tsavaris NB, Pangalis GA. Source: Annals of Hematology. 1998 January; 76(1): 1-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9486917
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New treatment approaches for chronic myelogenous leukemia. Author(s): Faderl S, Kantarjian HM, Talpaz M, O'Brien S. Source: Seminars in Oncology. 2000 October; 27(5): 578-86. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11049024
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New variant translocation (8;20)(q22;q13) in bone marrow cells of extramedullary blast crisis in chronic myelogenous leukemia. Author(s): Harada Y, Ishi K, Shirota T, Hayashi T. Source: Cancer Genetics and Cytogenetics. 2000 March; 117(2): 167-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10704692
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Non-leukemic autologous reconstitution after allogeneic bone marrow transplantation for Ph-positive chronic myelogenous leukemia: extended remission preceding eventual relapse. Author(s): Brunstein CG, Hirsch BA, Miller JS, McGlennen RC, Verfaillie CM, McGlave PB, Weisdorf DJ. Source: Bone Marrow Transplantation. 2000 December; 26(11): 1173-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11149727
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Novel chromosomal aberrations in Philadelphia negative cells of chronic myelogenous leukemia patients on imatinib: report of three cases. Author(s): Athanasiadou A, Stavroyianni N, Saloum R, Asteriou O, Anagnostopoulos A, Fassas A. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2004 May; 18(5): 1029-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15029210
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Novel oxime derivatives of radicicol induce erythroid differentiation associated with preferential G(1) phase accumulation against chronic myelogenous leukemia cells through destabilization of Bcr-Abl with Hsp90 complex. Author(s): Shiotsu Y, Neckers LM, Wortman I, An WG, Schulte TW, Soga S, Murakata C, Tamaoki T, Akinaga S. Source: Blood. 2000 September 15; 96(6): 2284-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10979978
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Novel therapies for chronic myelogenous leukemia. Author(s): Jahagirdar BN, Miller JS, Shet A, Verfaillie CM. Source: Experimental Hematology. 2001 May; 29(5): 543-56. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11376866
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NUP98 gene rearrangements and the clonal evolution of chronic myelogenous leukemia. Author(s): Ahuja HG, Popplewell L, Tcheurekdjian L, Slovak ML. Source: Genes, Chromosomes & Cancer. 2001 April; 30(4): 410-5. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11241795
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Occurrence of a Ki-1-positive anaplastic large-cell lymphoma in a patient with Ph' positive chronic myelogenous leukemia successfully treated by alpha-interferon. Author(s): Montefusco E, Lo Coco F, Burgio VL, Rondinelli B, Di Giorgio G, Mancini M, Diverio D, Andriani A, Avvisati G, Alimena G. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1993 November; 7(11): 1896-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8231259
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Occurrence of a pulmonary carcinoid following allogeneic stem cell transplantation for chronic myelogenous leukemia: a case report. Author(s): Fiebiger W, Kurtaran A, Novotny C, Kainberger F, Dekan G, Raderer M. Source: Annals of Hematology. 2003 June; 82(6): 374-6. Epub 2003 April 29. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12719884
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Occurrence of high-grade T-cell lymphoma in a patient with Philadelphia chromosome-negative chronic myelogenous leukemia with breakpoint cluster region rearrangement: case report and review of the literature. Author(s): Djulbegovic B, Hadley T, Yen F. Source: American Journal of Hematology. 1991 January; 36(1): 63-4. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1984685
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Occurrence of T-cell lymphoma in a patient with Philadelphia chromosome-positive chronic myelogenous leukemia with rearrangements of BCR and TCR-beta genes in the lymph nodes. Author(s): Tittley P, Trempe JM, van der Jagt R, Drouin J, Huebsch L, McLeish B, Cheng G. Source: American Journal of Hematology. 1993 February; 42(2): 229-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8438886
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Old age: a sign of poor prognosis in patients with chronic myelogenous leukemia. Author(s): Kantarjian HM, Keating MJ, McCredie KB, Walters R, Talpaz M, Smith TL, Freireich EJ. Source: Southern Medical Journal. 1987 October; 80(10): 1228-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3477869
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Oral idarubicin in patients with late chronic phase chronic myelogenous leukemia or chronic myelomonocytic leukemia. Author(s): Giles FJ, Wong GC, Clark SJ, Pierce S, Kantarjian HM, Keating MJ. Source: Leukemia & Lymphoma. 2000 March; 37(1-2): 87-95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10721772
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Overlapping cDNA clones define the complete coding region for the P210c-abl gene product associated with chronic myelogenous leukemia cells containing the Philadelphia chromosome. Author(s): Mes-Masson AM, McLaughlin J, Daley GQ, Paskind M, Witte ON. Source: Proceedings of the National Academy of Sciences of the United States of America. 1986 December; 83(24): 9768-72. Erratum In: Proc Natl Acad Sci U S a 1987 April; 84(8): 2507. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3540951
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Pathologic quiz case: systemic lymphadenopathy in a patient with chronic myelogenous leukemia. Author(s): Rodriguez-Pinilla SM, Gonzalez MA, Sanchez PM. Source: Archives of Pathology & Laboratory Medicine. 2003 May; 127(5): E249-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12708924
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Pegylated recombinant interferon alpha-2b vs recombinant interferon alpha-2b for the initial treatment of chronic-phase chronic myelogenous leukemia: a phase III study. Author(s): Michallet M, Maloisel F, Delain M, Hellmann A, Rosas A, Silver RT, Tendler C; PEG-Intron CML Study Group. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2004 February; 18(2): 309-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14671645
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P-glycoprotein-mediated drug efflux is a resistance mechanism of chronic myelogenous leukemia cells to treatment with imatinib mesylate. Author(s): Illmer T, Schaich M, Platzbecker U, Freiberg-Richter J, Oelschlagel U, von Bonin M, Pursche S, Bergemann T, Ehninger G, Schleyer E. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2004 March; 18(3): 401-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14724652
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Phase II study of troxacitabine, a novel dioxolane nucleoside analog, in patients with untreated or imatinib mesylate-resistant chronic myelogenous leukemia in blastic phase. Author(s): Giles FJ, Feldman EJ, Roboz GJ, Larson RA, Mamus SW, Cortes JE, Verstovsek S, Faderl S, Talpaz M, Beran M, Albitar M, O'Brien SM, Kantarjian HM. Source: Leukemia Research. 2003 December; 27(12): 1091-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12921945
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Practical aspects of the treatment of chronic myelogenous leukemia with imatinib mesylate. Author(s): Zonder JA, Schiffer CA. Source: Curr Hematol Rep. 2003 January; 2(1): 57-64. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12901155
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Prediction of initial cytogenetic response for subsequent major and complete cytogenetic response to imatinib mesylate therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia. Author(s): Drummond MW, Holyoake TL. Source: Cancer. 2003 October 15; 98(8): 1776-7; Author Reply 1777-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14534900
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Prediction of initial cytogenetic response for subsequent major and complete cytogenetic response to imatinib mesylate therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia. Author(s): Kantarjian H, Talpaz M, O'Brien S, Giles F, Rios MB, White K, Garcia-Manero G, Ferrajoli A, Verstovsek S, Wierda W, Kornblau S, Cortes J. Source: Cancer. 2003 May 1; 97(9): 2225-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12712475
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Predictors of oral mucositis in patients receiving hematopoietic cell transplants for chronic myelogenous leukemia. Author(s): Robien K, Schubert MM, Bruemmer B, Lloid ME, Potter JD, Ulrich CM. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2004 April 1; 22(7): 1268-75. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15051775
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Predominantly BCR-ABL negative myeloid precursors in interferon-alpha treated chronic myelogenous leukemia: a follow-up study of peripheral blood colonyforming cells with fluorescence in situ hybridization. Author(s): Sick C, Schultheis B, Pasternak G, Kottke I, Horner S, Heissig B, Hehlmann R. Source: Annals of Hematology. 2001 January; 80(1): 9-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11233781
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Progressive multifocal leukoencephalopathy in a patient with chronic myelogenous leukemia. Author(s): Swamy PA, Nardino R. Source: Conn Med. 2003 May; 67(5): 263-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12802840
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Qualitative functional deficiency of affinity-purified lactoferrin from neutrophils of patients with chronic myelogenous leukemia, and lactoferrin/H-ferritin-cell interactions in a patient with lactoferrin-deficiency with normal numbers of circulating leukocytes. Author(s): Broxmeyer HE, Bicknell DC, Cooper S, Sledge G Jr, Williams DE, McGuire WA, Coates TD. Source: Pathobiology : Journal of Immunopathology, Molecular and Cellular Biology. 1991; 59(1): 26-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2043267
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Quantification of Bcr-Abl transcripts in chronic myelogenous leukemia (CML) using standardized, internally controlled, competitive differential PCR (CD-PCR). Author(s): Nagel S, Schmidt M, Thiede C, Huhn D, Neubauer A. Source: Nucleic Acids Research. 1996 October 15; 24(20): 4102-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8918822
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Quantification of residual disease in chronic myelogenous leukemia patients on interferon-alpha therapy by competitive polymerase chain reaction. Author(s): Hochhaus A, Lin F, Reiter A, Skladny H, Mason PJ, van Rhee F, Shepherd PC, Allan NC, Hehlmann R, Goldman JM, Cross NC. Source: Blood. 1996 February 15; 87(4): 1549-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8608246
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Quantitative competitive reverse transcriptase-polymerase chain reaction for BCRABL on Philadelphia-negative leukaphereses allows the selection of lowcontaminated peripheral blood progenitor cells for autografting in chronic myelogenous leukemia. Author(s): Corsetti MT, Lerma E, Dejana A, Basta P, Ferrara R, Benvenuto F, Vassallo F, Abate M, Piaggio G, Parodi C, Sessarego M, Li Pira G, Manca F, Carella AM. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1999 July; 13(7): 999-1008. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10400414
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Quantitative measure of c-abl and p15 methylation in chronic myelogenous leukemia: biological implications. Author(s): Nguyen TT, Mohrbacher AF, Tsai YC, Groffen J, Heisterkamp N, Nichols PW, Yu MC, Lubbert M, Jones PA. Source: Blood. 2000 May 1; 95(9): 2990-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10779450
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Quantitative polymerase chain reaction monitoring of BCR-ABL during therapy with imatinib mesylate (STI571; gleevec) in chronic-phase chronic myelogenous leukemia. Author(s): Kantarjian HM, Talpaz M, Cortes J, O'Brien S, Faderl S, Thomas D, Giles F, Rios MB, Shan J, Arlinghaus R. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2003 January; 9(1): 160-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12538464
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Rapid improvement of disseminated intravascular coagulation by donor leukocyte infusions in a patient with promyelocytic crisis of chronic myelogenous leukemia after reduced-intensity stem cell transplantation from an HLA 2-antigen-mismatched mother. Author(s): Matsue K, Yamada K, Takeuchi M, Tabayashi T. Source: International Journal of Hematology. 2003 May; 77(4): 408-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12774933
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Recovery of normal hematopoiesis after severe bone marrow aplasia induced by interferon-alpha in a patient with chronic myelogenous leukemia. Author(s): Hishida A, Yamamoto K, Kato C, Yokozawa T, Emi N, Tanimoto M, Saito H. Source: International Journal of Hematology. 2003 January; 77(1): 55-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12568300
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Relationship between elevated levels of the alpha 1 acid glycoprotein in chronic myelogenous leukemia in blast crisis and pharmacological resistance to imatinib (Gleevec) in vitro and in vivo. Author(s): Larghero J, Leguay T, Mourah S, Madelaine-Chambrin I, Taksin AL, Raffoux E, Bastie JN, Degos L, Berthaud P, Marolleau JP, Calvo F, Chomienne C, Mahon FX, Rousselot P. Source: Biochemical Pharmacology. 2003 November 15; 66(10): 1907-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14599548
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Resolution of leukemic retinopathy following treatment with imatinib mesylate for chronic myelogenous leukemia. Author(s): Christoforidis JB, DeAngelo DJ, D'Amico DJ. Source: American Journal of Ophthalmology. 2003 March; 135(3): 398-400. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12614767
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Resolution of psoriasis following allogeneic bone marrow transplantation for chronic myelogenous leukemia: case report and review of the literature. Author(s): Kanamori H, Tanaka M, Kawaguchi H, Yamaji S, Fujimaki K, Tomita N, Fujisawa S, Ishigatsubo Y. Source: American Journal of Hematology. 2002 September; 71(1): 41-4. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12221673
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Results of decitabine (5-aza-2'deoxycytidine) therapy in 130 patients with chronic myelogenous leukemia. Author(s): Kantarjian HM, O'Brien S, Cortes J, Giles FJ, Faderl S, Issa JP, Garcia-Manero G, Rios MB, Shan J, Andreeff M, Keating M, Talpaz M. Source: Cancer. 2003 August 1; 98(3): 522-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12879469
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Reversal of the resistance to STI571 in human chronic myelogenous leukemia K562 cells. Author(s): Mukai M, Che XF, Furukawa T, Sumizawa T, Aoki S, Ren XQ, Haraguchi M, Sugimoto Y, Kobayashi M, Takamatsu H, Akiyama S. Source: Cancer Science. 2003 June; 94(6): 557-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12824882
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Role of pretransplant interferon-alpha(IFN) treatment in the outcome of stem cell transplantation (SCT) from related donors in chronic myelogenous leukemia (CML): results from three Turkish transplant centers. Author(s): Beksac M, Celebi H, Sargin D, Yalcin A, Topcuoglu P, Kalayoglu-Besisik S, Beyan C, Arslan O, Ozcan M, Gurman G, Ilhan O, Akan H. Source: Bone Marrow Transplantation. 2003 May; 31(10): 897-904. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12748666
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SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice. Author(s): Golas JM, Arndt K, Etienne C, Lucas J, Nardin D, Gibbons J, Frost P, Ye F, Boschelli DH, Boschelli F. Source: Cancer Research. 2003 January 15; 63(2): 375-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12543790
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Specific targeted therapy of chronic myelogenous leukemia with imatinib. Author(s): Deininger MW, Druker BJ. Source: Pharmacological Reviews. 2003 September; 55(3): 401-23. Epub 2003 July 17. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12869662
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Spontaneous reversion from blast to chronic phase after withdrawal of imatinib mesylate in a patient with chronic myelogenous leukemia. Author(s): Liu NS, O'Brien S. Source: Leukemia & Lymphoma. 2002 December; 43(12): 2413-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12613534
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Standardization criteria for the detection of BCR/ABL fusion in interphase nuclei of chronic myelogenous leukemia patients by fluorescence in situ hybridization. Author(s): Cohen N, Novikov I, Hardan I, Esa A, Brok-Simoni F, Amariglio N, Rechavi G, Ben-Bassat I, Trakhtenbrot L. Source: Cancer Genetics and Cytogenetics. 2000 December; 123(2): 102-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11150599
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Successful non-T cell-depleted HLA haplo-identical three-loci mismatched hematopoietic stem cell transplantation from mother to son based on the fetomaternal microchimerism in chronic myelogenous leukemia. Author(s): Ochiai N, Shimazaki C, Fuchida S, Okano A, Sumikuma T, Ashihara E, Inaba T, Fujita N, Maruya E, Nakagawa M. Source: Bone Marrow Transplantation. 2002 December; 30(11): 793-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12439703
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Successful pregnancy and delivery in a patient with chronic myelogenous leukemia (CML), and management of CML with leukapheresis during pregnancy: a case report and review of the literature. Author(s): Ali R, Ozkalemkas F, Ozkocaman V, Ozcelik T, Ozan U, Kimya Y, Tunali A. Source: Japanese Journal of Clinical Oncology. 2004 April; 34(4): 215-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15121759
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Successful treatment of extramedullary blast crisis of chronic myelogenous leukemia with imatinib mesylate (STI571). Author(s): Naito K, Mori T, Miyazaki K, Tsukada Y, Ikeda Y, Okamoto S. Source: Intern Med. 2003 August; 42(8): 740-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12924504
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Sudden onset of the blastic phase of chronic myelogenous leukemia: patterns and implications. Author(s): Kantarjian H, O'Brien S, Cortes J, Giles F, Thomas D, Kornblau S, Shan J, Beth Rios M, Keating M, Freireich E, Talpaz M. Source: Cancer. 2003 July 1; 98(1): 81-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12833459
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Synergistic activity of the new ABL-specific tyrosine kinase inhibitor STI571 and chemotherapeutic drugs on BCR-ABL-positive chronic myelogenous leukemia cells. Author(s): Topaly J, Zeller WJ, Fruehauf S. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2001 March; 15(3): 342-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11237055
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Synthetic peptides derived from the Wilms' tumor 1 protein sensitize human T lymphocytes to recognize chronic myelogenous leukemia cells. Author(s): Muller L, Knights A, Pawelec G. Source: The Hematology Journal : the Official Journal of the European Haematology Association / Eha. 2003; 4(1): 57-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12692522
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Testing the prognostic model of Marin et al in an independent chronic myelogenous leukemia study group. Author(s): Kantarjian H, Cortes J. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2004 March; 18(3): 650. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14737079
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The effect of cyclosporin A used alone and in combination with either 2chlorodeoxyadenosine or fludarabine on normal and chronic myelogenous leukemia progenitors in vitro. Author(s): Korycka A, Robak T. Source: Arch Immunol Ther Exp (Warsz). 2003; 51(1): 61-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12691305
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The effect of dose increase of imatinib mesylate in patients with chronic or accelerated phase chronic myelogenous leukemia with inadequate hematologic or cytogenetic response to initial treatment. Author(s): Zonder JA, Pemberton P, Brandt H, Mohamed AN, Schiffer CA. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2003 June; 9(6): 2092-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12796373
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The effects of STI571 on antigen presentation of dendritic cells generated from patients with chronic myelogenous leukemia. Author(s): Sato N, Narita M, Takahashi M, Yagisawa K, Liu A, Abe T, Nikkuni K, Furukawa T, Toba K, Aizawa Y. Source: Hematological Oncology. 2003 June; 21(2): 67-75. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12802811
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The significance of myelosuppression during therapy with imatinib mesylate in patients with chronic myelogenous leukemia in chronic phase. Author(s): Sneed TB, Kantarjian HM, Talpaz M, O'Brien S, Rios MB, Bekele BN, Zhou X, Resta D, Wierda W, Faderl S, Giles F, Cortes JE. Source: Cancer. 2004 January 1; 100(1): 116-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14692031
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Thrombocytopenia induced by imatinib mesylate (Glivec) in patients with chronic myelogenous leukemia: is 400 mg daily of imatinib mesylate an optimal starting dose for Japanese patients? Author(s): Miyazawa K, Nishimaki J, Katagiri T, Sashida G, Shoji N, Kawakubo K, Suzuki A, Shimamoto T, Gotoh A, Kuriyama Y, Ito Y, Tauchi T, Kawanishi Y, Kimura Y, Ohyashiki K. Source: International Journal of Hematology. 2003 January; 77(1): 93-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12568307
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Tophaceous gout in an amputation stump in a patient with chronic myelogenous leukemia. Author(s): Chung CB, Mohana-Borges A, Pathria M. Source: Skeletal Radiology. 2003 July; 32(7): 429-31. Epub 2003 June 03. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12783222
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Transplantation for chronic myelogenous leukemia: yes, no, maybe so. An Oregon perspective. Author(s): Maziarz RT, Mauro MJ. Source: Bone Marrow Transplantation. 2003 September; 32(5): 459-69. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12942091
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Treatment of Philadelphia chromosome-positive chronic myelogenous leukemia with weekly polyethylene glycol formulation of interferon-alpha-2b and low-dose cytosine arabinoside. Author(s): Garcia-Manero G, Talpaz M, Giles FJ, Cortes J, Faderl S, O'Brien S, Thomas D, Verstovsek S, Beth Rios M, Shan J, Ferrajoli A, Wierda W, Kantarjian HM. Source: Cancer. 2003 June 15; 97(12): 3010-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12784336
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Tyrosine kinase inhibitor as a therapeutic drug for chronic myelogenous leukemia and gastrointestinal stromal tumor. Author(s): Nakajima M, Toga W. Source: Nippon Yakurigaku Zasshi. Japanese Journal of Pharmacology. 2003 December; 122(6): 482-90. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14639002
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Uncommon syndromes and treatment manifestations of malignancy: Case 4. Periorbital edema and imatinib mesylate therapy for chronic myelogenous leukemia. Author(s): Ramar K, Potti A, Mehdi SA. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 January 1; 21(1): 172-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12506189
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Understanding the molecular basis of imatinib mesylate therapy in chronic myelogenous leukemia and the related mechanisms of resistance. Commentary re: A. N. Mohamed et al., The effect of imatinib mesylate on patients with Philadelphia chromosome-positive chronic myeloid leukemia with secondary chromosomal aberrations. Clin. Cancer Res., 9: 1333-1337, 2003. Author(s): Marcucci G, Perrotti D, Caligiuri MA. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2003 April; 9(4): 1248-52. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12684391
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Unexpected high incidence of severe toxicities associated with alpha interferon, lowdose cytosine arabinoside and all-trans retinoic acid in patients with chronic myelogenous leukemia. Author(s): Sacchi S, Kantarjian HM, Freireich EJ, O'Brien S, Cortes J, Rios MB, Kornblau S, Giles FJ, Koller C, Gajewski J, Talpaz M. Source: Leukemia & Lymphoma. 1999 November; 35(5-6): 483-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10609785
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Unrelated donor cord blood transplantation in adults with chronic myelogenous leukemia: results in nine patients from a single institution. Author(s): Sanz GF, Saavedra S, Jimenez C, Senent L, Cervera J, Planelles D, Bolufer P, Larrea L, Martin G, Martinez J, Jarque I, Moscardo F, Plume G, Andreu R, de la Rubia J, Barragan E, Solves P, Soler MA, Sanz MA. Source: Bone Marrow Transplantation. 2001 April; 27(7): 693-701. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11360108
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Unrelated donor marrow transplantation for chronic myelogenous leukemia: 9 years' experience of the national marrow donor program. Author(s): McGlave PB, Shu XO, Wen W, Anasetti C, Nademanee A, Champlin R, Antin JH, Kernan NA, King R, Weisdorf DJ. Source: Blood. 2000 April 1; 95(7): 2219-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10733488
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Unrelated donor transplant therapy for chronic myelogenous leukemia. Author(s): McGlave P. Source: Hematology/Oncology Clinics of North America. 1998 February; 12(1): 93-105. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9523227
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Use of leukemic dendritic cells for the generation of antileukemic cellular cytotoxicity against Philadelphia chromosome-positive chronic myelogenous leukemia. Author(s): Choudhury A, Gajewski JL, Liang JC, Popat U, Claxton DF, Kliche KO, Andreeff M, Champlin RE. Source: Blood. 1997 February 15; 89(4): 1133-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9028934
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Use of unrelated marrow grafts compensates for reduced graft-versus-leukemia reactivity after T-cell-depleted allogeneic marrow transplantation for chronic myelogenous leukemia. Author(s): Hessner MJ, Endean DJ, Casper JT, Horowitz MM, Keever-Taylor CA, Roth M, Flomenberg N, Drobyski WR. Source: Blood. 1995 November 15; 86(10): 3987-96. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7579370
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Usefulness of detection of minimal residual disease by 'hypermetaphase' fluorescent in situ hybridization after allogeneic BMT for chronic myelogenous leukemia. Author(s): Seong D, Giralt S, Fischer H, Hayes K, Glassman A, Arlinghaus R, Xu J, Kantarjian H, Siciliano M, Champlin R. Source: Bone Marrow Transplantation. 1997 March; 19(6): 565-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9085736
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Vaccination of patients with chronic myelogenous leukemia with bcr-abl oncogene breakpoint fusion peptides generates specific immune responses. Author(s): Pinilla-Ibarz J, Cathcart K, Korontsvit T, Soignet S, Bocchia M, Caggiano J, Lai L, Jimenez J, Kolitz J, Scheinberg DA. Source: Blood. 2000 March 1; 95(5): 1781-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10688838
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Value of PCR analysis for long term survivors after allogeneic bone marrow transplant for chronic myelogenous leukemia: a comparative study. Author(s): Costello RT, Kirk J, Gabert J. Source: Leukemia & Lymphoma. 1996 January; 20(3-4): 239-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8624462
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Variables influencing the timing of marrow transplantation in patients with chronic myelogenous leukemia. Author(s): Segel GB, Simon W, Lichtman MA. Source: Blood. 1986 November; 68(5): 1055-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3533178
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Weight loss, skin rash, and cough following bone marrow transplantation for chronic myelogenous leukemia. Author(s): Witherspoon RP, McGlave P, Campbell JB, Sigley T, Rolston KV. Source: Cancer Practice. 1998 July-August; 6(4): 202-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9767331
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WT1 in acute leukemia, chronic myelogenous leukemia and myelodysplastic syndrome: therapeutic potential of WT1 targeted therapies. Author(s): Rosenfeld C, Cheever MA, Gaiger A. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2003 July; 17(7): 1301-12. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12835718
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CHAPTER 2. NUTRITION AND CHRONIC MYELOGENOUS LEUKEMIA Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and chronic myelogenous leukemia.
Finding Nutrition Studies on Chronic Myelogenous Leukemia 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 “chronic myelogenous leukemia” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.
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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 “chronic myelogenous leukemia” (or a synonym): •
Allogeneic bone marrow transplantation in chronic myelogenous leukemia and its nutrition implications: A case study. Source: Beck, J. Top-Clin-Nutr. Frederick, Md. : Aspen Publishers. June 1992. volume 7 (3) page 34-40. 0883-5691
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Arginine butyrate downregulates p210 bcr-abl expression and induces apoptosis in chronic myelogenous leukemia cells. Author(s): Section of Hematology-Oncology and Biomolecular Medicine, Evans Research Foundation, Boston University Medical Center, MA, USA. Source: Urbano, A Koc, Y Foss, F M Leukemia. 1998 June; 12(6): 930-6 0887-6924
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Differentiation by a tumor promoter of lymphoblastoid cell lines with and without Ph1 chromosome from a chronic myelogenous leukemia patient. Source: Yamada, T Sasaki, M Jpn-J-Cancer-Res. 1987 May; 78(5): 499-504 0910-5050
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Establishment of novel cell lines derived from two patients with chronic myelogenous leukemia in blast crisis; IMS-BC1 and IMS-BC2 which exhibit markedly different sensitivity to apoptosis. Author(s): Department of Hematology/Oncology, Institute of Medical Science, University of Tokyo, Japan.
[email protected] Source: Nagamura, F Nagamura Inoue, T Tojo, A Minamihisamatsu, M Tanabe, T Zaike, Y Tani, K Saisho, H Asano, S Int-J-Hematol. 1998 April; 67(3): 283-94 0925-5710
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In vitro effects of STI 571-containing drug combinations on the growth of Philadelphia-positive chronic myelogenous leukemia cells. Author(s): Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. Source: Scappini, Barbara Onida, Francesco Kantarjian, Hagop M Dong, Li Verstovsek, Srdan Keating, Michael J Beran, Miloslav Cancer. 2002 May 15; 94(10): 2653-62 0008543X
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Long-term follow-up results of alpha interferon therapy in chronic myelogenous leukemia at M. D. Anderson Cancer Center. Author(s): Department of Hematology, M.D. Anderson Cancer Center, Houston, Texas 77030. Source: Kantarjian, H M Talpaz, M Leuk-Lymphoma. 1993; 11 Suppl 1169-74 1042-8194
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Long-term third chronic phase of chronic myelogenous leukemia maintained by interferon-alpha and methotrexate. Author(s): Department of Cell Therapy and Transplantation Medicine, Faculty of Medicine, University of Tokyo, Japan. Source: Kanda, Y Chiba, S Honda, H Hirai, H Yazaki, Y Leuk-Lymphoma. 1999 March; 33(1-2): 193-7 1042-8194
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Mechanism for homologous downregulation of thromboxane A2 receptors in cultured human chronic myelogenous leukemia (K562) cells. Author(s): Department of Medicine/Cardiology, University of Cincinnati College of Medicine, Ohio. Source: Dorn, G W 2nd J-Pharmacol-Exp-Ther. 1991 October; 259(1): 228-34 0022-3565
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Restoration of Th1 cytokine synthesis by T cells of patients with chronic myelogenous leukemia in cytogenetic and hematologic remission with interferonalpha. Author(s): Department of Laboratory Medicine, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
[email protected] Source: Reuben, J M Lee, B N Johnson, H Fritsche, H Kantarjian, H M Talpaz, M ClinCancer-Res. 2000 May; 6(5): 1671-7 1078-0432
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Results of therapy with interferon alpha and cyclic combination chemotherapy in patients with philadelphia chromosome positive chronic myelogenous leukemia in early chronic phase. Author(s): Department of Leukemia; University of Texas MD Anderson Cancer Center Houston, Texas 77030, USA. Source: Giles, F J Kantarjian, H O'Brien, S Rios, M B Cortes, J Beran, M Koller, C Keating, M Talpaz, M Leuk-Lymphoma. 2001 April; 41(3-4): 309-19 1042-8194
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Simultaneous occurrence of chronic myelogenous leukemia and non-Hodgkin lymphoma at diagnosis. Author(s): Department of Medical Genetics, Selcuk University, Konya, Turkey. Source: Acar, H Ecirli, S Gundogan, F Bulay, O Acar, A Cancer-Genet-Cytogenet. 1999 January 15; 108(2): 171-4 0165-4608
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The effects of 13-cis retinoic acid and interferon-alpha in chronic myelogenous leukemia cells in vivo in patients. Author(s): Rush Cancer Institute, Rush-Presbyterian-St. Lukes's Medical Center, Chicago, IL 60612, USA. Source: Handa, H Hegde, U P Kotelnikov, V M Mundle, S D Dong, L M Burke, P Rose, S Hsu, W T Gaskin, F Raza, A Preisler, H D Leuk-Res. 1997 Nov-December; 21(11-12): 1087-96 0145-2126
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The use of gemfibrozil in a patient with chronic myelogenous leukemia to successfully manage retinoid-induced hypertriglyceridemia. Author(s): Department of Dermatology, University of Texas Medical School, Houston. Source: Cohen, P R Clin-Investig. 1993 January; 71(1): 74-7 0941-0198
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Therapy of acute phase chronic myelogenous leukemia with intensive chemotherapy, blood cell autotransplant and cyclosporine A. Author(s): Oncohematologic and ABMT Unit, Ospedale S. Martino, Genoa, Italy. Source: Carella, A M Gaozza, E Raffo, M R Carlier, P Frassoni, F Valbonesi, M Lercari, G Sessarego, M Defferrari, R Guerrasio, A et al. Leukemia. 1991 June; 5(6): 517-21 08876924
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Topotecan-based combination chemotherapy in patients with transformed chronic myelogenous leukemia and advanced myelodysplastic syndrome. Author(s): Catholic Hemopoietic Stem Cell Transplantation Center, Department of Internal Medicine, Catholic University of Korea, College of Medicine, Seoul, Korea. Source: Park, S J Kim, D W Kim, H J Eom, H S Min, C K Lee, J W Min, W S Kim, C C Korean-J-Intern-Med. 2000 July; 15(2): 122-6 0494-4712
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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 chronic myelogenous leukemia; 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 K Alternative names: Menadione, Menaphthone, Menaquinone, Phylloquinone Source: Integrative Medicine Communications; www.drkoop.com
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Minerals Retinol Source: Integrative Medicine Communications; www.drkoop.com Vitamin A (Retinol) Source: Integrative Medicine Communications; www.drkoop.com
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CHAPTER 3. ALTERNATIVE MEDICINE AND CHRONIC MYELOGENOUS LEUKEMIA Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to chronic myelogenous leukemia. 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 chronic myelogenous leukemia 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 “chronic myelogenous leukemia” (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 chronic myelogenous leukemia: •
A phase II study of VP-16, intermediate-dose Ara-C and carboplatin (VAC) in advanced acute myelogenous leukemia and blastic chronic myelogenous leukemia. Author(s): Amadori S, Picardi A, Fazi P, Testi AM, Petti MC, Montefusco E, Mandelli F. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1996 May; 10(5): 766-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8656669
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Activated allogeneic cell therapy (allo-ACT) for relapsed chronic myelogenous leukemia (CML) refractory to buffy coat transfusions post-allogeneic bone marrow transplantation. Author(s): Kapelushnik J, Nagler A, Or R, Naparstek E, Ackerstein A, Samuel S, Morecki S, Nabet C, Slavin S.
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Source: Bone Marrow Transplantation. 1996 December; 18(6): 1153-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8971387 •
Amendment to clinical research projects. Genetic marking with retroviral vectors to study the feasibility of stem cell gene transfer and the biology of hematopoietic reconstitution after autologous transplantation in multiple myeloma, chronic myelogenous leukemia, or metastatic breast cancer. Author(s): Dunbar CE, Nienhuis AW, Stewart FM, Quesenberry P, O'Shaughnessy J, Cowan K, Cottler-Fox M, Leitman S, Goodman S, Sorrentino BP, et al. Source: Human Gene Therapy. 1993 April; 4(2): 205-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8098622
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Blast crisis of chronic myelogenous leukemia in long-lasting systemic lupus erythematosus: regression of both diseases after autologous bone marrow transplantation. Author(s): Meloni G, Capria S, Vignetti M, Mandelli F, Modena V. Source: Blood. 1997 June 15; 89(12): 4659. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9192793
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Chronic myelogenous leukemia following radiotherapy and chemotherapy for nonHodgkin lymphoma. Author(s): Cazzola M, Bergamaschi G, Melazzini M, Ponchio L, Rosti V, Molinari E. Source: Haematologica. 1990 September-October; 75(5): 477-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2097266
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Chronic myelogenous leukemia in a 16-yr-old. Author(s): Plezbert JA, Bose M, Carlisle G. Source: Journal of Manipulative and Physiological Therapeutics. 1994 NovemberDecember; 17(9): 610-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7884332
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Collection of 'normal' blood repopulating cells during early hemopoietic recovery after intensive conventional chemotherapy in chronic myelogenous leukemia. Author(s): Carella AM, Podesta M, Frassoni F, Raffo MR, Pollicardo N, Pungolino E, Vimercati R, Sessarego M, Parodi C, Rabitti C, et al. Source: Bone Marrow Transplantation. 1993 September; 12(3): 267-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7694724
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Effects of suggestion on pruritus with cutaneous lesions in chronic myelogenous leukemia. Author(s): Ament P, Milgrom H. Source: N Y State J Med. 1967 March 15; 67(6): 833-5. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=5230408
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Emergence of acute interstitial pneumonia following high dose interferon delta treatment in a case of chronic myelogenous leukemia. Author(s): Murata M, Nagai M, Bando S, Dobashi H, Takahara J. Source: Intern Med. 1993 September; 32(9): 716-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8142676
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Etoposide, intermediate-dose cytarabine and carboplatin (VAC): a combination therapy for the blastic phase of chronic myelogenous leukemia. Author(s): Montefusco E, Petti MC, Alimena G, Latagliata R, Celesti F, Capria S, Amadori S, Avvisati G, Mandelli F. Source: Annals of Oncology : Official Journal of the European Society for Medical Oncology / Esmo. 1997 February; 8(2): 175-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9093727
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Ex vivo purging with NK-92 prior to autografting for chronic myelogenous leukemia. Author(s): Maki G, Tam YK, Berkahn L, Klingemann HG.
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Fractionated total-body irradiation and high-dose etoposide as a preparatory regimen for bone marrow transplantation for 94 patients with chronic myelogenous leukemia in chronic phase. Author(s): Snyder DS, Negrin RS, O'Donnell MR, Chao NJ, Amylon MD, Long GD, Nademanee AP, Stein AS, Parker PM, Smith EP, et al. Source: Blood. 1994 September 1; 84(5): 1672-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8068956
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High doses of cyclophosphamide, etoposide and total body irradiation followed by autologous stem cell transplantation in the management of patients with chronic myelogenous leukemia. Author(s): Kantarjian HM, Talpaz M, Andersson B, Khouri I, Giralt S, Rios MB, Champlin R, Hester J, Deisseroth AB. Source: Bone Marrow Transplantation. 1994 July; 14(1): 57-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7951120
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High-dose chemo-radiotherapy followed by autologous Philadelphia chromosomenegative blood progenitor cell transplantation in patients with chronic myelogenous leukemia. Author(s): Carella AM, Chimirri F, Podesta M, Pitto A, Piaggio G, Dejana A, Lerma E, Pollicardo N, Vassallo F, Soracco M, Benvenuto F, Valbonesi M, Carlier P, Vimercati R, Prencipe E, Gatti AM, Ferrara RA, Incagliato M, Florio G, Frassoni F. Source: Bone Marrow Transplantation. 1996 February; 17(2): 201-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8640167
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Homoharringtonine and low-dose cytarabine in the management of late chronicphase chronic myelogenous leukemia. Author(s): Kantarjian HM, Talpaz M, Smith TL, Cortes J, Giles FJ, Rios MB, Mallard S, Gajewski J, Murgo A, Cheson B, O'Brien S. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2000 October 15; 18(20): 3513-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11032593
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Homoharringtonine therapy induces responses in patients with chronic myelogenous leukemia in late chronic phase. Author(s): O'Brien S, Kantarjian H, Keating M, Beran M, Koller C, Robertson LE, Hester J, Rios MB, Andreeff M, Talpaz M. Source: Blood. 1995 November 1; 86(9): 3322-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7579434
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Hypermetaphase fluorescence in situ hybridization for quantitative monitoring of Philadelphia chromosome-positive cells in patients with chronic myelogenous leukemia during treatment. Author(s): Seong DC, Kantarjian HM, Ro JY, Talpaz M, Xu J, Robinson JR, Deisseroth AB, Champlin RE, Siciliano MJ. Source: Blood. 1995 September 15; 86(6): 2343-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7662980
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Imatinib in combination with cytarabine for the treatment of Philadelphia-positive chronic myelogenous leukemia chronic-phase patients: rationale and design of phase I/II trials. Author(s): Guilhot F, Gardembas M, Rousselot P, Tulliez M, Vigier M, Buzyn A, RigalHuguet F, Legros L, Michallet M, Berthou C, Najman A, Maloisel F, Mahon FX, Facon T, Berthaud P, Guilhot J; CML French Group. Source: Semin Hematol. 2003 April; 40(2 Suppl 2): 92-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12783382
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In vitro effects of STI 571-containing drug combinations on the growth of Philadelphia-positive chronic myelogenous leukemia cells. Author(s): Scappini B, Onida F, Kantarjian HM, Dong L, Verstovsek S, Keating MJ, Beran M. Source: Cancer. 2002 May 15; 94(10): 2653-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12173333
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Intensive chemotherapy induction followed by interferon-alpha maintenance in patients with Philadelphia chromosome-positive chronic myelogenous leukemia. Author(s): Kantarjian HM, Talpaz M, Keating MJ, Estey EH, O'Brien S, Beran M, McCredie KB, Gutterman J, Freireich EJ. Source: Cancer. 1991 September 15; 68(6): 1201-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1873771
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Intensive combination chemotherapy (ROAP 10) and splenectomy in the management of chronic myelogenous leukemia. Author(s): Kantarjian HM, Vellekoop L, McCredie KB, Keating MJ, Hester J, Smith T, Barlogie B, Trujillo J, Freireich EJ. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 1985 February; 3(2): 192-200. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3855444
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Intensive combination chemotherapy and autologous bone marrow transplantation leads to the reappearance of Philadelphia chromosome-negative cells in chronic myelogenous leukemia. Author(s): Kantarjian HM, Talpaz M, LeMaistre CF, Spinolo J, Spitzer G, Yau J, Dicke K, Jagannath S, Deisseroth AB.
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Intensive combination chemotherapy and interferons in the management of chronic myelogenous leukemia. Author(s): Kantarjian HM, Talpaz M, Kurzrock R, Keating MJ, McCredie KB, Gutterman J, Freireich EJ. Source: Acta Haematologica. 1987; 78 Suppl 1: 70-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2449026
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Interactions of actin, myosin, and an actin-binding protein of chronic myelogenous leukemia leukocytes. Author(s): Boxer LA, Stossel TP. Source: The Journal of Clinical Investigation. 1976 April; 57(4): 964-76. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=133121
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Long-term follow-up results of alpha interferon therapy in chronic myelogenous leukemia at M. D. Anderson Cancer Center. Author(s): Kantarjian HM, Talpaz M. Source: Leukemia & Lymphoma. 1993; 11 Suppl 1: 169-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8251891
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Long-term third chronic phase of chronic myelogenous leukemia maintained by interferon-alpha and methotrexate. Author(s): Kanda Y, Chiba S, Honda H, Hirai H, Yazaki Y. Source: Leukemia & Lymphoma. 1999 March; 33(1-2): 193-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10194138
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Lymphoblastic conversion in chronic myelogenous leukemia. Author(s): Crist WM, Ragab AH, Ducos R. Source: Pediatrics. 1978 April; 61(4): 560-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=78481
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Mini-ice protocol is better than high-dose hydroxyurea to mobilize Ph-negative cells in earlier phases of chronic myelogenous leukemia. Author(s): Carella AM. Source: Leukemia & Lymphoma. 2001 January; 40(3-4): 447-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11426572
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Mini-ICE regimen allows mobilization of peripheral blood progenitor cells in a patient with chronic myelogenous leukemia failing the ICE protocol. Author(s): Salar A, Sureda A, Menendez B, Sierra J.
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Myelotoxicity of vincristine-prednisone therapy in treatment of chronic myelogenous leukemia in blastic transformation. Author(s): Stein RS, Roth DG. Source: American Journal of Hematology. 1976; 1(4): 387-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1070235
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Percentage of Philadelphia chromosome (Ph)-negative and Ph-positive cells found after autologous transplantation for chronic myelogenous leukemia depends on percentage of diploid cells induced by conventional-dose chemotherapy before collection of autologous cells. Author(s): Talpaz M, Kantarjian H, Liang J, Calvert L, Hamer J, Tibbits P, Durett A, Claxton D, Giralt S, Khouri I, et al. Source: Blood. 1995 June 1; 85(11): 3257-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7756658
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Philadelphia-chromosome-positive pre-B-cell leukemia presenting as blast crisis of chronic myelogenous leukemia. Author(s): Vogler LB, Crist WM, Vinson PC, Sarrif A, Brattain MG, Coleman MS. Source: Blood. 1979 November; 54(5): 1164-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=315245
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Possible effect of medroxyprogesterone acetate (MPA) in lymphoid blast crisis of chronic myelogenous leukemia. Author(s): Fink M. Source: Annals of Hematology. 1994 February; 68(2): 89-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8148420
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Rapid control of myeloid compartment with vindesine in chronic phase of chronic myelogenous leukemia. Author(s): Lahuerta-Palacios J, Fernandez-Debora F, Ortiz-Conde MC, Larregla S, Gutierrez-Rivas E. Source: Cancer Treat Rep. 1986 February; 70(2): 315-6. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3456274
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Response of chronic myelogenous leukemia patients to COAP-splenectomy. A Southwest Oncology Group study. Author(s): Hester JP, Waddell CC, Coltman CA Jr, Morrison FS, Stephens RL, Balcerzak SP, Baker LH, Chen TT.
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Results of a prospective phase 2 study combining imatinib mesylate and cytarabine for the treatment of Philadelphia-positive patients with chronic myelogenous leukemia in chronic phase. Author(s): Gardembas M, Rousselot P, Tulliez M, Vigier M, Buzyn A, Rigal-Huguet F, Legros L, Michallet M, Berthou C, Cheron N, Maloisel F, Mahon FX, Facon T, Berthaud P, Guilhot J, Guilhot F; CML French Group. Source: Blood. 2003 December 15; 102(13): 4298-305. Epub 2003 August 21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12933584
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Results of therapy with interferon alpha and cyclic combination chemotherapy in patients with philadelphia chromosome positive chronic myelogenous leukemia in early chronic phase. Author(s): Giles FJ, Kantarjian H, O'Brien S, Rios MB, Cortes J, Beran M, Koller C, Keating M, Talpaz M. Source: Leukemia & Lymphoma. 2001 April; 41(3-4): 309-19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11378543
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Results of triple therapy with interferon-alpha, cytarabine, and homoharringtonine, and the impact of adding imatinib to the treatment sequence in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in early chronic phase. Author(s): O'Brien S, Giles F, Talpaz M, Cortes J, Rios MB, Shan J, Thomas D, Andreeff M, Kornblau S, Faderl S, Garcia-Manero G, White K, Mallard S, Freireich E, Kantarjian HM. Source: Cancer. 2003 September 1; 98(5): 888-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12942553
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Selection of myeloid progenitors lacking BCR/ABL mRNA in chronic myelogenous leukemia patients after in vitro treatment with the tyrosine kinase inhibitor genistein. Author(s): Carlo-Stella C, Dotti G, Mangoni L, Regazzi E, Garau D, Bonati A, Almici C, Sammarelli G, Savoldo B, Rizzo MT, Rizzoli V. Source: Blood. 1996 October 15; 88(8): 3091-100. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8874208
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Sensitivity of K562 human chronic myelogenous leukemia blast cells transfected with a human multidrug resistance cDNA to cytotoxic drugs and differentiating agents. Author(s): Hait WN, Choudhury S, Srimatkandada S, Murren JR. Source: The Journal of Clinical Investigation. 1993 May; 91(5): 2207-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8098047
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Sequential homoharringtonine and interferon-alpha in the treatment of early chronic phase chronic myelogenous leukemia. Author(s): O'Brien S, Kantarjian H, Koller C, Feldman E, Beran M, Andreeff M, Giralt S, Cheson B, Keating M, Freireich E, Rios MB, Talpaz M. Source: Blood. 1999 June 15; 93(12): 4149-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10361112
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Simultaneous homoharringtonine and interferon-alpha in the treatment of patients with chronic-phase chronic myelogenous leukemia. Author(s): O'Brien S, Talpaz M, Cortes J, Shan J, Giles FJ, Faderl S, Thomas D, GarciaManero G, Mallard S, Beth M, Koller C, Kornblau S, Andreeff M, Murgo A, Keating M, Kantarjian HM. Source: Cancer. 2002 April 1; 94(7): 2024-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11932905
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Simultaneous occurrence of chronic myelogenous leukemia and non-Hodgkin lymphoma at diagnosis. Author(s): Acar H, Ecirli S, Gundogan F, Bulay O, Acar A. Source: Cancer Genetics and Cytogenetics. 1999 January 15; 108(2): 171-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9973949
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Simultaneous occurrence of kaposi's sarcoma and chronic myelogenous leukemia. Author(s): Vey N, Camerlo J, Xerri L, Petit N, Dermeche S, Maraninchi D. Source: Leukemia & Lymphoma. 2001 April; 41(3-4): 425-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11378557
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Terminal deoxynucleotidyl transferase activity and B cell markers in chronic myelogenous leukemia blast crisis. Author(s): Sasaki R, Takaku F, Sakamoto S, Kanoh Y. Source: Acta Haematologica. 1979; 62(3): 143-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=118612
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Terminal deoxynucleotidyl transferase activity in blastic phase of chronic myelogenous leukemia. Author(s): Srivastava BI, Khan SA, Minowada J, Gomez GA, Rakowski I. Source: Cancer Research. 1977 October; 37(10): 3612-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=269010
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Terminal deoxynucleotidyl transferase in the blastic phase of chronic myelogenous leukemia: an indicator of response to vincristine and prednisone therapy. Author(s): Tanaka M, Kaneda T, Hirota Y, Yoshida S, Kitajima K.
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Terminal transferase as a predictor of initial responsiveness to vincristine and prednisone in blastic chronic myelogenous leukemia: a co-operative study. Author(s): Marks SM, Baltimore D, McCaffrey R. Source: The New England Journal of Medicine. 1978 April 13; 298(15): 812-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=273142
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The treatment of chronic myelogenous leukemia in blastic crisis with the chemotherapy incorporating vindesine-prednisolone. Author(s): Saito Y, Uzuka Y, Takahashi H, Komatsu M, Ito T. Source: The Tohoku Journal of Experimental Medicine. 1986 January; 148(1): 65-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3458333
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The value of intensive combination chemotherapy for juvenile chronic myelogenous leukemia. Author(s): Chan HS, Estrov Z, Weitzman SS, Freedman MH. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 1987 December; 5(12): 1960-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2445935
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Therapy for chronic myelogenous leukemia in blast crisis with etoposide and 5azacitidine administered by continuous infusion: a Cancer and Leukemia group B Study. Author(s): Schiffer CA, Anderson K, Coleman M, Cuttner J. Source: Cancer Treat Rep. 1985 September; 69(9): 1027-8. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2411402
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Therapy for chronic myelogenous leukemia with marrow transplantation. Author(s): Miller JS, McGlave PB. Source: Current Opinion in Oncology. 1993 March; 5(2): 262-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8457612
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Therapy of acute phase chronic myelogenous leukemia with intensive chemotherapy, blood cell autotransplant and cyclosporine A. Author(s): Carella AM, Gaozza E, Raffo MR, Carlier P, Frassoni F, Valbonesi M, Lercari G, Sessarego M, Defferrari R, Guerrasio A, et al. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1991 June; 5(6): 517-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1676080
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Therapy of lymphoid and undifferentiated chronic myelogenous leukemia in blast crisis with continuous vincristine and adriamycin infusions plus high-dose decadron. Author(s): Walters RS, Kantarjian HM, Keating MJ, Talpaz M, Childs CC, McCredie KB, Freireich EJ. Source: Cancer. 1987 October 15; 60(8): 1708-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3477315
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Treatment of blast crisis of chronic myelogenous leukemia with vincristine, prednisone, and cytarabine. Author(s): Cervantes F, Rozman C, Blade J, Montserrat E, Granena A. Source: Cancer Treat Rep. 1985 July-August; 69(7-8): 923-4. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3860299
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Treatment of chronic myelogenous leukemia in blastic crisis with chemotherapy incorporating vindesine-prednisolone. Author(s): Uzuka Y, Saito Y. Source: Cancer Treat Rep. 1985 November; 69(11): 1297-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3867403
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Treatment of chronic myelogenous leukemia. Author(s): Giralt S, Kantarjian H, Talpaz M. Source: Seminars in Oncology. 1995 August; 22(4): 396-404. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7638636
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Treatment of chronic myelogenous leukemia. Author(s): Kitajima K. Source: Nippon Ketsueki Gakkai Zasshi. 1980 December; 43(6): 1086-94. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6949428
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Treatment of myeloid blastic crisis of chronic myelogenous leukemia. Author(s): Preisler HD, Raza A, Higby D, Kirshner J, Woll J, Bennett J, Winton L, Weiner R, Richman C, Golomb H, et al. Source: Cancer Treat Rep. 1984 November; 68(11): 1351-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6388833
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Treatment of the blast crisis of chronic myelogenous leukemia with 5-azacitidine and VP-16-213. Author(s): Schiffer CA, DeBellis R, Kasdorf H, Wiernik PH. Source: Cancer Treat Rep. 1982 February; 66(2): 267-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6173123
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Treatment of the blastic crisis of chronic myelogenous leukemia with the combination of vindesine and prednisolone, and cytosine arabinoside. Author(s): Uzuka Y, Saito Y. Source: The Tohoku Journal of Experimental Medicine. 1983 April; 139(4): 419-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6575487
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Two consecutive spontaneous regressions to chronic phase in a patient with blastic transformation of chronic myelogenous leukemia. Author(s): Cagirgan S, Sencan M, Tombuloglu M, Ozdemir E, Hekimgil M, Buyukkececi F. Source: Leukemia & Lymphoma. 1998 April; 29(3-4): 423-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9684940
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Unrelated donor and autologous marrow transplant therapy of chronic myelogenous leukemia (CML). Author(s): McGlave P. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1993 July; 7(7): 1082-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8321029
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Use of granulocyte-macrophage colony-stimulating factor (GM-CSF) in combination with hydroxyurea as post-transplant therapy in chronic myelogenous leukemia patients autografted with unmanipulated hematopoietic cells. Author(s): Carlo-Stella C, Regazzi E, Andrizzi C, Savoldo B, Garau D, Montefusco E, Vignetti M, Mandelli F, Rizzoli V, Meloni G. Source: Haematologica. 1997 May-June; 82(3): 291-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9234574
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 chronic myelogenous leukemia; 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 Marrow Disorders Source: Integrative Medicine Communications; www.drkoop.com Chronic Myelogenous Leukemia Source: Integrative Medicine Communications; www.drkoop.com Myelofibrosis Source: Integrative Medicine Communications; www.drkoop.com Myeloproliferative Disorders Source: Integrative Medicine Communications; www.drkoop.com Polycythemia Vera Source: Integrative Medicine Communications; www.drkoop.com Thrombocytosis Source: Integrative Medicine Communications; www.drkoop.com
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Herbs and Supplements Eleuthero Alternative names: Siberian Ginseng, Eleuthero; Acanthopanax/Eleutherococcus senticosus Rupr. & Maxim. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Menadione Source: Integrative Medicine Communications; www.drkoop.com Menaphthone Source: Integrative Medicine Communications; www.drkoop.com Menaquinone Source: Integrative Medicine Communications; www.drkoop.com Phylloquinone Source: Integrative Medicine Communications; www.drkoop.com
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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. 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 CHRONIC MYELOGENOUS LEUKEMIA Overview In this chapter, we will give you a bibliography on recent dissertations relating to chronic myelogenous leukemia. 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 “chronic myelogenous leukemia” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on chronic myelogenous leukemia, we have not necessarily excluded non-medical dissertations in this bibliography.
Dissertations on Chronic Myelogenous Leukemia 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 chronic myelogenous leukemia. 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: •
Regulation of Bcr-Abl signal transduction in the differentiation and survival of chronic myelogenous leukemia cells by Dorsey, Jay Fitzgerald, PhD from University of South Florida, 2003, 124 pages http://wwwlib.umi.com/dissertations/fullcit/3079979
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 CHRONIC MYELOGENOUS LEUKEMIA 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 “chronic myelogenous leukemia” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on chronic myelogenous leukemia, we have not necessarily excluded non-medical patents in this bibliography.
Patents on Chronic Myelogenous Leukemia By performing a patent search focusing on chronic myelogenous leukemia, 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 8Adapted
from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.
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descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We 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 chronic myelogenous leukemia: •
Carbohydrate specific to chronic myelogenous leukemia granulocytes Inventor(s): Fukuda; Michiko (San Diego, CA), Fukuda; Minoru (San Diego, CA) Assignee(s): La Jolla Cancer Research Foundation (La Jolla, CA) Patent Number: 4,939,083 Date filed: October 30, 1986 Abstract: A substantially purified carbohydrate is provided which is isolated from chronic myelogenous leukemia cells. The carbohydrate is immunogenic and can be utilized to raise both polyclonal and monoclonal antibodies. Excerpt(s): This invention relates generally to the area of carbohydrate chemistry and more specifically to unique carbohydrates specific to cancer cells. Cancer is currently the second leading cause of death in the United States. As a result, substantial efforts have been directed towards developing methods to detect and combat malignancies. However, because cancer affects many different types of cells, separate diagnostic and therapeutic methods must be established for individual cancers. Unique cell surface markers, or biochemical moieties, present on the membranes of particular malignant cells are of import as indicators of a particular type of cancer. The determination of specific cell surface markers potentially permits the targeting of therapeutics specific to malignant cells. Tumor specific cell surface markers have previously been identified for certain cancers of the colon and reproductive tract. Thus there is a great and long-felt need for a chemical marker which is specific to cells exhibiting CML but is absent on their normal counterparts. In addition to aiding in the understanding of CML, such a marker would be potentially useful in, for example, both the early diagnosis as well as the specific treatment of the malignancy. The present invention satisfies these needs and provides other related advantages as well. Web site: http://www.delphion.com/details?pn=US04939083__
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Detection of genomic abnormalities with unique aberrant gene transcripts Inventor(s): Lee; Ming-Sheng (Houston, TX) Assignee(s): The Board of Regents, The University of Texas System (Austin, TX) Patent Number: 4,999,290 Date filed: March 31, 1988 Abstract: The present invention involves a method for detecting the unique aberrant gene transcripts of a targeted cellular genomic abnormality in a tissue sample. This method comprises a series of steps. Initially, total cellular RNA or m-RNA is preferred from the tissue sample to be analyzed for the presence of a genomic abnormality. The total cellular RNA or m-RNA is then mixed with at least one synthetic DNA oligonucleotide complementary to the unique RNA sequence of the targeted cellular genomic abnormality being detected. The mixing is under conditions facilitating formation of double stranded DNA-RNA heteroduplexes when a strand of synthetic DNA oligonucleotide is complementary to an RNA strand obtained from the tissue
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sample. The conditions are those such as time, salt concentration, temperature and pH 10. The synthetic DNA oligonucleotide is preferably about several hundred nucleotides in length, more preferably about 60 to about 150 nucleotides in length.In a most preferred embodiment, the method of the present invention may be applied to the detection of residual cells of chronic myelogenous leukemia with its characteristic Philadelphia chromosome (Ph.sup.1). For this situation, the first primer is primer bcr Ex III(+) or bcr Ex II (+), most preferably a mixture of primer bcr Ex III (+) and bcr Ex II (+). In certain instances the second primer may also be a mixture of two different primers, particularly where there is a variable breakpoint in the second chromosomal member of the translocation characteristic of a neoplasm. Where residual cells of chronic myelogenous leukemia are being detected, the second primer is most preferably primer abl (-). Excerpt(s): The present invention involves using a new technique for the detection of genomic abnormalities. Such detection may prove particularly useful to predict recurrence of cancer, or early detection of cancer. High frequency of recurrence is one of the major problems in cancer treatment. Relapse from clinically undetectable residual disease is the most likely mechanism (1). Detection of minimal disease is extremely difficult since tumor specific markers are not readily available. Molecular technology has provided a means to demonstrate residual disease by identifying clonal gene rearrangement patterns that may present, for example, in malignant hematopoietic cells (2). Southern blot hybridization may detect neoplastic cells at levels as low as 1% of the total number of cells (3). However, one of the major drawbacks in using such traditional methods is that it is difficult to be certain that faint nongermline bands indeed represent clonal rearrangements representative of neoplastic cells. Furthermore, no rearranged bands can usually be detected by traditional methods in cases in which the concentration of neoplastic cells is below 1%. It is expected that such a low concentration occurs frequently while patients are in remission. Saiki et al. have recently utilized a new technique, sequence amplification by polymerase chain reaction (PCR), to diagnose sickle cell anemia prenatally (4). This technique is highly sensitive. It requires small amounts of DNA (less than 1 ug) and can amplify copies of target DNA sequences exponentially. Web site: http://www.delphion.com/details?pn=US04999290__ •
DR-nm23 and compositions, methods of making and methods of using the same Inventor(s): Calabretta; Bruno (Philadelphia, PA), Martinez; Robert V. (Philadelphia, PA), Venturelli; Donatella (Philadelphia, PA) Assignee(s): Thomas Jefferson University (Philadelphia, PA) Patent Number: 5,817,783 Date filed: June 20, 1996 Abstract: DR-nm23 protein is disclosed. A nucleotide sequence encoding the same and fragments thereof, recombinant expression vectors that comprise the nucleotide sequence, host cell comprising the recombinant expression vectors and methods of making DR-nm23 protein are disclosed. Oligonucleotide molecules comprising a nucleotide sequence complementary to a portion of the nucleotide sequence that encodes DR-nm23 and methods of using the same to inhibit DR-nm23 expression are disclosed. Isolated antibodies that bind to an epitope on DR-nm23 are disclosed. Methods of tracking the progress on chronic myelogenous leukemia and methods of
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detecting the onset of blast crisis phase in an individual with chronic myelogenous leukemia are disclosed. Excerpt(s): This application claims priority U.S. Provisional application 60/000,427 filed Jun. 22, 1995. The invention relates to the identification and cloning of Dr-nm23, a gene related to nm-23. The invention relates to the isolated protein, the nucleic acid molecules that encode the protein, to related compositions including antibodies, probes, primers and antisense compositions, and to methods of making and using the same. Hematopoiesis is a regulated developmental cascade that generates at least eight distinct lineages that differentiate into mature blood cells. Central to the process are pluripotent stem cells which generate a hierarchy of developmental transients consisting of multipotent and unipotent progenitor cells. Since most mature blood cells have short lifespans, the continuous regeneration of multipotent and unipotent progenitors is essential to hematopoietic homeostasis. Web site: http://www.delphion.com/details?pn=US05817783__ •
Human gene/protein involved in chronic myelogenous leukemia Inventor(s): Carpino; Nicholas A. (Memphis, TN), Clarkson; Bayard D. (New York, NY), Kobayashi; Ryuji (Syosset, NY), Strife; Annabel O'C. (New York, NY), Wisniewski; David G. (Staten Island, NY) Assignee(s): Cold Spring Harbor Laboratory (Cold Spring Harbor, NY), Sloan-Kettering Institute for Cancer Research (New York, NY) Patent Number: 6,100,386 Date filed: January 22, 1997 Abstract: Characteristic of chronic myelogenous leukemia (CML) is the presence of the chimeric p120.sup.bcr-abl protein possessing elevated protein tyrosine kinase activity relative to normal c-abl tyrosine kinase. Hematopoietic progenitors isolated from CML patients in the chronic phase contain a constitutively tyrosine phosphorylated protein that migrates at approximately 62 kDa by SDS-PAGE and associates with the p120 ras GTPase-activating protein (GAP). This novel protein, called p62.sup.dok (p62 protein downstream of tyrosine kinases), was isolated from a hematopoietic cell line expressing p120.sup.bcr-abl. Association of p62.sup.dok with GAP correlates with its tyrosine phosphorylation. p62.sup.dok is rapidly tyrosine phosphorylated upon activation of the c-kit receptor, implicating it as a component of a signal transduction pathway downstream of receptor tyrosine kinases. Excerpt(s): Chronic myelogenous leukemia (CML) is a disease having clinical and pathological features distinct from those of other forms of leukemia. It is widely accepted that the cause of CML is a specific chromosomal translocation between human chromosome 9 and human chromosome 22. The N chromosome resulting from this translocation is commonly referred to as the Philadelphia chromosome. Darnell, J. et al., Molecular Cell Biology, 2nd Ed., W. H. Freeman and Co., New York (1990), p. 992. The gene for c-abl (ABL), a tyrosine kinase thought to be involved in growth control, resides on the distal arm of human chromosome 9, while the gene for c-bcr (BCR) resides on human chromosome 22. The translocation places the promoter distal three exons of ABL, including those elements which encode the tyrosine kinase domain, downstream of either the first or second exon of BCR. Chung, S. and Wong, P. M. C., Oncogene, 10:1261-1268 (1995). The product of the translocation between human chromosome 9 and human chromosome 22 is a chimeric gene, BCR-ABL, which encodes a fusion
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protein, often referred to as p185.sup.bcr-abl or p210.sup.bcr-abl, depending upon the inclusion of the second exon of BCR. Bartram, C. R., et al., Nature, 306:277-280 (1983). p185.sup.bcr-abl causes acute leukemia, typically lymphoblastic; p210.sup.bcr-abl usually causes CML, but can occasionally also cause acute leukemia. Compared to normal c-abl, bcr-abl has increased tyrosine kinase activity. Konopka, J., et al., Cell, 37:1035-1042 (1984). Additionally, c-abl, as a non-receptor tyrosine kinase, functions both in the nucleus and the cytoplasm and bcr-abl functions exclusively in the cytoplasm. These two characteristics of bcr-abl are essential elements of its transforming abilities. McWhirter, J. R., et al., Mol. Cell Bio., 11:1553-1565 (1991). Following this chromosomal translocation within a single, primitive myeloid stem cell, the progeny of the affected cell gradually populate the entire intermediate and late hematopoietic maturational compartments. Despite the presence of the Philadelphia chromosome, these progeny, referred to as Ph.sup.+ cells, are able to differentiate and mature along the various myeloid lineages while retaining the capacity to function as their normal, unaffected counterparts. Invariably, in an average span of three to five years, the disease progresses into a malignant stage known as blast crisis. The affected cells acquire additional chromosomal abnormalities and lose their ability to differentiate and mature, resulting in the functional breakdown of the hematopoietic system. Clarkson, B. and Strife, A., Leukemia, 7:1683-1721 (1993). Daley, G. Q. and Ben Neriah, Y., Adv. Cancer Res., 57:151-184 (1991). Deisseroth, A. B. and Arlinghaus, R. B., eds. Chronic Myelogenous Leukemia-Molecular Approaches to Research and Therapy, New York, Marcel Dekker (1991). Sawyers, C. L. et al., Cell, 64:337-350 (1991). Web site: http://www.delphion.com/details?pn=US06100386__ •
Method and composition for detection of human chronic myelogenous leukemia Inventor(s): Konopka; James (Santa Monica, CA), Watanabe; Susan (Santa Monica, CA), Witte; Owen N. (Santa Monica, CA) Assignee(s): The Regents of the University of California (Berkeley, CA) Patent Number: 4,599,305 Date filed: July 16, 1984 Abstract: A method for detecting chronic myelogenous leukemia in a human comprising the step of testing a biological sample from a patient to determine the presence of a marker protein (P210) which is characterized as a c-abl protein having tyrosine kinase activity and a molecular weight of approximately 210,000. Antisera which are specific for the P210 protein are disclosed which can be used to precipitate the P210 protein to allow identification by gel electrophoresis or other technique. Excerpt(s): The present invention relates generally to methods and reagents used in the detection of cancer. More particularly, the present invention relates to a new diagnostic approach for the detection of chronic myelogenous leukemia. Leukemia is a malignant disease of the blood-forming organs which involves the distorted proliferation and development of leukocytes and their precursors in bone marrow and blood. There are different types of leukemia which are classified according to two basic considerations: (1) the duration and character of the disease--acute or chronic and (2) the type of cell involved--myeloid (myelogenous) or lymphoid (lymphogenous). In general, the different types of leukemia are restricted to different age groups. For example, acute lymphoid leukemia generally occurs in young children while acute myelogenous leukemia is found principally in young adults. The chronic forms of leukemia are found principally in adults.
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Web site: http://www.delphion.com/details?pn=US04599305__ •
Method for the treatment of chronic myelogenous leukemia Inventor(s): Sherwin; Stephen A. (San Francisco, CA) Assignee(s): Genentech, Inc. (South San Francisco, CA) Patent Number: 4,851,219 Date filed: November 18, 1986 Abstract: Gamma interferon is employed in the treatment of chronic myelogenous leukemia. Patients treated in the benign stage exhibit partial and, in some cases, complete responses to gamma interferon. Successful results have also been obtained with some patients in the blast stage of the disease as well as patients who had been found to be refractory to treatment with alpha interferon. Excerpt(s): This invention relates to the therapy of patients afflicted with chronic myelogenous leukemia (CML). Chronic myelogenous leukemia (CML) is a chronic form of leukemia originating in a primitive myeloid stem cell in which the leukemic cells retain the capacity for differentiation and are able to perform the essential functions of normal hematopoietic cells that they replace in the marrow. The leukemic cells have a pronounced tendency to undergo further malignant transformation with loss of ability to differentiate in later stages of the disease. Although commonly included among other myeloproliferative disorders, CML is a distinct entity that is easily recognized because the leukemic cells have a distinctive cytogenetic abnormality, the Philadelphia (Ph.sup.1) chromosome (also designated Ph.sup.+). The etiology is unknown. The majority of patients with CML have no history of excessive exposure to ionizing radiation or chemical leukemogens, but the incidence increases greatly with exposure to high doses of radiation. Web site: http://www.delphion.com/details?pn=US04851219__
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Method of detecting abnormalities
genetic
translocations
identified
with
chromosomal
Inventor(s): Gray; Joe W. (Livermore, CA), Pinkel; Daniel (Walnut Creek, CA), Tkachuk; Douglas (Livermore, CA) Assignee(s): The Regents of the University of California (Oakland, CA) Patent Number: 6,280,929 Date filed: June 7, 1995 Abstract: Methods and compositions for staining based upon nucleic acid sequence that employ nucleic acid probes are provided. Said methods produce staining patterns that can be tailored for specific cytogenetic analyses. Said probes are appropriate for in situ hybridization and stain both interphase and metaphase chromosomal material with reliable signals. The nucleic acid probes are typically of a complexity greater than 50 kb, the complexity depending upon the cytogenetic application. Methods and reagents are provided for the detection of genetic rearrangements. Probes and test kits are provided for use in detecting genetic rearrangements, particularly for use in tumor cytogenetics, in the detection of disease related loci, specifically cancer, such as chronic myelogenous leukemia (CML) and for biological dosimetry. Methods and reagents are described for
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cytogenetic research, for the differentiation of cytogenetically similar but genetically different diseases, and for many prognostic and diagnostic applications. Excerpt(s): The invention relates generally to the field of cytogenetics, and more particularly, to the field of molecular cytogenetics. The invention concerns methods for identifying and classifying chromosomes. Still more particularly, this invention concerns nucleic acid probes which can be designed by the processes described herein to produce staining distributions that can extend along one or more whole chromosomes, and/or along a region or regions on one or more chromosomes, including staining patterns that extend over the whole genome. Staining patterns can be tailored for any desired cytogenetic application, including prenatal, tumor and disease related cytogenetic applications, among others. The invention provides for compositions of nucleic acid probes and for methods of staining chromosomes therewith to identify normal chromosomes and chromosomal abnormalities in metaphase spreads and in interphase nuclei. The probe-produced staining patterns of this invention facilitate the microscopic and/or flow cytometric identification of normal and abnormal chromosomes and the characterization of the genetic nature of particular abnormalities. The particular focus of this application is that wherein the abnormalities are genetic rearrangements. Although most of the examples herein concern human chromosomes and much of the language herein is directed to human concerns, the concept of using nucleic acid probes for staining or painting chromosomes is applicable to chromosomes from any source including both plants and animals. Chromosome abnormalities are associated with genetic disorders, degenerative diseases, and exposure to agents known to cause degenerative diseases, particularly cancer, German, "Studying Human Chromosomes Today," American Scientist, Vol. 58, pgs. 182-201 (1970); Yunis, "The Chromosomal Basis of Human Neoplasia," Science, Vol. 221, pgs. 227-236 (1983); and German, "Clinical Implication of Chromosome Breakage," in Genetic Damage in Man Caused by Environmental Agents, Berg, Ed., pgs. 65-86 (Academic Press, New York, 1979). Chromosomal abnormalities can be of several types, including: extra or missing individual chromosomes, extra or missing portions of a chromosome (segmental duplications or deletions), breaks, rings and chromosomal rearrangements, among others. Chromosomal or genetic rearrangements include translocations (transfer of a piece from one chromosome onto another chromosome), dicentrics (chromosomes with two centromeres), inversions (reversal in polarity of a chromosomal segment), insertions, amplifications, and deletions. Web site: http://www.delphion.com/details?pn=US06280929__ •
Oncogene fusion protein peptide vaccines Inventor(s): Bocchia; Monica (New York, NY), Scheinberg; David A. (New York, NY), Sette; Alessandro (La Jolla, CA) Assignee(s): Cytel Corporation (San Diego, CA), Sloan-Kettering Institute for Cancer Research (New York, NY) Patent Number: 6,156,316 Date filed: May 8, 1995 Abstract: Fusion-point spanning peptides, for example BCR-ABL fusion breakpoint peptides associated with chronic myelogenous leukemia (CML), bind major histompatibility complex molecules, such as HLA class I molecules, and induce cytotoxic T cell proliferation. The breakpoint peptides can be used as vaccines.
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Excerpt(s): Throughout this application, various references are referred to within parenthesis. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains. Full bibliographic citation for these references may be found at the end of this application, preceding the sequence listing and the claims. Most human leukemia are associated with chromosomal abnormalities resulting from genetic mutations or translocations that can create new hybrid genes capable of expressing mutated or fused proteins. The encoded abnormal fusion proteins are characterized by a joining region segment composed of a unique sequence of amino acids that is potentially immunogenic. In chronic myelogenous leukemia (CML), the t(9;22) translocation results in a chimeric bcr-abl gene which encodes a 210 kD fusion protein. Two chimeric P210 bcr-abl proteins comprising products of either the b2a2 exon junction or the b3a2 exon junction can be alternatively expressed in CML cells. The junctional sequences represent unique tumor specific determinants, not only because they contain a joined set of amino acid sequences that are normally not expressed on the same protein, but also because at the exact fusion point, a codon for a new amino acid is present (1,2). Web site: http://www.delphion.com/details?pn=US06156316__ •
Therapeutic treatment of chronic myelogenous leukemia by administration of 2chloro-2'-deoxy adenosine Inventor(s): Beutler; Ernest (La Jolla, CA) Assignee(s): The Scripps Research Institute (La Jolla, CA) Patent Number: 5,401,724 Date filed: February 25, 1994 Abstract: A process for the treatment of chronic myelogenous leukemia in mammals is disclosed that utilizes a 2-halo-2'-deoxyadenosine derivative as the active treating agent. Excerpt(s): This invention relates to a novel treatment for chronic myelogenous leukemia. More particularly, this invention relates to a process for the treatment of chronic myelogenous leukemia involving the administration of a 2-halo-2'deoxyadenosine. An adult human has about 7000 white blood cells per microliter (.mu.l) of blood. Of those white cells, about 65 percent are granulocytes (about 4500/.mu.l), about 30 percent are monocytes (about 2100/.mu.l) and about five percent are lymphocytes (about 350/.mu.l). Geyton, Textbook of Medical Physiology, Seventh ed., W. B. Saunders Co., Philadelphia (1986). The above cell numbers are, of course, generalized average values, and granulocyte counts for normal patients; i.e., patients that do not have DML or a similar disease exhibiting an increased or decreased granulocyte count, typically have granulocyte counts ranging from about 2000 to about 7000 cells/.mu.l. Chronic myelogenous leukemia (CML), also known as chronic granulocytic leukemia (CGL), is a neoplastic disorder of the hematopoietic stem cell. In its early phases it is characterized by leukocytosis, the presence of increased numbers of immature granulocytes in the peripheral blood, splenomegaly and anemia. These immature granulocytes include basophils, eosinophils, and neutrophils. The immature granulocytes also accumulate in the bone marrow, spleen, liver, and occasionally in other tissues. Patients presenting with this disease characteristically have more than 75,000 white blood cells per microliter (.mu.l), and the count may exceed 500,000/.mu.l. Web site: http://www.delphion.com/details?pn=US05401724__
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•
Thrombopoietin signaling defect in polycythemia vera platelets Inventor(s): Moliterno; Alison (Baltimore, MD), Spivak; Jerry (Baltimore, MD) Assignee(s): Johns Hopkins University (Baltimore, MD) Patent Number: 6,027,902 Date filed: May 20, 1998 Abstract: Impaired TPO-mediated platelet protein tyrosine phosphorylation was consistently observed in patients with polycythemia vera (PV) as well as those with idiopathic myelofibrosis (IMF), in contrast to patients with essential thrombocytosis, chronic myelogenous leukemia, secondary erythrocytosis, iron deficiency anemia, hemochromatosis or normal volunteers. Moreover, the platelet TPO receptor, Mpl, was not detectable by immunoblotting with an antibody to the extracellular domain, by chemical crosslinking of TPO to the surface of platelets, or by flow cytometry using an antibody to the extracellular domain, in 34 of 34 PV patients and also in 13 of 14 IMF patients. Impaired TPO-induced protein tyrosine phosphorylation in PV and IMF platelets was uniformly associated with markedly reduced or absent expression of the extracellular domain of Mpl. Thus the reduced detectablility of Mpl by these methods can be used a marker of PV and IMF. The abnormality appears to distinguish PV from other forms of erythrocytosis and may be involved in the platelet function defect associated with PV. Excerpt(s): Polycythemia vera (PV), idiopathic myelofibrosis (IMF), chronic myelogenous leukemia (CML) and essential thrombocythemia (ET) are classified as the chronic myeloproliferative disorders because their pathophysiology involves the clonal expansion of a multipotent hematopoietic progenitor cell with the over-production of one or more of the formed elements of the blood (1,2,3,4). However, with the exception of CML, these disorders lack a clonal marker, their pathogenesis is unknown, and their diagnosis therefore is dependent upon clinical criteria. Remarkably, in spite of their origin from a transformed clone, the mature circulating blood cells in these disorders are morphologically normal and, in contrast to CML, progression to acute leukemia is far less common in PV, ET and IMF. Furthermore, while these latter disorders can mimic each other clinically, they have distinctly different clinical courses and differ with respect to their treatment. Therefore, the identification of a diagnostic marker would be very useful. Polycythemia vera is the commonest of the chronic myeloproliferative disorders and although its hallmark is trilineage hyperplasia, erythrocytosis is its most prominent clinical manifestation. For this reason, most investigators have focused on erythropoiesis in PV in an attempt to define its etiology but without notable success. There is a need in the art for diagnostic methods for distinguishing PV from other diseases involving erythrocytosis. Web site: http://www.delphion.com/details?pn=US06027902__
Patent Applications on Chronic Myelogenous Leukemia 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
9
This has been a common practice outside the United States prior to December 2000.
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several years.) The following patent applications have been filed since December 2000 relating to chronic myelogenous leukemia: •
BAALC expression as a diagnostic marker for acute leukemia Inventor(s): de la Chapelle, Albert; (Delaware, OH), Tanner, Stephan Markus; (Columbus, OH) Correspondence: Calfee Halter & Griswold, Llp; 800 Superior Avenue; Suite 1400; Cleveland; OH; 44114; US Patent Application Number: 20030119043 Date filed: November 12, 2002 Abstract: Overexpression of the gene, BAALC, in biological samples from a patient is prognostic for tumor aggressiveness and unfavorable patient outcome. The present invention provides polynucleotide primers and probes for assaying for overexpression of BAALC transcripts. Kits containing the primers and probes are also provided. Also provided are antibodies for assaying for overexpression of BAALC proteins as well as peptide immunogens for producing the anti-BAALC antibodies. The present invention also provides methods for characterizing acute myelogenous leukemia, chronic myelogenous leukemia and prostate cancer in a patient, base on detection of BAALC overexpression. Excerpt(s): This application claims priority to U.S. Provisional Application S/ No. 60/348,210, filed Nov. 9, 2001, which is incorporated herein in its entirety. Leukemias comprise approximately 2% of adult cancers and are a heterogeneous group. There are two broad categories of leukemias. Acute leukemias arise when there is a block in the normal differentiation of cells to mature blood cells that results in large accumulations of immature cells or blasts in the blood. Examples of such cancers are acute myelogenous leukemia (AML; other names are acute myeloid leukemia and acute nonlymphocytic leukemia) and acute lymphoblastic leukemia (ALL). In chronic leukemia, on the other hand, there is unregulated proliferation of cells that have differentiated to mature blood cells. Examples of such cancers are chronic lymphocytic leukemia (CLL) and chronic myelogenous leukemia (CML). CML has a chronic phase which then progresses to a phase called blast crisis where immature, blast cells are present in the blood. Both acute and chronic leukemias involve the myeloid cells of the bone marrow, including white cells, red cells, megakaryocytes and cells of the lymphoid lineage. The cytogenetics of many leukemias are characterized by balanced chromosomal translocations that give rise to gene rearrangements. In acute myeloid leukemia (AML) for example, about 55% of adult de novo cases have clonal cytogenetic abnormalities, many of which are specific translocations. However, in the remaining cases, no visible cytogenetic abnormalities are found, although genetic changes are detected methods other than cytogenetics. In adult acute lymphoblastic leukemia (ALL), the proportion of patients with no cytogenetic abnormality is about 31%. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Bcr-Abl oligomerization domain polypeptides and uses therefor Inventor(s): Ghaffari, Saghi; (Boston, MA), Kim, Peter S.; (Bryn Mawr, PA), Lodish, Harvey F.; (Brookline, MA), Malashkevich, Vladimir N.; (Revere, MA), Zhao, Xun; (San Diego, CA) Correspondence: Hamilton, Brook, Smith & Reynolds, P.C.; 530 Virginia Road; P.O. Box 9133; Concord; MA; 01742-9133; US Patent Application Number: 20030064061 Date filed: July 9, 2002 Abstract: Recombinant Bcr-Abl polypeptides that form a stable.alpha.-helical structure; nucleic acids encoding recombinant Bcr-Abl polypeptides; methods of identifying or designing inhibitors of Bcr-Abl oligomerization and methods of inhibiting Bcr-Abl oligomerization in cells and in individuals in need of inhibiting Bcr-Abl oligomerization, such as individuals who have developed or are at risk of developing chronic myelogenous leukemia or acute lymphoblastic leukemia. Excerpt(s): This application claims the benefit of U.S. Provisional Application No. 60/303,857 filed Jul. 9, 2001. The entire teachings of the above-referenced application are incorporated herein by reference in their entirety. The invention described herein is related, at least in part, to the determination of the crystal structure of the Bcr-Abl oligomerization domain and the modes of Bcr-Abl oligomer formation which result in transformation of Bcr-Abl expressing cells. It has also been determined that Bcr-Abl oligomerization is inhibited in a dominant negative manner, with the result that the transforming potential of Bcr-Abl is also inhibited, thus demonstrating the therapeutic potential of inhibiting Bcr-Abl oligomerization in reducing proliferation and oncogenesis of Bcr-Abl expressing cells. The crystal structure of the Bcr-Abl oligomerization domain, understanding of the process by which Bcr-Abl oligomerization occurs and recombinant Bcr.sub.172 described herein provide methods and compositions useful in inhibiting and in identifying or designing inhibitors of BcrAbl oligomerization. Described herein are isolated forms of the Bcr-Abl oligomerization domain; nucleic acids, e.g., DNA, RNA, that encode the recombinant forms of the oligomerization domain; vectors that contain and express nucleic acids that encodes recombinant oligomerization domains; cells, such as prokaryotic cells, e.g., bacteria, and eukaryotic cells, particularly mammalian, e.g., human cells, that contain the vectors and in which the recombinant oligomerization domains are expressed; and antibodies that bind recombinant oligomerization domains of the present invention. Also described herein are methods of expressing recombinant oligomerization domains; methods of inhibiting Bcr-Abl oligomerization and, thus, Bcr-Abl transformation of eukaryotic cells, e.g., mammalian cells, such as human cells; methods of identifying or designing agents or drugs that inhibit Bcr-Abl oligomerization; agents or drugs identified or designed by the methods of the present invention and methods of inhibiting Bcr-Abl oligomerization and, thus, Bcr-Abl transformation of cells/constitutive activation of Abl tyrosine kinase activity, in an individual in need of such inhibition, e.g., an individual, such as a human, who has developed or is at risk of developing CML or ALL. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Chromosome-specific staining to detect genetic rearrangements Inventor(s): Gray, Joe W.; (Livermore, CA), Pinkel, Daniel; (Walnut Creek, CA), Tkachuk, Douglas; (Livermore, CA) Correspondence: R. Danny Huntington, ESQ.; Burns, Doane, Swecker & Mathis, L.L.P.; P.O. Box 1404; Alexandria; VA; 22313-1404; US Patent Application Number: 20020177130 Date filed: January 22, 2001 Abstract: Methods and compositions for staining based upon nucleic acid sequence that employ nucleic acid probes are provided. Said methods produce staining patterns that can be tailored for specific cytogenetic analyses. Said probes are appropriate for in situ hybridization and stain both interphase and metaphase chromosomal material with reliable signals. The nucleic acid probes are typically of a complexity greater than 50 kb, the complexity depending upon the cytogenetic application. Methods and reagents are provided for the detection of genetic rearrangements. Probes and test kits are provided for use in detecting genetic rearrangements, particularly for use in tumor cytogenetics, in the detection of disease related loci, specifically cancer, such as chronic myelogenous leukemia (CML) and for biological dosimetry. Methods and reagents are described for cytogenetic research, for the differentiation of cytogenetically similar but genetically different diseases, and for many prognostic and diagnostic applications. Excerpt(s): Chromosome abnormalities are associated with genetic disorders, degenerative diseases, and exposure to agents known to cause degenerative diseases, particularly cancer, German, "Studying Human Chromosomes Today," American Scientist, Vol. 58, pgs. 182-201 (1970); Yunis, "The Chromosomal Basis of Human Neoplasia," Science, Vol. 221, pgs. 227-236 (1983); and German, "Clinical Implication of Chromosome Breakage," in Genetic Damage in Man Caused by Environmental Agents, Berg, Ed., pgs. 65-86 (Academic Press, New York, 1979). Chromosomal abnormalities can be of several types, including: extra or missing individual chromosomes, extra or missing portions of a chromosome (segmental duplications or deletions), breaks, rings and chromosomal rearrangements, among others. Chromosomal or genetic rearrangements include translocations (transfer of a piece from one chromosome onto another chromosome), dicentrics (chromosomes with two centromeres), inversions (reversal in polarity of a chromosomal segment), insertions, amplifications, and deletions. Measures of the frequency of structurally aberrant chromosomes, for example, dicentric chromosomes, caused by clastogenic agents, such as, ionizing radiation or chemical mutagens, are widely used as quantitative indicators of genetic damage caused by such agents, Biochemical Indicators of Radiation Injury in Man (International Atomic Energy Agency, Vienna, 1971); and Berg, Ed. Genetic Damage in Man Caused by Environmental Agents (Academic Press, New York, 1979). A host of potentially carcinogenic and teratogenic chemicals are widely distributed in the environment because of industrial and agricultural activity. These chemicals include pesticides, and a range of industrial wastes and by-products, such as halogenated hydrocarbons, vinyl chloride, benzene, arsenic, and the like, Kraybill et al., Eds., Environmental Cancer (Hemisphere Publishing Corporation, New York, 1977). Sensitive measures of chromosomal breaks and other abnormalities could form the basis of improved dosimetric and risk assessment methodologies for evaluating the consequences of exposure to such occupational and environmental agents. Current procedures for genetic screening and bio- logical dosimetry involve the analysis of karyotypes. A karyotype is the particular chromosome complement of an individual or of a related group of individuals, as defined both by the number and morphology of the
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chromosomes usually in mitotic metaphase. It includes such things as total chromosome number, copy number of individual chromosome types (e.g., the number of copies of chromosome X), and chromosomal morphology, e.g., as measured by length, centromeric index, connectedness, or the like. Chromosomal abnormalities can be detected by examination of karyotypes. Karyotypes are conventionally determined by staining an organism's metaphase, or otherwise condensed (for example, by premature chromosome condensation) chromosomes. Condensed chromosomes are used because, until recently, it has not been possible to visualize interphase chromosomes due to their dispersed condition and the lack of visible boundaries between them in the cell nucleus. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Herbal based composition for treating acute and chronic myeloid leukemia Inventor(s): Bandyopadhyay, Gautam; (Kolkata, IN), Bandyopadhyay, Santu; (Calcutta, IN), Bhattacharya, Samir; (Kolkata, IN), Biswas, Tanusree; (Kolkata, IN), Pal, Bikash Chandra; (Kolkata, IN), Ray, Mitali; (Kolkata, IN), Roy, Keshab Chandra; (Calcutta, IN) Correspondence: Fitzpatrick Cella Harper & Scinto; 30 Rockefeller Plaza; New York; NY; 10112; US Patent Application Number: 20040043086 Date filed: May 30, 2003 Abstract: A new herbal-based composition and method for treatment of CD33+ acute and chronic myeloid leukemia by Piper betel leaf extracts, and to provide a process for the isolation of active fractions from leaves or any other plant parts of Piper betel to treat CD3 3+ AML and CML with a simplified method of isolation of active components from all plant parts of Piper betel possessing biological activities relevant to the treatment of CD33+ AML and CML. Excerpt(s): This invention relates to a herbal based composition for treatment of CD33+ acute and chronic myeloid leukemia by Piper betel leaf extracts, fractions of Piper betel leaf extracts and 3-O-p-coumaryl quinic acid purified from Piper betel leaves extract. Mycloid leukemia, both acute (AML) and chronic (CML) are lethal, there is no drug directing towards the destruction of the myeloid cells and these cells poorly respond to chemotherapy, which is always non-specific, thus adversely affecting normal cells. Unique property of the therapy with Piper betel components is the killing of myeloid cancer cells by recognizing CD33+ marker on the cell membrane, leaving normal cells without getting affected. Myeloid leukemia is usually subdivided into two groups: Acute Myeloid Leukemia (AML) and Chronic Myeloid Leukemia (CML). AML is characterized by an increase in the number of myeloid cells in the bone marrow and an arrest in their maturation. In the United States, the annual incidence of AML is approximately 2.4 per 100,000 and it increases progressively with age, to a peak of 12.6 per 100,000 in adults of 65 years age or older. The CML is a malignant clonal disorder of hematopoietic stem cells. The median age at presentation is 53 years, but it occurs at all age groups, including children. The natural history of CML is progression from a benign chronic phase to a rapidly fatal blast crisis within three to five years or even earlier. The prognosis of CML is also poor inspite of vast advancement of clinical medicine (1). CD33 represents a specific and useful marker in the process of myeloid cell differentiation (2). Recent reports suggest that engagement of CD33 by monoclonal antibody induced apoptosis leading to growth inhibition of proliferation of AML and CML cells in vitro (2,3). Exploiting the myeloid specific expression of CD33, humanized anti-CD33 monoclonal antibody conjugated with anti-cancer drug has been tried in AML patients
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with significant success (4). With the extract from Piper betel leaves anti-myeloid activity was claimed earlier (Patent filed no. PCT/INOO/00118 dated Dec. 12, 2000). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Herbal composition for treating CD33+ acute and chronic myeloid leukemia and a method thereof Inventor(s): Bandyopadhyay, Santu; (Calcutta, IN), Banerjee, Goutam; (Calcutta, IN), Bhattacharya, Samir; (Calcutta, IN), Biswas, Tanusree; (Calcutta, IN), Pal, Bikash Chandra; (Calcutta, IN), Ray, Mitali; (Calcutta, IN), Roy, Keshab Chandra; (Calcutta, IN) Correspondence: Fitzpatrick Cella Harper & Scinto; 30 Rockefeller Plaza; New York; NY; 10112; US Patent Application Number: 20030049334 Date filed: July 30, 2002 Abstract: The present invention relates to a method of treating CD33+ acute and chronic myeloid leukemia in animals including humans, using fraction nos. 1 and 9 obtained from water:methanol fraction by column chromatography, with ratio of water and methanol ranging between 1:5 to 5:1, wherein said water:methanol fraction is obtained from the polar extract of piper betel by HPLC, with retention time of 3.6 and 24.0 minutes respectively, with said fractions used both individually, and in combination, and a composition comprising the said fraction nos. 1 and 9. Excerpt(s): This invention also relates to a method of treating Myeloid leukemia using the betel leaf extract to an animal including human beings suffering from Myeloid leukemia. Further, this invention also relates to a herbal based composition for treatment of CD33+ acute and chronic myeloid leukemia by Piper betel leaf extracts, fractions of Piper betel leaf extracts and 3-O-p-coumaryl quinic acid purified from Piper betel leaves extract. Betel leaves have a strong pungent aromatic flavor and are widely used as a masticatory. Generally, mature or over mature leaves, which have ceased growing but not yet become brittle are used for chewing. The basic preparation for chewing purposes consists of betel leaf smeared with hydrated lime and catechu to which scrapings of arecanut are added; flavorings such as coconut shavings, clove, cardamom, fennel, powdered liquorice, nutmeg and also tobacco are used according to one's taste. In some places prepared pan is covered with silver or gold leaf. As a masticatory, it is credited with many properties: it is aromatic, digestive, stimulant and carminative. Medicinally it is useful in catarrhal and pulmonary infections; it is also used for poultices. The effects of chewing of betel with arecanut and other adjuncts are the excitation of the salivary glands and the irritation of the mucous membrane of the mouth. The red coloration produced is due to a pigment in the arecanut, which manifests itself under the action of alkali in time and catechu. A mild degree of stimulation is produced, resulting in a sensation of warmth and well being, besides imparting a pleasant odor. The most important factor determining the aromatic value of the leaf is the amount and particularly the nature of the essential oil present. Betel leaves from different regions vary in smell and taste. The most pungent is the Sanchi type, while the most mild and sweet ones are from Madras. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Immunotherapy for chronic myelocytic leukemia Inventor(s): Goldenberg, David M.; (Mendham, NJ), Hansen, Hans J.; (Sidell, LA) Correspondence: Bernhard D. Saxe; Foley & Lardner; Washington Harbour; 3000 K Street, Suite 500; Washington; DC; 20007-5109; US Patent Application Number: 20020022031 Date filed: August 8, 2001 Abstract: Immunotherapy utilizing naked anti-granulocyte antibodies provides an effective means for treating chronic myelocytic leukemia (CML). Such antibodies can be administered alone or in combination with other therapies, such as immunoconjugates or chemotherapeutics. In either format, an effective therapy for treating CML is provided, which avoids the toxic side-effects typically associated with cancer therapy. The disclosed immunotherapy also is effective for treating acute myelocytic leukemia (AML) when co-administered with inducing agents which induce expression of antigens minimally displayed on the surface of myeloblasts. Excerpt(s): Chronic myelocytic leukemia (CML) is a highly specific disease that is defined by strict hematologic parameters that include a pathognomonic differential leukocyte count. Usually, CML is accompanied by the presence, in bone marrow cells, of the Ph chromosome, the first chromosomal anomaly to be regularly associated with a human neoplastic disease. Chronic myelocytic leukemia is a disease of worldwide distribution and predominantly appears during middle age. The disease is characterized by an initial chronic phase when it behaves as a differentiated neoplasm and responds very well to simple, nonintensive therapy. After a variable interval, CML metamorphosizes to a refractory phase that responds poorly or not at all to therapy, even when intensive. See Spiers, Semin. Oncol., 22(4):380-95 (1995). At the stage of metamorphosis a great variety of clinical and hematologic pictures occur, and CML may mimic a myeloproliferative disease, a myelodysplasia, a subacute leukemia, acute myelocytic leukemia (AML), or acute lymphocytic leukemia (ALL). The old concept of an abrupt, explosive transition from the chronic phase to a so-called blastic crisis is incorrect. See Spiers, Semin. Oncol., 22(4):380-95 (1995). In most cases, CML is observed to undergo two or more stepwise evolutions, e.g., from chronic phase to an accelerated myeloproliferative phase to a phase that resembles AML. A variety of therapies have been used to treat CML. Traditional methods for treating leukemia, including chemotherapy and radiotherapy, have limited utility due to toxic side effects. The use of monoclonal antibodies to direct radionuclides, toxins or other therapeutic agents selectively to tumor sites has reduced the level of toxicity to normal tissues. However, due to the large quantities of conjugate which must be administered, such therapies continue to produce toxic side-effects. These aspects limit the effectiveness and duration of such treatments. Another therapy, allogeneic bone marrow transplants, has had the largest impact on survival among patients with CML. See Clarkson, J. Clin. Oncol., 3:135-139 (1985). Like the previous therapies, however, bone marrow transplants are poorly tolerated by patients. Recent studies suggest that immunotherapy utilizing naked antibodies can be an effective tool for treating certain cancers. The use of naked, humanized, anti-CD33 antibodies has proved effective in treating acute myelocytic leukemia and in reducing the residual disease in patients. See Caron et al., Clin. Cancer Res., 4:1421-1428 (1998); Jurcic et al., Clin. Cancer Res., 6:372-380 (2000). Similarly, immunotherapy comprising naked, humanized, anti-HER2/neu antibodies has produced promising results in the treatment of breast cancer. See Baselga et al., Semin. Oncol., 26:78-83 (1999); Weiner, Semin. Oncol., 26:43-51 (1999). Unconjugated immunoglobulins directed against CD20 have been shown to induce partial and
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complete responses in up to 50% of patients with advanced, indolent non-Hodgkin's lymphoma. See Weiner, Semin. Oncol., 26:43-51 (1999). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Inhibition of chronic myelogenous leukemic cell growth by liposomal-antisense oligodeoxy-nucleotides targeting to Grb2 or Crk1 Inventor(s): Arlinghaus, Ralph B.; (Bellaire, TX), Lopez-Berestein, Gabriel; (Bellaire, TX), Tari, Ana M.; (Houston, TX) Correspondence: Fulbright & Jaworski L.L.P.; 600 Congress AVE.; Suite 2400; Austin; TX; 78701; US Patent Application Number: 20030153526 Date filed: December 20, 2002 Abstract: The present invention provides novel compositions and methods for use in the treatment of cancer, specifically, in the treatment of chronic myelogenous leukemia (CML). The compositions contain antisense oligonucleotides that hybridize to Grb2 and Crkl nucleic acids, the gene products of which are known to interact with the tumorigenic protein bcr-abl. Used alone, in conjunction with each other, and even in conjunction with antisense oligonucleotides directed to bcr-abl nucleic acids, these compositions inhibit the proliferation of CML cancer cells. Excerpt(s): The present invention relates to the field of cancer therapy, specifically, the treatment of chronic myelogenous leukemia. More particularly, these treatments involve the use of antisense oligonucleotides and liposomal formulations thereof. Chronic myelogenous leukemia (CML) is a hematologic malignancy in which uncontrolled proliferation of granulocytes occurs. It often is characterized by the reciprocal translocation of chromosomes 9 and 22, which relocates the Ableson (abl) protooncogene onto the 3'-end of the breakpoint cluster region (bcr). This produces a chimeric bcr-abl gene encoding a p210.sup.bcr-abl fusion protein, which is tumorigenic and is necessary for the growth of CML cells (Szczylik et al., 1991; Skorski et al., 1994; Tari et al., 1994; McGahon et al., 1994; Bedi et al., 1994). The bcr-abl protein can autophosphorylate at the 177 tyrosine amino acid found within the first exon of bcr. When phosphorylated, the bcr domain of the bcr-abl protein binds to the SH2 domain of the growth factor receptor-bound protein 2 (Grb2) adaptor protein. Through the SH3 domain, Grb2 binds to the human Son of sevenless 1 (hSos1) GDP/GTP exchange factor resulting in ras protein activation. The bcr-abl protein can also transphorylate the 177 tyrosine amino acid found within the normal bcr protein. It is believed that when the normal bcr protein becomes tyrosine phosphorylated at amino acid 177, it also will complex with Grb2. When the bcr-abl protein is expressed, the p46 and p52 Shc (Puil et al., 1994) proteins become tyrosine phosphorylated as well. These Shc proteins have also been shown to form stable complexes with Grb2. Therefore, Grb2 appears to play a very important role in the tumorigenicity mediated by the bcr-abl protein (Puil et al., 1994; Pendergast et al., 1993). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Method for treating chronic myelogenous leukemia Inventor(s): Lyons, John; (Moraga, CA) Correspondence: Wilson Sonsini Goodrich & Rosati; 650 Page Mill Road; Palo Alto; CA; 943041050 Patent Application Number: 20030147813 Date filed: February 7, 2002 Abstract: Methods, compositions and kits are provided for treating cancer associated with protein tyrosine kinase activity such as chronic myelogenous leukemia. In particular, a treatment method is provided comprising: administering to a patient having chronic myelogenous leukemia and a degree of resistance to imatinib mesylate, a therapeutically effective amount of a DNA methylation inhibitor which mitigates the imatinib mesylate resistance. Excerpt(s): The invention relates to methods, compositions, and kits for treating cancer associated with protein tyrosine kinase activity, and more particularly for treating chronic myelogenous leukemia. Chronic Myelogenous Leukemia (CML) is a myeloproliferative disorder of a pluripotent hematopoietic stem cell with a particular cytogenetic abnormality, the Philadelphia chromosome. Faderl et al (1999) Ann. Intern. Med. 131: 207-219. In childhood, it accounts for only 2 to 5% of all malignant disorders and presents as either of two distinct clinical entities, adult-type CML and juvenile CML. Adult-type CML of childhood is indistinguishable from that seen in older patients. However, juvenile CML is restricted to children and is Philadelphia chromosome negative. Grier and Civin (1998) in (Nathan and Oski, eds) Hematology of Infancy and Childhood, volume 2, 5th ed, W. B. Saunders Company, 34:1286-1459. CML is a progressive, uniformly fatal disease in untreated patients. It is characterized by three distinct phases: a chronic phase lasting three to five years; an acute or accelerated phase lasting three to six months; and a brief blastic crisis phase. The progression of the disease to blast crisis results in rapid death due to infections, bleeding and leukemic organ infiltration. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Method to identify genes associated with chronic myelogenous leukemia Inventor(s): Verfaillie, Catherine; (St Paul, MN) Correspondence: Schwegman, Lundberg, Woessner & Kluth, P.A.; P.O. Box 2938; Minneapolis; MN; 55402; US Patent Application Number: 20040076978 Date filed: November 17, 2003 Abstract: A method to detect genes that are differentially expressed in chronic myelogenous leukemia is provided. Excerpt(s): This application claims the benefit of the filing date of U.S. application Serial No. 60/248,403, filed Nov. 14, 2000, under 35 U.S.C.sctn. 119(e). Chronic myelogenous leukemia (CML) is a lethal disease of hematopoietic stem cells, characterized by a specific chromosomal translocation between human chromosome 9 and human chromosome 22. The chromosome resulting from this translocation is commonly referred to as the Philadelphia chromosome (Darnell et al., 1990). The c-abl gene (ABL), a tyrosine kinase thought to be involved in growth control, resides on the distal arm of
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human chromosome 9, while the c-bcr gene (BCR) resides on human chromosome 22. The translocation places the promoter distal three exons of ABL, including those elements which encode the tyrosine kinase domain, downstream of either the first or second exon of BCR (Chung and Wong, 1995). The product of the translocation between human chromosome 9 and human chromosome 22 is a chimeric gene, BCR-ABL, which encodes a fusion protein, often referred to as p185.sup.BCR-ABL or p210.sup.BCR-ABL, depending upon the inclusion of the second exon of BCR (Bartram et al., 1983). p185.sup.BCR-ABL causes acute leukemia, typically lymphoblastic; p210.sup.BCR-ABL usually causes CML, but can occasionally also cause acute leukemia. Following the chromosomal translocation between chromosomes 9 and 22 within a single, primitive myeloid stem cell, the progeny of the affected cell gradually populate the entire intermediate and late hematopoietic maturational compartments. Despite the presence of the Philadelphia chromosome, these progeny, referred to as Ph.sup.+ cells, are able to differentiate and mature along the various myeloid lineages while retaining the capacity to function as their normal, unaffected counterparts. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Methods of therapy and diagnosis using targeting of cells that express toll-like receptor proteins Inventor(s): Dedea, Douglas; (Castro Valley, CA) Correspondence: Luisa Bigornia; Hyseq, INC.; 670 Almanor Avenue; Sunnyvale; CA; 94085; US Patent Application Number: 20040022786 Date filed: November 22, 2002 Abstract: Certain cells, including types of cancer cells such as B-cell lymphomas, T cell lymphomas, Hodgkin's disease and myeloid leukemias, are capable of expressing Tolllike Receptor 9 (TLR9) or Toll-like Receptor 10 (TLR10) mRNA. Immunotargeting using TLR9 or TLR10 polypeptides, nucleic acids encoding for TLR9 or TLR10 polypeptides and anti-TLR9 or anti-TLR10 antibodies provides a method of killing or inhibiting that growth of cancer cells that express the TLR9 or TLR10 protein. Methods of immunotherapy and diagnosis of disorders associated with TLR9 or TLR10 proteinexpressing cells, such as B-cell lymphoma, T cell lymphoma, acute myeloid leukemia, Hodgkin's disease, B cell leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia and myelodysplastic syndromes, are described. Excerpt(s): This application is a continuation-in-part of U.S. application Ser. No. 10/077,676 filed on Feb. 14, 2002, entitled "Methods of Therapy and Diagnosis Using Targeting of Cells that Expressing Toll-Like Receptor 9 Protein", Attorney Docket No. HYS-49, which in turn is a continuation-in-part of U.S. application Ser. No. 09/687,527 filed on Oct. 12, 2000, entitled "Full Length Novel Nucleic Acids and Polypeptides", Attorney Docket No. 795, and U.S. application Ser. No. 09/488,725 filed on Jan. 21, 2000, entitled "Novel Contigs Obtained from Various Libraries," Attorney Docket No. 784. This and all other U.S. Patents and Patent Applications cited herein are hereby incorporated by reference in their entirety. This invention relates to compositions and methods for targeting Toll-like Receptor 9 (TLR9) protein- and Toll-like Receptor 10 (TLR10) protein-expressing cells and their use in the therapy and diagnosis of various pathological states, including cancer, autoimmune disease, organ transplant rejection, and allergic reactions. Antibody therapy for cancer involves the use of antibodies, or antibody fragments, against a tumor antigen to target antigen-expressing cells.
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Antibodies, or antibody fragments, may have direct or indirect cytotoxic effects or may be conjugated or fused to cytotoxic moieties. Direct effects include the induction of apoptosis, the blocking of growth factor receptors, and anti-idiotype antibody formation. Indirect effects include antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-mediated cellular cytotoxicity (CMCC). When conjugated or fused to cytotoxic moieties, the antibodies, or fragments thereof, provide a method of targeting the cytotoxicity towards the tumor antigen expressing cells. (Green, et al., Cancer Treatment Reviews, 26:269-286 (2000)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Methods to impair hematologic cancer progenitor cells and compounds related thereto Inventor(s): Jordan, Craig; (Lexington, KY) Correspondence: Mcdermott, Will & Emery; 600 13th Street, N.W.; Washington; DC; 20005-3096; US Patent Application Number: 20030039611 Date filed: March 6, 2001 Abstract: Primitive or progenitor hematologic cancer cells have been implicated in the early stages and development of leukemia and malignant lymphoproliferative disorders, including acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML) and chronic lymphoid leukemia (CLL). Interleukin-3 receptor alpha chain (IL-3R.alpha. or CD123) is strongly expressed on progenitor hematologic cancer cells, but is virtually undetectable on normal bone marrow cells. The present invention provides methods of impairing progenitor hematologic cancer (e.g., leukemia and lymphomic) cells by selectively targeting cells expressing CD123. These methods are useful in the detection and treatment of leukemias and malignant lymphoproliferative disorders. Also provided are compounds useful for selectively binding to CD123 and impairing progenitor hematologic cancer cells. These compounds may include cytotoxic moieites such as, for example, radioisotopes or chemotherapeutics. Excerpt(s): The present application claims the benefit of priority to U.S. Provisional Patent Application Nos. 60/187,123, filed Mar. 6, 2000, and 60/227,295, filed Aug. 24, 2000, the disclosures of which are incorporated by reference herein in their entirety. The present invention is related to methods of impairing progenitor hematologic cancer cells or treating hematologic cancer by targeting a cell surface marker specific for progenitor hematologic cancer cells. The present invention is also related to a method for diagnosing hematologic cancer. Stem cells are commonly found in a variety of mammalian tissue systems. While the criteria by which such cells are defined vary depending upon the specific context, two properties are generally regarded as central features of stem cell populations: (1) stem cells must exhibit some capacity for selfreplication or self-renewal, and (2) stem cells must be capable of differentiating into appropriate lineages (Potten CS: Stem Cells. London, Academic Press, 1997). Cells of this nature have been described for a number of tissues including hematopoietic, embryonic, neural, muscle and hepatic systems (Lemischka I R. Clonal, in vivo behavior of the totipotent hematopoietic stem cell. Semin Immunol 1991, 3: 349-55; Morrison S J, et al., The biology of hematopoietic stem cells. Annu. Rev. Cell Dev. Biol. 1995, 11: 35-71; Robertson E J., Using embryonic stem cells to introduce mutations into the mouse germ line. Biol Reprod 1991, 44: 238-45; Gage F H., Mammalian neural stem cells. Science 2000, 287: 1433-8; and, Alison M, et al., Hepatic stem cells. J Hepatol 1998, 29: 676-82).
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Thus, it is perhaps not surprising that similar cells have recently been documented in the context of malignant populations (Bonnet D, et al., Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat. Med. 1997, 3: 730-737; Blair A, et al., Most acute myeloid leukemia progenitor cells with long-term proliferative ability in vitro and in vivo have the phenotype CD34(+)/CD71()/HLA-DR-. Blood 1998, 92: 4325-35; Cobaleda C, et al., A primitive hematopoietic cell is the target for the leukemic transformation in human Philadelphia-positive acute lymphoblastic leukemia. Blood 2000, 95: 1007-13). Indeed, a stem cell is in some respects the ideal target for malignant transformation in that relatively little biological change is required. Since stem cells already possess the genetic programming necessary to be highly proliferative and developmentally plastic, one can imagine that relatively subtle perturbations might be sufficient to induce disease. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Soluble tumor necrosis factor receptor treatment of medical disorders Inventor(s): Pluenneke, John D.; (Parkville, MO) Correspondence: Immunex Corporation; Law Department; 51 University Street; Seattle; WA; 98101 Patent Application Number: 20030148955 Date filed: December 9, 2002 Abstract: The invention pertains to methods and compositions for reducing resistance to STI 571 in a chronic myelogenous leukemia patient by administering a TNF.alpha. inhibitor, such as recombinant TNFR:Fc to such patient. Excerpt(s): This application is a continuation-in-part of U.S. patent application Ser. No. 09/778,403, filed Feb. 7, 2001, which is a continuation-in-part of Ser. No. 09/726,781, filed Nov. 29, 2000, which is a continuation-in-part of Ser. No. 09/602,351, filed Jun. 23, 2000, which is a continuation-in-part of PCT/US00/10565, filed Apr. 19, 2000, (claiming the benefit of priority from U.S. provisional applications 60/184,864, filed Feb. 25, 2000, and 60/164,676, filed Nov. 10, 1999), which is a continuation-in-part of 09/373,828, filed Aug. 13, 1999 (claiming the benefit of priority from U.S. provisional applications 60/148,234, filed Aug. 11, 1999; 60/143,959, filed Jul. 15, 1999; 60/134,320, filed May 14, 1999; and 60/130,074, filed Apr. 19, 1999). The invention pertains to methods for treating various medical disorders that are characterized by abnormal or excessive TNF.alpha. levels by administering a TNF.alpha. antagonist, such as a soluble TNF.alpha. The TNF.alpha. inhibitor may be administered in combination with other biologically active molecules. The pleiotropic cytokine tumor necrosis factor alpha (TNF.alpha.) is associated with inflammation and binds to cells through membrane receptor molecules, including two molecules having molecular weights of approximately 55 kDa and 75 kDa (p55 and p75). In addition to binding TNF.alpha., the p55 and p75 TNF.alpha. receptors mediate the binding to cells of homotrimers of TNF.beta., which is another cytokine associated with inflammation and which shares structural similarities with TNF.alpha. (e.g., see Cosman, Blood Cell Biochem 7:51-77, 1996). TNF.beta. is also known as lymphotoxin-.alpha. (LT.alpha.). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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•
Strategy for leukemia therapy Inventor(s): Vigneri, Paolo; (Catania, IT), Wang, Jean Y J; (San Diego, CA) Correspondence: Colleen J Mckiernan; James W Mcclain; Brown Martin Haller & Mcclain; 1660 Union Street; San Diego; CA; 92101-2926; US Patent Application Number: 20030162740 Date filed: December 27, 2002 Abstract: The chimeric Bcr-Abl oncoprotein is the molecular hallmark of chronic myelogenous leukemia (CML). In the cytoplasm, the protein transduces a growth signal that is responsible for overexpansion of cells. In the nucleus, the protein induces apoptosis. The invention is a method of treating cancer/killing Bcr-Abl expressing cells by inducing the translocation of Bcr-Abl to the nucleus to activate the apoptotic pathway in cancer cells. Excerpt(s): This application claims the benefit of priority of U.S. provisional application Ser. No. 60/215,595 filed Jun. 30, 2000 which is incorporated herein by reference in its entirety. Chronic myeloid leukemia (CML) is a hematological stem cell disorder characterized by excessive proliferation of cells of the myeloid lineage. The hallmark of CML is the Philadelphia chromosome, which arises from a reciprocal translocation between chromosomes 9 and 22 (Rowley, 1973). The molecular consequence of this translocation is the replacement of the first exon of c-Abl with sequences from the Bcr gene resulting in a Bcr-Abl fusion gene whose protein product shows enhanced tyrosine kinase activity (Bartram, et al., 1983; Ben-Neriah, et al., 1986; Heisterkamp et al, 1983; Konopka, et al., 1984; Shtivelman et al., 1985). The Bcr-Abl oncoprotein in CML is a 210kD protein that contains 902 or 927 amino acids of Bcr fused to the expression product of exons 2-11 of c-Abl (Ben-Neriah, et al., 1986; Shtivelman et al., 1985). Found in 95% of patients with CML, p210 Bcr-Abl is also present in approximately 5-10% of adults with acute leukemia for whom there is no evidence of antecedent CML (Kruzrock, et al., 1988). Another Bcr-Abl fusion protein of 185 kD containing Bcr sequences from exon 1 (426 amino acids) fused to exons 2-11 of c-Abl, occurs in 10% of adult cases and 5-10% of pediatric cases of acute lymphoblastic leukemia (ALL), but not in CML (Clark, et al., 1988; Hermans et al., 1987). It is believed that this single chromosomal rearrangement is sufficient to initiate the development of these diseases and may be the only molecular abnormality in early stage disease. A kinase inhibitor, STI-571 (4-[(4-methylpiperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyrodnyl)-2pyrimidinyl]amin]phenyl]benzamide methanesul-fonate; Glivec, Novartis, Basel, Switzerland) was initially identified in a screen for inhibitors of the platelet derived growth factor receptor (PDGFR) (Buchdunger et al., 1995). This ATP analog of the class 2-phenylaminopyrimidine, was found to have some selectivity for specific kinases including cdc2/cyclin B, c-FGR, protein kinase C.gamma. and v-Abl. As the constitutive activation of v-Abl is believed to be sufficient for the development of CML, it was seen as an ideal target for validating the clinical utility of protein kinase inhibitors in the treatment of cancer. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Treatment of chronic myelogenous leukemia, resistant or intolerant to ST1571, involving homoharringtonine alone or combined with other agents Inventor(s): Blanchard, Julie; (Rouillon, FR), Mahon, Francois-Xavier; (Bordeaux, FR), Maisonneuve, Herve; (La Roche Sur Yon, FR), Maloisel, Frederick; (Illkirch Graffenstaden, FR), Robin, Jean-Pierre; (Charlottesville, VA) Correspondence: R. Danny Huntington; Burns, Doane, Swecker & Mathis, Llp; P.O. Box 1404; Alexandria; VA; 22313-1404; US Patent Application Number: 20040019036 Date filed: March 27, 2003 Abstract: The present invention concerns a method of treating chronic myelogenous leukemia, a related myeloproliferative disorder or a Ph-positive acute lymphocytic leukemia in a subject animal, comprising:(a) selecting or identifying an animal suffering from chronic myelogenous leukemia or a related myeloproliferative disorder and showing resistance or intolerance to treatment with STI571; and(b) administering to the animal homoharringtonine.In a preferred embodiment, the animal is a human being. Excerpt(s): The invention relates to methods for treating subjects suffering from chronic myelogenous leukemia which is resistant or intolerant to treatment with STI571, involving treating the subjects with homoharringtonine alone or combined with STI571 and/or other antileukemic agents. Chronic myelogenous leukemia (CML) is a mycloproliferative disease which strikes about 4,500 new cases per year in the U.S. or in Europe. The median survival of this disease is around 3 years without treatment. Since the introduction of standard therapy by interferon alpha (INF) the median survival of this leukemia reaches about 7 years. However when patients become resistant to interferon, progression to acute phases occurs. Until these recent years there were only a few drugs able to induce a new remission. [Ref 1-5] Homoharringtonine, an alkaloid isolated from the genus Cephalotaxus [Ref 1, 2, 6, 7] and more recently STI571, a synthetic product, are recent drugs able to give a new remission to patients resistant to INF. Moreover STI571 was recently approved in the U.S. as major therapy of CML. There is therefore a need for improved methods of treating CML which provide longer term remission. In view of the limitations of STI571, there is a need for therapies providing improved results in the treatment of accelerated phase CML and blastic phase. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
Keeping Current In order to stay informed about patents and patent applications dealing with chronic myelogenous leukemia, 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 “chronic myelogenous leukemia” (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 chronic myelogenous leukemia.
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You can also use this procedure to view pending patent applications concerning chronic myelogenous leukemia. 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. PERIODICALS AND NEWS ON CHRONIC MYELOGENOUS LEUKEMIA Overview In this chapter, we suggest a number of news sources and present various periodicals that cover chronic myelogenous leukemia.
News Services and Press Releases One of the simplest ways of tracking press releases on chronic myelogenous leukemia 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 “chronic myelogenous leukemia” (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 chronic myelogenous leukemia. 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 “chronic myelogenous leukemia” (or synonyms). The following was recently listed in this archive for chronic myelogenous leukemia: •
Interferon Plus Cytarabine Effective In Chronic Myelogenous Leukemia Patients Source: Reuters Medical News Date: July 24, 1997
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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 Market Wire’s home page at http://www.marketwire.com/mw/home, type “chronic myelogenous leukemia” (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 “chronic myelogenous leukemia” (or synonyms). If you know the name of a company that is relevant to chronic myelogenous leukemia, 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 “chronic myelogenous leukemia” (or synonyms).
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Academic Periodicals covering Chronic Myelogenous Leukemia Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to chronic myelogenous leukemia. In addition to these sources, you can search for articles covering chronic myelogenous leukemia 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 7. 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 chronic myelogenous leukemia. 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 non-profit 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 chronic myelogenous leukemia. 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-
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interaction risks, etc.). The following drugs have been mentioned in the Pharmacopeia and other sources as being potentially applicable to chronic myelogenous leukemia: Busulfan •
Systemic - U.S. Brands: Busulfex; Myleran http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202101.html
Imatinib •
Systemic - U.S. Brands: Gleevec http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/500297.html
Interferons, Alpha •
Systemic - U.S. Brands: Alferon N; Intron A; Roferon-A http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202299.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.
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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 chronic myelogenous leukemia 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.” On this page (http://www.rarediseases.org/search/noddsearch.html), type “chronic myelogenous leukemia” (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 chronic myelogenous leukemia: •
Tazofurin (2-Beta-D-ribofuranosy1-4-thiazolecarbox http://www.rarediseases.org/nord/search/nodd_full?code=1081
•
Tiazofurin (2-Beta-D-ribofuranosy1-4-thiazolecarbo http://www.rarediseases.org/nord/search/nodd_full?code=1091
•
Imatinib (trade name: Glivec) http://www.rarediseases.org/nord/search/nodd_full?code=1095
•
Imatinib (trade name: Gleevec) http://www.rarediseases.org/nord/search/nodd_full?code=1115
•
homoharringtonine (trade name: NONE Assigned) http://www.rarediseases.org/nord/search/nodd_full?code=1242
•
arsenic trioxide (trade name: trisenox) http://www.rarediseases.org/nord/search/nodd_full?code=1146
•
Imatinib (trade name: Gleevec) http://www.rarediseases.org/nord/search/nodd_full?code=1170
•
Arenic Trioxide (trade name: Trisenox) http://www.rarediseases.org/nord/search/nodd_full?code=1212
•
homoharringtonine http://www.rarediseases.org/nord/search/nodd_full?code=1270
•
Anagrelide (trade name: Agrelin) http://www.rarediseases.org/nord/search/nodd_full?code=553
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•
Interferon alfa-2a (trade name: Roferon A) http://www.rarediseases.org/nord/search/nodd_full?code=77
•
Idarubicin (trade name: Idamycin) http://www.rarediseases.org/nord/search/nodd_full?code=774
•
Peginteron alfa-2a (trade name: PEGASYS) http://www.rarediseases.org/nord/search/nodd_full?code=994
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
•
National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/news/facts/
•
National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html
•
National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancerinfo/list.aspx?viewid=5f35036e-5497-4d86-8c2c714a9f7c8d25
•
National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/order/index.htm
•
National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm
•
National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375
•
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
•
National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/
•
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm
•
National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm
•
National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/
•
National Institute of Dental and Craniofacial Research (NIDCR); guidelines available at http://www.nidr.nih.gov/health/
•
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); guidelines available at http://www.niddk.nih.gov/health/health.htm
•
National Institute on Drug Abuse (NIDA); guidelines available at http://www.nida.nih.gov/DrugAbuse.html
•
National Institute of Environmental Health Sciences (NIEHS); environmental health information available at http://www.niehs.nih.gov/external/facts.htm
•
National Institute of Mental Health (NIMH); guidelines available at http://www.nimh.nih.gov/practitioners/index.cfm
•
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
•
National Institute of Nursing Research (NINR); publications on selected illnesses at http://www.nih.gov/ninr/news-info/publications.html
•
National Institute of Biomedical Imaging and Bioengineering; general information at http://grants.nih.gov/grants/becon/becon_info.htm
•
Center for Information Technology (CIT); referrals to other agencies based on keyword searches available at http://kb.nih.gov/www_query_main.asp
•
National Center for Complementary and Alternative Medicine (NCCAM); health information available at http://nccam.nih.gov/health/
•
National Center for Research Resources (NCRR); various information directories available at http://www.ncrr.nih.gov/publications.asp
•
Office of Rare Diseases; various fact sheets available at http://rarediseases.info.nih.gov/html/resources/rep_pubs.html
•
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
•
Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html
•
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/
•
Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html
•
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
•
Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html
•
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
•
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 “chronic myelogenous leukemia” (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 12307 27 960 7 71 13372
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 “chronic myelogenous leukemia” (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 chronic myelogenous leukemia 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 chronic myelogenous leukemia. 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 chronic myelogenous leukemia. 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 “chronic myelogenous leukemia”:
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Bone Marrow Diseases http://www.nlm.nih.gov/medlineplus/bonemarrowdiseases.html Lymphoma http://www.nlm.nih.gov/medlineplus/lymphoma.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 chronic myelogenous leukemia. 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
•
Family Village: http://www.familyvillage.wisc.edu/specific.htm
•
Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/
•
Med Help International: http://www.medhelp.org/HealthTopics/A.html
•
Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/
•
Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/
•
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 chronic myelogenous leukemia. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with chronic myelogenous leukemia.
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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 chronic myelogenous leukemia. 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 “chronic myelogenous leukemia” (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 “chronic myelogenous leukemia”. 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 “chronic myelogenous leukemia” (or synonyms) into the “For these words:” box. You should check back periodically with this database since it is updated every three months. 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 “chronic myelogenous leukemia” (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/
•
Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)
•
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
•
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
•
California: Gateway Health Library (Sutter Gould Medical Foundation)
•
California: Health Library (Stanford University Medical Center), http://wwwmed.stanford.edu/healthlibrary/
•
California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp
•
California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html
•
California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/
•
California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/
•
California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/
•
California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html
•
California: Washington Community Health Resource Library (Fremont), http://www.healthlibrary.org/
•
Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.saintjosephdenver.org/yourhealth/libraries/
•
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
•
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
•
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
•
Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library, Honolulu), http://hml.org/CHIS/
•
Idaho: DeArmond Consumer Health Library (Kootenai Medical Center, Coeur d’Alene), http://www.nicon.org/DeArmond/index.htm
•
Illinois: Health Learning Center of Northwestern Memorial Hospital (Chicago), http://www.nmh.org/health_info/hlc.html
•
Illinois: Medical Library (OSF Saint Francis Medical Center, Peoria), http://www.osfsaintfrancis.org/general/library/
•
Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital, Lexington), http://www.centralbap.com/education/community/library.cfm
•
Kentucky: University of Kentucky - Health Information Library (Chandler Medical Center, Lexington), http://www.mc.uky.edu/PatientEd/
•
Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation, New Orleans), http://www.ochsner.org/library/
•
Louisiana: Louisiana State University Health Sciences Center Medical LibraryShreveport, http://lib-sh.lsuhsc.edu/
•
Maine: Franklin Memorial Hospital Medical Library (Franklin Memorial Hospital, Farmington), http://www.fchn.org/fmh/lib.htm
•
Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center, Lewiston), http://www.cmmc.org/library/library.html
•
Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm
•
Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/
•
Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/
•
Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10
•
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
•
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
•
Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/
•
Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html
•
Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm
•
Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp
•
Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/
•
Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html
•
Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/
•
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/
•
Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html
•
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
•
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
•
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
•
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
•
Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html
•
Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html
•
Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml
•
Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp
•
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/
•
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). The NIH suggests the following Web sites in the ADAM Medical Encyclopedia when searching for information on chronic myelogenous leukemia: •
Basic Guidelines for Chronic Myelogenous Leukemia Chronic myelogenous leukemia (CML) Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000570.htm
•
Signs & Symptoms for Chronic Myelogenous Leukemia Anemia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000560.htm Bone pain Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003180.htm Bruising Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003235.htm Enlarged spleen Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003276.htm
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Fatigue Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003088.htm Fever Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003090.htm Leukemia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001299.htm Petechiae Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003235.htm Stress Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003211.htm Sweating, excessive Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003218.htm Weakness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003174.htm •
Diagnostics and Tests for Chronic Myelogenous Leukemia Bone marrow aspiration Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003658.htm CBC Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003642.htm Differential Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003657.htm Leukocyte alkaline phosphatase Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003651.htm Philadelphia chromosome Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003935.htm Platelet count Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003647.htm Vitamin B-12 level Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003705.htm White blood cell count Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003643.htm
•
Nutrition for Chronic Myelogenous Leukemia Protein in diet Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002467.htm
Online Glossaries 185
•
Surgery and Procedures for Chronic Myelogenous Leukemia Bone marrow transplant Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003009.htm
•
Background Topics for Chronic Myelogenous Leukemia Bleeding Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000045.htm Cancer - support group Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002166.htm Chemotherapy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002324.htm Chronic Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002312.htm Leukemia - support group Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002151.htm Peripheral Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002273.htm Physical examination Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002274.htm Radiation therapy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001918.htm Support group Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002150.htm
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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CHRONIC MYELOGENOUS LEUKEMIA DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 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] Aberrant: Wandering or deviating from the usual or normal course. [EU] Accelerated phase: Refers to chronic myelogenous leukemia that is progressing. The number of immature, abnormal white blood cells in the bone marrow and blood is higher than in the chronic phase, but not as high as in the blast phase. [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] Acetylglucosamine: The N-acetyl derivative of glucosamine. [NIH] Actin: Essential component of the cell skeleton. [NIH] 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 myelogenous 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 myeloid leukemia or acute nonlymphocytic 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 nonlymphocytic leukemia: A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myeloid leukemia or acute myelogenous leukemia. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adenine: A purine base and a fundamental unit of adenine nucleotides. [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] Adolescence: The period of life beginning with the appearance of secondary sex characteristics and terminating with the cessation of somatic growth. The years usually referred to as adolescence lie between 13 and 18 years of age. [NIH]
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Adoptive Transfer: Form of passive immunization where previously sensitized immunologic agents (cells or serum) are transferred to non-immune recipients. When transfer of cells is used as a therapy for the treatment of neoplasms, it is called adoptive immunotherapy (immunotherapy, adoptive). [NIH] Adverse Effect: An unwanted side effect of treatment. [NIH] Aerosol: A solution of a drug which can be atomized into a fine mist for inhalation therapy. [EU]
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] Age Groups: Persons classified by age from birth (infant, newborn) to octogenarians and older (aged, 80 and over). [NIH] Aged, 80 and Over: A person 80 years of age and older. [NIH] 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] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alkaline: Having the reactions of an alkali. [EU] Alkaline Phosphatase: An enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate. EC 3.1.3.1. [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]
Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Allo: A female hormone. [NIH] Allogeneic: Taken from different individuals of the same species. [NIH] Allogeneic bone marrow transplantation: A procedure in which a person receives stem cells, the cells from which all blood cells develop, from a compatible, though not genetically identical, donor. [NIH] Allograft: An organ or tissue transplant between two humans. [NIH]
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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] 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] Amine: An organic compound containing nitrogen; any member of a group of chemical compounds formed from ammonia by replacement of one or more of the hydrogen atoms by organic (hydrocarbon) radicals. The amines are distinguished as primary, secondary, and tertiary, according to whether one, two, or three hydrogen atoms are replaced. The amines include allylamine, amylamine, ethylamine, methylamine, phenylamine, propylamine, and many other compounds. [EU] Amino Acid Motifs: Commonly observed structural components of proteins formed by simple combinations of adjacent secondary structures. A commonly observed structure may be composed of a conserved sequence which can be represented by a consensus sequence. [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] Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [NIH] Amputation: Surgery to remove part or all of a limb or appendage. [NIH] Amyloid: A general term for a variety of different proteins that accumulate as extracellular fibrils of 7-10 nm and have common structural features, including a beta-pleated sheet conformation and the ability to bind such dyes as Congo red and thioflavine (Kandel, Schwartz, and Jessel, Principles of Neural Science, 3rd ed). [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] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] 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] Analytes: A component of a test sample the presence of which has to be demonstrated. The term "analyte" includes where appropriate formed from the analyte during the analyses. [NIH]
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
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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] Anaplastic: A term used to describe cancer cells that divide rapidly and bear little or no resemblance to normal 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] 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] Annealing: The spontaneous alignment of two single DNA strands to form a double helix. [NIH]
Anomalies: Birth defects; abnormalities. [NIH] Antecedent: Existing or occurring before in time or order often with consequential effects. [EU]
Anthracycline: A member of a family of anticancer drugs that are also antibiotics. [NIH] Anthrax: An acute bacterial infection caused by ingestion of bacillus organisms. Carnivores may become infected from ingestion of infected carcasses. It is transmitted to humans by contact with infected animals or contaminated animal products. The most common form in humans is cutaneous anthrax. [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] Antifungal: Destructive to fungi, or suppressing their reproduction or growth; effective against fungal infections. [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 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
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molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes immune complex diseases. [NIH] Antigen-presenting cell: APC. A cell that shows antigen on its surface to other cells of the immune system. This is an important part of an immune response. [NIH] Anti-inflammatory: Having to do with reducing 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] 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]
Antiproliferative: Counteracting a process of proliferation. [EU] Antiserum: The blood serum obtained from an animal after it has been immunized with a particular antigen. It will contain antibodies which are specific for that antigen as well as antibodies specific for any other antigen with which the animal has previously been immunized. [NIH] Antiviral: Destroying viruses or suppressing their replication. [EU] Anus: The opening of the rectum to the outside of the body. [NIH] Aplasia: Lack of development of an organ or tissue, or of the cellular products from an organ or tissue. [EU] Aplastic anemia: A condition in which the bone marrow is unable to produce blood cells. [NIH]
Apolipoproteins: The protein components of lipoproteins which remain after the lipids to which the proteins are bound have been removed. They play an important role in lipid transport and metabolism. [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] Applicability: A list of the commodities to which the candidate method can be applied as presented or with minor modifications. [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] Arsenic trioxide: An anticancer drug that induces programmed cell death (apoptosis) in certain cancer cells. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU] Arteriosclerosis: Thickening and loss of elasticity of arterial walls. Atherosclerosis is the most common form of arteriosclerosis and involves lipid deposition and thickening of the intimal cell layers within arteries. Additional forms of arteriosclerosis involve calcification of
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the media of muscular arteries (Monkeberg medial calcific sclerosis) and thickening of the walls of small arteries or arterioles due to cell proliferation or hyaline deposition (arteriolosclerosis). [NIH] Aspiration: The act of inhaling. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] ATP: ATP an abbreviation for adenosine triphosphate, a compound which serves as a carrier of energy for cells. [NIH] Autoantibodies: Antibodies that react with self-antigens (autoantigens) of the organism that produced them. [NIH] Autoantigens: Endogenous tissue constituents that have the ability to interact with autoantibodies and cause an immune response. [NIH] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autoimmunity: Process whereby the immune system reacts against the body's own tissues. Autoimmunity may produce or be caused by autoimmune diseases. [NIH] Autologous: Taken from an individual's own tissues, cells, or DNA. [NIH] Autologous bone marrow transplantation: A procedure in which bone marrow is removed from a person, stored, and then given back to the person after intensive treatment. [NIH] Autologous lymphocytes: A person's white blood cells. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infection and disease. [NIH] Avidity: The strength of the interaction of an antiserum with a multivalent antigen. [NIH] Azacitidine: A pyrimidine analogue that inhibits DNA methyltransferase, impairing DNA methylation. It is also an antimetabolite of cytidine, incorporated primarily into RNA. Azacytidine has been used as an antineoplastic agent. [NIH] Bacillus: A genus of Bacillaceae that are spore-forming, rod-shaped cells. Most species are saprophytic soil forms with only a few species being pathogenic. [NIH] 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] Bacterium: Microscopic organism which may have a spherical, rod-like, or spiral unicellular or non-cellular body. Bacteria usually reproduce through asexual processes. [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]
Beta-pleated: Particular three-dimensional pattern of amyloidoses. [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
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fats in the duodenum. [NIH] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] 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 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] Biomolecular: A scientific field at the interface between advanced computing and biotechnology. [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] Bladder: The organ that stores urine. [NIH] Blast Crisis: Rapid increase in the proportion of blast cells in the blood and bone marrow. [NIH]
Blast phase: The phase of chronic myelogenous leukemia in which the number of immature, abnormal white blood cells in the bone marrow and blood is extremely high. Also called blast crisis. [NIH] Blasts: Immature blood cells. [NIH] Blood Cell Count: A count of the number of leukocytes and erythrocytes per unit volume in a sample of venous blood. A complete blood count (CBC) also includes measurement of the hemoglobin, hematocrit, and erythrocyte indices. [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] Blood Volume: Volume of circulating blood. It is the sum of the plasma volume and erythrocyte volume. [NIH]
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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] Body Fluids: Liquid components of living organisms. [NIH] 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 Marrow Cells: Cells contained in the bone marrow including fat cells, stromal cells, megakaryocytes, and the immediate precursors of most blood cells. [NIH] Bone Marrow Transplantation: The transference of bone marrow from one human or animal to another. [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] Breeding: The science or art of changing the constitution of a population of plants or animals through sexual reproduction. [NIH] Bronchial: Pertaining to one or more bronchi. [EU] Bryostatin-1: A drug used for its antitumor activity. [NIH] Busulfan: An anticancer drug that belongs to the family of drugs called alkylating agents. [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] Calculi: An abnormal concretion occurring mostly in the urinary and biliary tracts, usually composed of mineral salts. Also called stones. [NIH] Candidiasis: Infection with a fungus of the genus Candida. It is usually a superficial infection of the moist cutaneous areas of the body, and is generally caused by C. albicans; it most commonly involves the skin (dermatocandidiasis), oral mucous membranes (thrush, def. 1), respiratory tract (bronchocandidiasis), and vagina (vaginitis). Rarely there is a systemic infection or endocarditis. Called also moniliasis, candidosis, oidiomycosis, and formerly blastodendriosis. [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]
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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]
Cardiac: Having to do with the heart. [NIH] Cardiovascular: Having to do with the heart and blood vessels. [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] Caspase: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] CDC2: It is crucial for entry into mitosis of eukaryotic cells. [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 Adhesion: Adherence of cells to surfaces or to other cells. [NIH] Cell Cycle: The complex series of phenomena, occurring between the end of one cell 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 Extracts: Preparations of cell constituents or subcellular materials, isolates, or substances. [NIH] Cell Lineage: The developmental history of cells as traced from the first division of the original cell or cells in the embryo. [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 motility: The ability of a cell to move. [NIH] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [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]
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Cell Transplantation: Transference of cells within an individual, between individuals of the same species, or between individuals of different species. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [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] Chemokines: Class of pro-inflammatory cytokines that have the ability to attract and activate leukocytes. They can be divided into at least three structural branches: C (chemokines, C), CC (chemokines, CC), and CXC (chemokines, CXC), according to variations in a shared cysteine motif. [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] Chemotherapeutics: Noun plural but singular or plural in constructions : chemotherapy. [EU]
Chemotherapy: Treatment with anticancer drugs. [NIH] Chimeras: Organism that contains a mixture of genetically different cells. [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] 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 granulocytic leukemia: A slowly progressing disease in which too many white blood cells are made in the bone marrow. Also called chronic myelogenous leukemia or chronic myeloid leukemia. [NIH] Chronic leukemia: A slowly progressing cancer of the blood-forming tissues. [NIH] Chronic phase: Refers to the early stages of chronic myelogenous leukemia or chronic lymphocytic leukemia. The number of mature and immature abnormal white blood cells in the bone marrow and blood is higher than normal, but lower than in the accelerated or blast phase. [NIH] Chronic phase chronic myelogenous leukemia: A phase of chronic myelogenous leukemia that may last from several months to several years. Although there may be no symptoms of leukemia, there are too many white blood cells. [NIH] Cirrhosis: A type of chronic, progressive liver disease. [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] Cisplatin: An inorganic and water-soluble platinum complex. After undergoing hydrolysis, it reacts with DNA to produce both intra and interstrand crosslinks. These crosslinks appear to impair replication and transcription of DNA. The cytotoxicity of cisplatin correlates with cellular arrest in the G2 phase of the cell cycle. [NIH] C-kit receptor: A protein on the surface of some cells that binds to stem cell factor (a
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substance that causes certain types of cells to grow). Altered forms of this receptor may be associated with some types of cancer. [NIH] Cladribine: An antineoplastic agent used in the treatment of lymphoproliferative diseases including hairy-cell leukemia. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [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 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] Coagulation: 1. The process of clot formation. 2. In colloid chemistry, the solidification of a sol into a gelatinous mass; an alteration of a disperse phase or of a dissolved solid which causes the separation of the system into a liquid phase and an insoluble mass called the clot or curd. Coagulation is usually irreversible. 3. In surgery, the disruption of tissue by physical means to form an amorphous residuum, as in electrocoagulation and photocoagulation. [EU] Codon: A set of three nucleotides in a protein coding sequence that specifies individual amino acids or a termination signal (codon, terminator). Most codons are universal, but some organisms do not produce the transfer RNAs (RNA, transfer) complementary to all codons. These codons are referred to as unassigned codons (codons, nonsense). [NIH] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Colchicine: A major alkaloid from Colchicum autumnale L. and found also in other Colchicum species. Its primary therapeutic use is in the treatment of gout, but it has been used also in the therapy of familial Mediterranean fever (periodic disease). [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] 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] 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
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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] Complete remission: The disappearance of all signs of cancer. Also called a complete response. [NIH] Complete response: The disappearance of all signs of cancer in response to treatment. This does not always mean the cancer has been cured. [NIH] Compliance: Distensibility measure of a chamber such as the lungs (lung compliance) or bladder. Compliance is expressed as a change in volume per unit change in pressure. [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] Concomitant: Accompanying; accessory; joined with another. [EU] Conjugated: Acting or operating as if joined; simultaneous. [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] Consensus Sequence: A theoretical representative nucleotide or amino acid sequence in
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which each nucleotide or amino acid is the one which occurs most frequently at that site in the different sequences which occur in nature. The phrase also refers to an actual sequence which approximates the theoretical consensus. A known conserved sequence set is represented by a consensus sequence. Commonly observed supersecondary protein structures (amino acid motifs) are often formed by conserved sequences. [NIH] Conserved Sequence: A sequence of amino acids in a polypeptide or of nucleotides in DNA or RNA that is similar across multiple species. A known set of conserved sequences is represented by a consensus sequence. Amino acid motifs are often composed of conserved sequences. [NIH] Continuous infusion: The administration of a fluid into a blood vessel, usually over a prolonged period of time. [NIH] Contraceptive: An agent that diminishes the likelihood of or prevents conception. [EU] 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] 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] Cornea: The transparent part of the eye that covers the iris and the pupil and allows light to enter the inside. [NIH] Corticosteroid: Any of the steroids elaborated by the adrenal cortex (excluding the sex hormones of adrenal origin) in response to the release of corticotrophin (adrenocorticotropic hormone) by the pituitary gland, to any of the synthetic equivalents of these steroids, or to angiotensin II. They are divided, according to their predominant biological activity, into three major groups: glucocorticoids, chiefly influencing carbohydrate, fat, and protein metabolism; mineralocorticoids, affecting the regulation of electrolyte and water balance; and C19 androgens. Some corticosteroids exhibit both types of activity in varying degrees, and others exert only one type of effect. The corticosteroids are used clinically for hormonal replacement therapy, for suppression of ACTH secretion by the anterior pituitary, as antineoplastic, antiallergic, and anti-inflammatory agents, and to suppress the immune response. Called also adrenocortical hormone and corticoid. [EU] 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] Cultured cells: Animal or human cells that are grown in the laboratory. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Cutaneous: Having to do with the skin. [NIH] 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]
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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] Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [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]
Cytidine: A pyrimidine nucleoside that is composed of the base cytosine linked to the fivecarbon sugar D-ribose. [NIH] Cytogenetics: A branch of genetics which deals with the cytological and molecular behavior of genes and chromosomes during cell division. [NIH] 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] Cytoskeleton: The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. [NIH] Cytostatic: An agent that suppresses cell growth and multiplication. [EU] Cytotoxic: Cell-killing. [NIH] Cytotoxicity: Quality of being capable of producing a specific toxic action upon cells of special organs. [NIH] De novo: In cancer, the first occurrence of cancer in the body. [NIH] Decarboxylation: The removal of a carboxyl group, usually in the form of carbon dioxide, from a chemical compound. [NIH] Decitabine: An anticancer drug that belongs to the family of drugs called antimetabolites. [NIH]
Defense Mechanisms: Unconscious process used by an individual or a group of individuals in order to cope with impulses, feelings or ideas which are not acceptable at their conscious level; various types include reaction formation, projection and self reversal. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Denaturation: Rupture of the hydrogen bonds by heating a DNA solution and then cooling
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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] Dendritic: 1. Branched like a tree. 2. Pertaining to or possessing dendrites. [EU] Dendritic cell: A special type of antigen-presenting cell (APC) that activates T lymphocytes. [NIH]
Deoxycytidine: A drug that protects healthy tissues from the toxic effects of anticancer drugs. [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] Desensitization: The prevention or reduction of immediate hypersensitivity reactions by administration of graded doses of allergen; called also hyposensitization and immunotherapy. [EU] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diagnostic procedure: A method used to identify a disease. [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] 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] Dinucleotide Repeats: The most common of the microsatellite tandem repeats (microsatellite repeats) dispersed in the euchromatic arms of chromosomes. They consist of two nucleotides repeated in tandem; guanine and thymine, (GT)n, is the most frequently seen. [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] Disease Progression: The worsening of a disease over time. This concept is most often used for chronic and incurable diseases where the stage of the disease is an important determinant of therapy and prognosis. [NIH] Disease-Free Survival: Period after successful treatment in which there is no appearance of the symptoms or effects of the disease. [NIH] Disparity: Failure of the two retinal images of an object to fall on corresponding retinal points. [NIH] 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
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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] 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] Dominance: In genetics, the full phenotypic expression of a gene in both heterozygotes and homozygotes. [EU] 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] Drug Combinations: Single preparations containing two or more active agents, for the purpose of their concurrent administration as a fixed dose mixture. It is differentiated from combination drug therapy in which two or more drugs are administered separately for a combined effect. [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] Duct: A tube through which body fluids pass. [NIH] Dyes: Chemical substances that are used to stain and color other materials. The coloring may or may not be permanent. Dyes can also be used as therapeutic agents and test reagents in medicine and scientific research. [NIH] Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Effector cell: A cell that performs a specific function in response to a stimulus; usually used
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to describe cells in the immune system. [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] Effusion: The escape of fluid into a part or tissue, as an exudation or a transudation. [EU] Electrocoagulation: Electrosurgical procedures used to treat hemorrhage (e.g., bleeding ulcers) and to ablate tumors, mucosal lesions, and refractory arrhythmias. [NIH] 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]
Elementary Particles: Individual components of atoms, usually subatomic; subnuclear particles are usually detected only when the atomic nucleus decays and then only transiently, as most of them are unstable, often yielding pure energy without substance, i.e., radiation. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Embryogenesis: The process of embryo or embryoid formation, whether by sexual (zygotic) or asexual means. In asexual embryogenesis embryoids arise directly from the explant or on intermediary callus tissue. In some cases they arise from individual cells (somatic cell embryoge). [NIH] Enalapril: An angiotensin-converting enzyme inhibitor that is used to treat hypertension. [NIH]
Encapsulated: Confined to a specific, localized area and surrounded by a thin layer of tissue. [NIH]
Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endotoxin: Toxin from cell walls of bacteria. [NIH] Enhancers: Transcriptional element in the virus genome. [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] Eosinophil: A polymorphonuclear leucocyte with large eosinophilic granules in its cytoplasm, which plays a role in hypersensitivity reactions. [NIH] Epigastric: Having to do with the upper middle area of the abdomen. [NIH]
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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] Epitope: A molecule or portion of a molecule capable of binding to the combining site of an antibody. For every given antigenic determinant, the body can construct a variety of antibody-combining sites, some of which fit almost perfectly, and others which barely fit. [NIH]
Erythrocyte Indices: Quantification of size and cell hemoglobin content or concentration of the erythrocyte, usually derived from erythrocyte count, blood hemoglobin concentration, and hematocrit. Includes the mean cell volume (MCV), mean cell hemoglobin (MCH), and mean cell hemoglobin concentration (MCHC). Use also for cell diameter and thickness. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Erythroid Progenitor Cells: Committed, erythroid stem cells derived from myeloid stem cells. The progenitor cells develop in two phases: erythroid burst-forming units (BFU-E) followed by erythroid colony-forming units (CFU-E). BFU-E differentiate into CFU-E on stimulation by erythropoietin, and then further differentiate into erythroblasts when stimulated by other factors. [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] 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]
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] Evaluable patients: Patients whose response to a treatment can be measured because enough information has been collected. [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] 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]
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Exoribonucleases: A family of enzymes that catalyze the exonucleolytic cleavage of RNA. It includes EC 3.1.13.-, EC 3.1.14.-, EC 3.1.15.-, and EC 3.1.16.-. EC 3.1.- [NIH] Extensor: A muscle whose contraction tends to straighten a limb; the antagonist of a flexor. [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] Extremity: A limb; an arm or leg (membrum); sometimes applied specifically to a hand or foot. [EU] 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] Femoral: Pertaining to the femur, or to the thigh. [EU] Femur: The longest and largest bone of the skeleton, it is situated between the hip and the knee. [NIH] Ferritin: An iron-containing protein complex that is formed by a combination of ferric iron with the protein apoferritin. [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] Fibronectin: An adhesive glycoprotein. One form circulates in plasma, acting as an opsonin; another is a cell-surface protein which mediates cellular adhesive interactions. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [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] Flavopiridol: Belongs to the family of anticancer drugs called flavinols. [NIH] 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] Fluconazole: Triazole antifungal agent that is used to treat oropharyngeal candidiasis and cryptococcal meningitis in AIDS. [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
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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] Foam Cells: Lipid-laden macrophages originating from monocytes or from smooth muscle cells. [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] 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] Gangrene: Death and putrefaction of tissue usually due to a loss of blood supply. [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] Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal stromal tumor: GIST. A type of tumor that usually begins in cells in the wall of the gastrointestinal tract. It can be benign or malignant. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gemfibrozil: A lipid-regulating agent that lowers elevated serum lipids primarily by decreasing serum triglycerides with a variable reduction in total cholesterol. These decreases occur primarily in the VLDL fraction and less frequently in the LDL fraction. Gemfibrozil increases HDL subfractions HDL2 and HDL3 as well as apolipoproteins A-I and A-II. Its mechanism of action has not been definitely established. [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 Deletion: A genetic rearrangement through loss of segments of DNA or RNA, bringing sequences which are normally separated into close proximity. This deletion may be detected using cytogenetic techniques and can also be inferred from the phenotype, indicating a deletion at one specific locus. [NIH] Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Gene Rearrangement: The ordered rearrangement of gene regions by DNA recombination such as that which occurs normally during development. [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
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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 Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic Screening: Searching a population or individuals for persons possessing certain genotypes or karyotypes that: (1) are already associated with disease or predispose to disease; (2) may lead to disease in their descendants; or (3) produce other variations not known to be associated with disease. Genetic screening may be directed toward identifying phenotypic expression of genetic traits. It includes prenatal genetic screening. [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] Genital: Pertaining to the genitalia. [EU] Genitourinary: Pertaining to the genital and urinary organs; urogenital; urinosexual. [EU] Genotype: The genetic constitution of the individual; the characterization of the genes. [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] Gestation: The period of development of the young in viviparous animals, from the time of fertilization of the ovum until birth. [EU] 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] Glomeruli: Plural of glomerulus. [NIH] Glomerulosclerosis: Scarring of the glomeruli. It may result from diabetes mellitus (diabetic glomerulosclerosis) or from deposits in parts of the glomerulus (focal segmental glomerulosclerosis). The most common signs of glomerulosclerosis are proteinuria and kidney failure. [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]
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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] Gout: Hereditary metabolic disorder characterized by recurrent acute arthritis, hyperuricemia and deposition of sodium urate in and around the joints, sometimes with formation of uric acid calculi. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Gp120: 120-kD HIV envelope glycoprotein which is involved in the binding of the virus to its membrane receptor, the CD4 molecule, found on the surface of certain cells in the body. [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] Graft-versus-tumor: An immune response to a person's tumor cells by immune cells present in a donor's transplanted tissue, such as bone marrow or peripheral blood. [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] Granulocyte-Macrophage Colony-Stimulating Factor: An acidic glycoprotein of MW 23 kDa with internal disulfide bonds. The protein is produced in response to a number of inflammatory mediators by mesenchymal cells present in the hemopoietic environment and at peripheral sites of inflammation. GM-CSF is able to stimulate the production of neutrophilic granulocytes, macrophages, and mixed granulocyte-macrophage colonies from bone marrow cells and can stimulate the formation of eosinophil colonies from fetal liver progenitor cells. GM-CSF can also stimulate some functional activities in mature granulocytes and macrophages. [NIH] Granuloma: A relatively small nodular inflammatory lesion containing grouped mononuclear phagocytes, caused by infectious and noninfectious agents. [NIH] Granuloma Annulare: Benign granulomatous disease of unknown etiology characterized by a ring of localized or disseminated papules or nodules on the skin and palisading histiocytes surrounding necrobiotic tissue resulting from altered collagen structures. [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
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therapy. [NIH] Growth Inhibitors: Endogenous or exogenous substances which inhibit the normal growth of human and animal cells or micro-organisms, as distinguished from those affecting plant growth (plant growth regulators). [NIH] Habitual: Of the nature of a habit; according to habit; established by or repeated by force of habit, customary. [EU] 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] Hematocrit: Measurement of the volume of packed red cells in a blood specimen by centrifugation. The procedure is performed using a tube with graduated markings or with automated blood cell counters. It is used as an indicator of erythrocyte status in disease. For example, anemia shows a low hematocrit, polycythemia, high values. [NIH] Hematologic Diseases: Disorders of the blood and blood forming tissues. [NIH] Hematologic malignancies: Cancers of the blood or bone marrow, including leukemia and lymphoma. Also called hematologic cancers. [NIH] Hematologist: A doctor who specializes in treating diseases of the blood. [NIH] Hematology: A subspecialty of internal medicine concerned with morphology, physiology, and pathology of the blood and blood-forming tissues. [NIH] Hematopoiesis: The development and formation of various types of blood cells. [NIH] Hematopoietic growth factors: A group of proteins that cause blood cells to grow and mature. [NIH] Hematopoietic Stem Cell Transplantation: The transference of stem cells from one animal or human to another (allogeneic), or within the same individual (autologous). The source for the stem cells may be the bone marrow or peripheral blood. Stem cell transplantation has been used as an alternative to autologous bone marrow transplantation in the treatment of a variety of neoplasms. [NIH] Hematopoietic Stem Cells: Progenitor cells from which all blood cells derive. [NIH] Hemin: Chloro(7,12-diethenyl-3,8,13,17-tetramethyl-21H,23H-porphine-2,18dipropanoato(4-)-N(21),N(22),N(23),N(24)) ferrate(2-) dihydrogen. [NIH] Hemochromatosis: A disease that occurs when the body absorbs too much iron. The body stores the excess iron in the liver, pancreas, and other organs. May cause cirrhosis of the liver. Also called iron overload disease. [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] Hemoglobinopathies: A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. [NIH]
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Hemorrhage: Bleeding or escape of blood from a vessel. [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] 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] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] Heterodimers: 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]
Heterozygotes: Having unlike alleles at one or more corresponding loci on homologous chromosomes. [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] Histidine: An essential amino acid important in a number of metabolic processes. It is required for the production of histamine. [NIH] Histocompatibility: The degree of antigenic similarity between the tissues of different individuals, which determines the acceptance or rejection of allografts. [NIH] Homeobox: Distinctive sequence of DNA bases. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homoharringtonine: An anticancer drug that belongs to the plant alkaloid family of drugs. [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] Homozygotes: An individual having a homozygous gene pair. [NIH] 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] Humoral: Of, relating to, proceeding from, or involving a bodily humour - now often used of endocrine factors as opposed to neural or somatic. [EU] Humour: 1. A normal functioning fluid or semifluid of the body (as the blood, lymph or bile) especially of vertebrates. 2. A secretion that is itself an excitant of activity (as certain hormones). [EU] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hybridization: The genetic process of crossbreeding to produce a hybrid. Hybrid nucleic
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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] 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] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a hydrophobic colloid. [EU] Hydroxyurea: An antineoplastic agent that inhibits DNA synthesis through the inhibition of ribonucleoside diphosphate reductase. [NIH] Hyperlipoproteinemia: Metabolic disease characterized by elevated plasma cholesterol and/or triglyceride levels. The inherited form is attributed to a single gene mechanism. [NIH] Hyperplasia: An increase in the number of cells in a tissue or organ, not due to tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. [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] Hyperthyroidism: Excessive functional activity of the thyroid gland. [NIH] Hypertriglyceridemia: Condition of elevated triglyceride concentration in the blood; an inherited form occurs in familial hyperlipoproteinemia IIb and hyperlipoproteinemia type IV. It has been linked to higher risk of heart disease and arteriosclerosis. [NIH] Hypertrophy: General increase in bulk of a part or organ, not due to tumor formation, nor to an increase in the number of cells. [NIH] Hyperuricemia: A buildup of uric acid (a byproduct of metabolism) in the blood; a side effect of some anticancer drugs. [NIH] Idarubicin: An orally administered anthracycline antibiotic. The compound has shown activity against breast cancer, lymphomas and leukemias, together with potential for reduced cardiac toxicity. [NIH] Idiopathic: Describes a disease of unknown cause. [NIH] Idiopathic myelofibrosis: A progressive disease in which the bone marrow is replaced by fibrous tissue and is unable to produce red blood cells; the cause is unknown. [NIH] Idiotype: The unique antigenic determinant in the variable region. [NIH] Ifosfamide: Positional isomer of cyclophosphamide which is active as an alkylating agent and an immunosuppressive agent. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]
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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]
Immunocompromised: Having a weakened immune system caused by certain diseases or treatments. [NIH] Immunoconjugates: Combinations of diagnostic or therapeutic substances linked with specific immune substances such as immunoglobulins, monoclonal antibodies or antigens. Often the diagnostic or therapeutic substance is a radionuclide. These conjugates are useful tools for specific targeting of drugs and radioisotopes in the chemotherapy and radioimmunotherapy of certain cancers. [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] Immunogenetics: A branch of genetics which deals with the genetic basis of the immune response. [NIH] Immunogenic: Producing immunity; evoking an immune response. [EU] Immunoglobulins: Glycoproteins present in the blood (antibodies) and in other tissue. They are classified by structure and activity into five classes (IgA, IgD, IgE, IgG, IgM). [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] Immunophenotyping: Process of classifying cells of the immune system based on structural and functional differences. The process is commonly used to analyze and sort Tlymphocytes into subsets based on CD antigens by the technique of flow cytometry. [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
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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 prevent graft rejection. [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 Situ Hybridization: A technique that localizes specific nucleic acid sequences within intact chromosomes, eukaryotic cells, or bacterial cells through the use of specific nucleic acid-labeled probes. [NIH] 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] Indolent: A type of cancer that grows slowly. [NIH] Indolent lymphoma: Lymphoma that grows slowly and has few symptoms. [NIH] 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] Induction therapy: Treatment designed to be used as a first step toward shrinking the cancer and in evaluating response to drugs and other agents. Induction therapy is followed by additional therapy to eliminate whatever cancer remains. [NIH] Industrial Waste: Worthless, damaged, defective, superfluous or effluent material from industrial operations. It represents an ecological problem and health hazard. [NIH] Infancy: The period of complete dependency prior to the acquisition of competence in walking, talking, and self-feeding. [NIH] Infant, Newborn: An infant during the first month after birth. [NIH] Infantile: Pertaining to an infant or to infancy. [EU] 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]
Infiltration: The diffusion or accumulation in a tissue or cells of substances not normal to it or in amounts of the normal. Also, the material so accumulated. [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] Informed Consent: Voluntary authorization, given to the physician by the patient, with full comprehension of the risks involved, for diagnostic or investigative procedures and medical and surgical treatment. [NIH]
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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 step in a carcinogenic process. [NIH] Inorganic: Pertaining to substances not of organic origin. [EU] Inositol: An isomer of glucose that has traditionally been considered to be a B vitamin although it has an uncertain status as a vitamin and a deficiency syndrome has not been identified in man. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1379) Inositol phospholipids are important in signal transduction. [NIH] Insecticides: Pesticides designed to control insects that are harmful to man. The insects may be directly harmful, as those acting as disease vectors, or indirectly harmful, as destroyers of crops, food products, or textile fabrics. [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] Integrins: A family of transmembrane glycoproteins consisting of noncovalent heterodimers. They interact with a wide variety of ligands including extracellular matrix glycoproteins, complement, and other cells, while their intracellular domains interact with the cytoskeleton. The integrins consist of at least three identified families: the cytoadhesin receptors, the leukocyte adhesion receptors, and the very-late-antigen receptors. Each family contains a common beta-subunit combined with one or more distinct alpha-subunits. These receptors participate in cell-matrix and cell-cell adhesion in many physiologically important processes, including embryological development, hemostasis, thrombosis, wound healing, immune and nonimmune defense mechanisms, and oncogenic transformation. [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] Interphase: The interval between two successive cell divisions during which the chromosomes are not individually distinguishable and DNA replication occurs. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intestines: The section of the alimentary canal from the stomach to the anus. It includes the large intestine and small intestine. [NIH]
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Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] Intrathecal: Describes the fluid-filled space between the thin layers of tissue that cover the brain and spinal cord. Drugs can be injected into the fluid or a sample of the fluid can be removed for testing. [NIH] Intravascular: Within a vessel or vessels. [EU] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] 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]
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] 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, 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] Kaposi: A tumor characterized by development, essentially in men, of violet red patches and nodules on the skin. This disease also affects deeper organs. [NIH] Karyotype: The characteristic chromosome complement of an individual, race, or species as defined by their number, size, shape, etc. [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] Killer Cells: Lymphocyte-like effector cells which mediate antibody-dependent cell cytotoxicity. They kill antibody-coated target cells which they bind with their Fc receptors. [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] Larva: Wormlike or grublike stage, following the egg in the life cycle of insects, worms, and other metamorphosing animals. [NIH] Laser therapy: The use of an intensely powerful beam of light to kill cancer cells. [NIH] Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH] Leg Ulcer: Ulceration of the skin and underlying structures of the lower extremity. About 90% of the cases are due to venous insufficiency (varicose ulcer), 5% to arterial disease, and
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the remaining 5% to other causes. [NIH] Lesion: An area of abnormal tissue change. [NIH] 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]
Leukapheresis: The preparation of leukocyte concentrates with the return of red cells and leukocyte-poor plasma to the donor. [NIH] Leukocyte Count: A count of the number of white blood cells per unit volume in venous blood. A differential leukocyte count measures the relative numbers of the different types of white cells. [NIH] Leukocytosis: A transient increase in the number of leukocytes in a body fluid. [NIH] Leukoencephalopathy: A condition with spongy holes in the brain's white matter. [NIH] Leukotrienes: A family of biologically active compounds derived from arachidonic acid by oxidative metabolism through the 5-lipoxygenase pathway. They participate in host defense reactions and pathophysiological conditions such as immediate hypersensitivity and inflammation. They have potent actions on many essential organs and systems, including the cardiovascular, pulmonary, and central nervous system as well as the gastrointestinal tract and the immune system. [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] Linkage: 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] 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]
Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver Neoplasms: Tumors or cancer of the liver. [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] Locomotion: Movement or the ability to move from one place or another. It can refer to humans, vertebrate or invertebrate animals, and microorganisms. [NIH] 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] Lupus: A form of cutaneous tuberculosis. It is seen predominantly in women and typically involves the nasal, buccal, and conjunctival mucosa. [NIH]
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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]
Lymphadenopathy: Disease or swelling of the lymph nodes. [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] Lymphedema: Edema due to obstruction of lymph vessels or disorders of the lymph nodes. [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 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] Lymphocytic: Referring to lymphocytes, a type of white blood cell. [NIH] Lymphocytosis: Excess of normal lymphocytes in the blood or in any effusion. [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] Lymphoproliferative: Disorders characterized by proliferation of lymphoid tissue, general or unspecified. [NIH] Lymphoproliferative Disorders: Disorders characterized by proliferation of lymphoid tissue, general or unspecified. [NIH] Lymphotoxin: Soluble substance released by lymphocytes activated by antigens or T-cell mitogens, that is cytotoxic to other cells. It is involved in allergies and chronic inflammatory diseases. Lymphotoxin is antigenically distinct from tumor necrosis factor-alpha (tumor necrosis factor), though they both share a common receptor, biological activities, and significant amino acid sequences. [NIH] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] Mafosfamide: A form of cyclophosphamide that can be administered as an intrathecal infusion. Mafosfamide is being studied as an anticancer drug; it belongs to the family of drugs called alkylating agents. [NIH] Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy
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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] Magnetic Resonance Spectroscopy: Spectroscopic method of measuring the magnetic moment of elementary particles such as atomic nuclei, protons or electrons. It is employed in clinical applications such as NMR Tomography (magnetic resonance imaging). [NIH] Maintenance therapy: Treatment that is given to help a primary (original) treatment keep working. Maintenance therapy is often given to help keep cancer in remission. [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 tumor: A tumor capable of metastasizing. [NIH] Mammary: Pertaining to the mamma, or breast. [EU] Mastectomy: Surgery to remove the breast (or as much of the breast tissue as possible). [NIH] Mastication: The act and process of chewing and grinding food in the mouth. [NIH] Masticatory: 1. subserving or pertaining to mastication; affecting the muscles of mastication. 2. a remedy to be chewed but not swallowed. [EU] 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] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Medroxyprogesterone Acetate: An injectable contraceptive, generally marketed under the name Depo-Provera. [NIH] Megakaryocytes: Very large bone marrow cells which release mature blood platelets. [NIH] Melanin: The substance that gives the skin its color. [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] 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] Mental Processes: Conceptual functions or thinking in all its forms. [NIH] Mentors: Senior professionals who provide guidance, direction and support to those persons desirous of improvement in academic positions, administrative positions or other career development situations. [NIH] Mercury: A silver metallic element that exists as a liquid at room temperature. It has the
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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] Metabolic disorder: A condition in which normal metabolic processes are disrupted, usually because of a missing enzyme. [NIH] Metamorphosis: The ontogeny of insects, i. e. the series of changes undergone from egg, through larva and pupa, or through nymph, to adult. [NIH] Metaphase: The second phase of cell division, in which the chromosomes line up across the equatorial plane of the spindle prior to separation. [NIH] Metaplasia: A condition in which there is a change of one adult cell type to another similar adult cell type. [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] Metastatic: Having to do with metastasis, which is the spread of cancer from one part of the body to another. [NIH] Methanol: A colorless, flammable liquid used in the manufacture of formaldehyde and acetic acid, in chemical synthesis, antifreeze, and as a solvent. Ingestion of methanol is toxic and may cause blindness. [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] Methyltransferase: A drug-metabolizing enzyme. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [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] Micro-organism: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microsatellite Repeats: A variety of simple di- (dinucleotide repeats), tri- (trinucleotide repeats), tetra-, and pentanucleotide tandem repeats (usually less than 100 bases long). They are dispersed in the euchromatic arms of most chromosomes. [NIH] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] Minor Histocompatibility Antigens: Allelic alloantigens often responsible for weak graft rejection in cases when (major) histocompatibility has been established by standard tests. In the mouse they are coded by more than 500 genes at up to 30 minor histocompatibility loci. The most well-known minor histocompatibility antigen in mammals is the H-Y antigen. [NIH]
Minor Histocompatibility Loci: Genetic loci responsible for the encoding of histocompatibility antigens other than those encoded by the major histocompatibility
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complex. The antigens encoded by these genes are often responsible for graft rejection in cases where histocompatibility has been established by standard tests. The location of some of these loci on the X and Y chromosomes explains why grafts from males to females may be rejected while grafts from females to males are accepted. In the mouse roughly 30 minor histocompatibility loci have been recognized, comprising more than 500 genes. [NIH] Mitochondrial Swelling: Increase in volume of mitochondria due to an influx of fluid; it occurs in hypotonic solutions due to osmotic pressure and in isotonic solutions as a result of altered permeability of the membranes of respiring mitochondria. [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] 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] 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] 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] 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] 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] Multidrug resistance: Adaptation of tumor cells to anticancer drugs in ways that make the drugs less effective. [NIH]
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Multiple Myeloma: A malignant tumor of plasma cells usually arising in the bone marrow; characterized by diffuse involvement of the skeletal system, hyperglobulinemia, Bence-Jones proteinuria, and anemia. [NIH] Multivalent: Pertaining to a group of 5 or more homologous or partly homologous chromosomes during the zygotene stage of prophase to first metaphasis in meiosis. [NIH] Multivariate Analysis: A set of techniques used when variation in several variables has to be studied simultaneously. In statistics, multivariate analysis is interpreted as any analytic method that allows simultaneous study of two or more dependent variables. [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] Mutagenic: Inducing genetic mutation. [EU] Mycophenolate mofetil: A drug that is being studied for its effectiveness in preventing graft-versus-host disease and autoimmune disorders. [NIH] Myelodysplasia: Abnormal bone marrow cells that may lead to myelogenous leukemia. [NIH]
Myelodysplastic Syndromes: Conditions in which the bone marrow shows qualitative and quantitative changes suggestive of a preleukemic process, but having a chronic course that does not necessarily terminate as acute leukemia. [NIH] Myelofibrosis: A disorder in which the bone marrow is replaced by fibrous tissue. [NIH] Myelogenous: Produced by, or originating in, the bone marrow. [NIH] Myeloid Cells: Cells which include the monocytes and the granulocytes. [NIH] Myeloid Progenitor Cells: One of the two stem cells derived from hematopoietic stem cells the other being the lymphoid progenitor cell. Derived from these myeloid progenitor cells are the erythroid progenitor cells and the myeloid cells (monocytes and granulocytes). [NIH] Myeloma: Cancer that arises in plasma cells, a type of white blood cell. [NIH] Myeloproliferative Disorders: Disorders in which one or more stimuli cause proliferation of hemopoietically active tissue or of tissue which has embryonic hemopoietic potential. [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] Myosin: Chief protein in muscle and the main constituent of the thick filaments of muscle fibers. In conjunction with actin, it is responsible for the contraction and relaxation of muscles. [NIH] Natural killer cells: NK cells. A type of white blood cell that contains granules with enzymes that can kill tumor cells or microbial cells. Also called large granular lymphocytes (LGL). [NIH] Natural selection: A part of the evolutionary process resulting in the survival and reproduction of the best adapted individuals. [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]
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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] Neoplasia: Abnormal and uncontrolled cell growth. [NIH] Neoplasm: A new growth of benign or malignant tissue. [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] Neuroblastoma: Cancer that arises in immature nerve cells and affects mostly infants and children. [NIH] Neurology: A medical specialty concerned with the study of the structures, functions, and diseases of the nervous system. [NIH] 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] Neurosurgery: A surgical specialty concerned with the treatment of diseases and disorders of the brain, spinal cord, and peripheral and sympathetic nervous system. [NIH] Neurotoxicity: The tendency of some treatments to cause damage to the nervous system. [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] Neutropenia: An abnormal decrease in the number of neutrophils, a type of white blood cell. [NIH] Neutrophil: A type of white blood cell. [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] 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]
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Nucleic Acid Hybridization: The process whereby two single-stranded polynucleotides form a double-stranded molecule, with hydrogen bonding between the complementary bases in the two strains. [NIH] Nucleic Acid Probes: Nucleic acid which complements a specific mRNA or DNA molecule, or fragment thereof; used for hybridization studies in order to identify microorganisms and for genetic studies. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nurse Practitioners: Nurses who are specially trained to assume an expanded role in providing medical care under the supervision of a physician. [NIH] Nymph: The immature stage in the life cycle of those orders of insects characterized by gradual metamorphosis, in which the young resemble the imago in general form of body, including compound eyes and external wings; also the 8-legged stage of mites and ticks that follows the first moult. [NIH] Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU] 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] Oncogenic: Chemical, viral, radioactive or other agent that causes cancer; carcinogenic. [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] Organ Culture: The growth in aseptic culture of plant organs such as roots or shoots, beginning with organ primordia or segments and maintaining the characteristics of the organ. [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] 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] Outpatient: A patient who is not an inmate of a hospital but receives diagnosis or treatment in a clinic or dispensary connected with the hospital. [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] Ovum: A female germ cell extruded from the ovary at ovulation. [NIH] Oxidative metabolism: A chemical process in which oxygen is used to make energy from carbohydrates (sugars). Also known as aerobic respiration, cell respiration, or aerobic metabolism. [NIH] P53 gene: A tumor suppressor gene that normally inhibits the growth of tumors. This gene is altered in many types of cancer. [NIH]
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Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior 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] Pancytopenia: Deficiency of all three cell elements of the blood, erythrocytes, leukocytes and platelets. [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 Glands: Two small paired endocrine glands in the region of the thyroid gland. They secrete parathyroid hormone and are concerned with the metabolism of calcium and phosphorus. [NIH] Parathyroid hormone: A substance made by the parathyroid gland that helps the body store and use calcium. Also called parathormone, parathyrin, or PTH. [NIH] Partial remission: The shrinking, but not complete disappearance, of a tumor in response to therapy. Also called partial response. [NIH] Partial response: A decrease in the size of a tumor, or in the extent of cancer in the body, in response to treatment. [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] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Pediatrics: A medical specialty concerned with maintaining health and providing medical care to children from birth to adolescence. [NIH] Pelvic: Pertaining to the pelvis. [EU] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Peptide T: N-(N-(N(2)-(N-(N-(N-(N-D-Alanyl L-seryl)-L-threonyl)-L-threonyl) L-threonyl)L-asparaginyl)-L-tyrosyl) L-threonine. Octapeptide sharing sequence homology with HIV envelope protein gp120. It is potentially useful as antiviral agent in AIDS therapy. The core pentapeptide sequence, TTNYT, consisting of amino acids 4-8 in peptide T, is the HIV envelope sequence required for attachment to the CD4 receptor. [NIH] Pericardial Effusion: Presence of fluid within the pericardium. [NIH] Pericardium: The fibroserous sac surrounding the heart and the roots of the great vessels. [NIH]
Peripheral blood: Blood circulating throughout the body. [NIH] Peripheral stem cell transplantation: A method of replacing blood-forming cells destroyed by cancer treatment. Immature blood cells (stem cells) in the circulating blood that are similar to those in the bone marrow are given after treatment to help the bone marrow recover and continue producing healthy blood cells. Transplantation may be autologous (an individual's own blood cells saved earlier), allogeneic (blood cells donated by someone else),
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or syngeneic (blood cells donated by an identical twin). Also called peripheral stem cell support. [NIH] Peripheral stem cells: Immature cells found circulating in the bloodstream. New blood cells develop from peripheral stem cells. [NIH] Pesticides: Chemicals used to destroy pests of any sort. The concept includes fungicides (industrial fungicides), insecticides, rodenticides, etc. [NIH] Pharmacodynamics: The study of the biochemical and physiological effects of drugs and the mechanisms of their actions, including the correlation of actions and effects of drugs with their chemical structure; also, such effects on the actions of a particular drug or drugs. [EU] 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] 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 of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Philadelphia Chromosome: An aberrant form of human chromosome 22 characterized by translocation of genetic material from chromosome 22, usually to the long arms of chromosome 9. It is present in the bone marrow cells of 80 to 90 per cent of patients with chronic myelocytic leukemia. [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] Phosphorylate: Attached to a phosphate group. [NIH] Phosphorylated: 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] Phosphotyrosine: An amino acid that occurs in endogenous proteins. Tyrosine phosphorylation and dephosphorylation plays a role in cellular signal transduction and possibly in cell growth control and carcinogenesis. [NIH] Photocoagulation: Using a special strong beam of light (laser) to seal off bleeding blood vessels such as in the eye. The laser can also burn away blood vessels that should not have grown in the eye. This is the main treatment for diabetic retinopathy. [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]
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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 Projects: Small-scale tests of methods and procedures to be used on a larger scale if the pilot study demonstrates that these methods and procedures can work. [NIH] Pilot study: The initial study examining a new method or treatment. [NIH] Placenta: A highly vascular fetal organ through which the fetus absorbs oxygen and other nutrients and excretes carbon dioxide and other wastes. It begins to form about the eighth day of gestation when the blastocyst adheres to the decidua. [NIH] Plant Growth Regulators: Any of the hormones produced naturally in plants and active in controlling growth and other functions. There are three primary classes: auxins, cytokinins, and gibberellins. [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] 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] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [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] Polyarthritis: An inflammation of several joints together. [EU] Polycythemia Vera: A myeloproliferative disorder of unknown etiology, characterized by abnormal proliferation of all hematopoietic bone marrow elements and an absolute increase in red cell mass and total blood volume, associated frequently with splenomegaly, leukocytosis, and thrombocythemia. Hematopoiesis is also reactive in extramedullary sites (liver and spleen). In time myelofibrosis occurs. [NIH] Polyethylene: A vinyl polymer made from ethylene. It can be branched or linear. Branched or low-density polyethylene is tough and pliable but not to the same degree as linear polyethylene. Linear or high-density polyethylene has a greater hardness and tensile strength. Polyethylene is used in a variety of products, including implants and prostheses. [NIH]
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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 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] 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] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [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] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [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] Practicability: A non-standard characteristic of an analytical procedure. It is dependent on the scope of the method and is determined by requirements such as sample throughout and costs. [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] 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] 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] Prednisone: A synthetic anti-inflammatory glucocorticoid derived from cortisone. It is biologically inert and converted to prednisolone in the liver. [NIH] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Prenatal Care: Care provided the pregnant woman in order to prevent complications, and decrease the incidence of maternal and prenatal mortality. [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] Progeny: The offspring produced in any generation. [NIH]
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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] Progressive disease: Cancer that is increasing in scope or severity. [NIH] Prokaryotic Cells: Cells, such as those of bacteria and the blue green algae, which lack a nuclear membrane so that the nuclear material is either scattered in the cytoplasm or collected in a nucleoid region. [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]
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] 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] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] 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 Conformation: The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. Quaternary protein structure describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). [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] Proteinuria: The presence of protein in the urine, indicating that the kidneys are not working properly. [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
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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] 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] Pruritus: An intense itching sensation that produces the urge to rub or scratch the skin to obtain relief. [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] Psychiatric: Pertaining to or within the purview of psychiatry. [EU] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [NIH] Psychoactive: Those drugs which alter sensation, mood, consciousness or other psychological or behavioral functions. [NIH] Psychology: The science dealing with the study of mental processes and behavior in man and animals. [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] 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]
Pupa: An inactive stage between the larval and adult stages in the life cycle of insects. [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] Putrefaction: The process of decomposition of animal and vegetable matter by living organisms. [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] 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] Race: A population within a species which exhibits general similarities within itself, but is
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both discontinuous and distinct from other populations of that species, though not 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] Radioactive: Giving off radiation. [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] Radiolabeled: Any compound that has been joined with a radioactive substance. [NIH] Radiology: A specialty concerned with the use of x-ray and other forms of radiant energy in the diagnosis and treatment of disease. [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] 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. 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] 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] 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
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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] 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] 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] Regeneration: The natural renewal of a structure, as of a lost tissue or part. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] 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 cancer in the body. [NIH] Repopulation: The replacement of functional cells, usually by proliferation, following or during irradiation. [NIH] Reproductive cells: Egg and sperm cells. Each mature reproductive cell carries a single set of 23 chromosomes. [NIH] Research Personnel: Those individuals engaged in research. [NIH] Research Support: Financial support of research activities. [NIH] Residual disease: Cancer cells that remain after attempts have been made to remove the cancer. [NIH] 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] 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] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It
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occurs in hereditary and nonhereditary (sporadic) forms. [NIH] Retinoid: Vitamin A or a vitamin A-like compound. [NIH] Retinopathy: 1. Retinitis (= inflammation of the retina). 2. Retinosis (= degenerative, noninflammatory condition of the retina). [EU] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [NIH] Retrovirus: A member of a group of RNA viruses, the RNA of which is copied during viral replication into DNA by reverse transcriptase. The viral DNA is then able to be integrated into the host chromosomal DNA. [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] Rheumatoid arthritis: A form of arthritis, the cause of which is unknown, although infection, hypersensitivity, hormone imbalance and psychologic stress have been suggested as possible causes. [NIH] Ribonuclease: RNA-digesting enzyme. [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] Rigidity: Stiffness or inflexibility, chiefly that which is abnormal or morbid; rigor. [EU] 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] Rodenticides: Substances used to destroy or inhibit the action of rats, mice, or other rodents. [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] Salivary glands: Glands in the mouth that produce saliva. [NIH] Sarcoma: A connective tissue neoplasm formed by proliferation of mesodermal cells; it is usually highly malignant. [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,
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depersonalization), speech (digressive, vague, overelaborate), and behavior (inappropriate affect in social interactions, frequently social isolation) that are not severe enough to characterize schizophrenia. [NIH] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Screening: Checking for disease when there are no symptoms. [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] 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] Sedimentation: The act of causing the deposit of sediment, especially by the use of a centrifugal machine. [EU] Segmental: Describing or pertaining to a structure which is repeated in similar form in successive segments of an organism, or which is undergoing segmentation. [NIH] Segmentation: The process by which muscles in the intestines move food and wastes through the body. [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] Semisynthetic: Produced by chemical manipulation of naturally occurring substances. [EU] Septic: Produced by or due to decomposition by microorganisms; putrefactive. [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] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Sex Characteristics: Those characteristics that distinguish one sex from the other. The primary sex characteristics are the ovaries and testes and their related hormones. Secondary sex characteristics are those which are masculine or feminine but not directly related to reproduction. [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
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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] 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] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [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] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] 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
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the extents of these reactions. [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 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] Spleen: An organ that is part of the lymphatic system. The spleen produces lymphocytes, filters the blood, stores blood cells, and destroys old blood cells. It is located on the left side of the abdomen near the stomach. [NIH] Splenectomy: An operation to remove the spleen. [NIH] Splenomegaly: Enlargement of the spleen. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Spores: The reproductive elements of lower organisms, such as protozoa, fungi, and cryptogamic plants. [NIH] Spotting: A slight discharge of blood via the vagina, especially as a side-effect of oral contraceptives. [EU] Squamous: Scaly, or platelike. [EU] Stabilization: The creation of a stable state. [EU] 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] Statistically significant: Describes a mathematical measure of difference between groups. The difference is said to be statistically significant if it is greater than what might be expected to happen by chance alone. [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 Cell Factor: Hematopoietic growth factor and the ligand of the c-kit receptor CD117 (proto-oncogene protein C-kit). It is expressed during embryogenesis and provides a key signal in multiple aspects of mast-cell differentiation and function. [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] Stereotactic: Radiotherapy that treats brain tumors by using a special frame affixed directly to the patient's cranium. By aiming the X-ray source with respect to the rigid frame, technicians can position the beam extremely precisely during each treatment. [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] Stimulant: 1. Producing stimulation; especially producing stimulation by causing tension on
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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] 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] Stroma: The middle, thickest layer of tissue in the cornea. [NIH] Stromal: Large, veil-like cell in the bone marrow. [NIH] Stromal Cells: Connective tissue cells of an organ found in the loose connective tissue. These are most often associated with the uterine mucosa and the ovary as well as the hematopoietic system and elsewhere. [NIH] Stump: The end of the limb after amputation. [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] 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] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]
Substrate: A substance upon which an enzyme acts. [EU] Support group: A group of people with similar disease who meet to discuss how better to cope with their cancer and treatment. [NIH] Supportive care: Treatment given to prevent, control, or relieve complications and side effects and to improve the comfort and quality of life of people who have cancer. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Surface Plasmon Resonance: A biosensing technique in which biomolecules capable of binding to specific analytes or ligands are first immobilized on one side of a metallic film. Light is then focused on the opposite side of the film to excite the surface plasmons, that is, the oscillations of free electrons propagating along the film's surface. The refractive index of light reflecting off this surface is measured. When the immobilized biomolecules are bound by their ligands, an alteration in surface plasmons on the opposite side of the film is created which is directly proportional to the change in bound, or adsorbed, mass. Binding is measured by changes in the refractive index. The technique is used to study biomolecular interactions, such as antigen-antibody binding. [NIH]
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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] Sympathetic Nervous System: The thoracolumbar division of the autonomic nervous system. Sympathetic preganglionic fibers originate in neurons of the intermediolateral column of the spinal cord and project to the paravertebral and prevertebral ganglia, which in turn project to target organs. The sympathetic nervous system mediates the body's response to stressful situations, i.e., the fight or flight reactions. It often acts reciprocally to the parasympathetic system. [NIH] Symphysis: A secondary cartilaginous joint. [NIH] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [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] Systemic: Affecting the entire body. [NIH] Systemic lupus erythematosus: SLE. A chronic inflammatory connective tissue disease marked by skin rashes, joint pain and swelling, inflammation of the kidneys, inflammation of the fibrous tissue surrounding the heart (i.e., the pericardium), as well as other problems. Not all affected individuals display all of these problems. May be referred to as lupus. [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] 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] Teratogenic: Tending to produce anomalies of formation, or teratism (= anomaly of formation or development : condition of a monster). [EU] Terminator: A DNA sequence sited at the end of a transcriptional unit that signals the end of transcription. [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] Tetany: 1. Hyperexcitability of nerves and muscles due to decrease in concentration of extracellular ionized calcium, which may be associated with such conditions as parathyroid hypofunction, vitamin D deficiency, and alkalosis or result from ingestion of alkaline salts; it is characterized by carpopedal spasm, muscular twitching and cramps, laryngospasm with inspiratory stridor, hyperreflexia and choreiform movements. 2. Tetanus. [EU] Tetracycline: An antibiotic originally produced by Streptomyces viridifaciens, but used
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mostly in synthetic form. It is an inhibitor of aminoacyl-tRNA binding during protein synthesis. [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] Thigh: A leg; in anatomy, any elongated process or part of a structure more or less comparable to a leg. [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] Thrombocytes: Blood cells that help prevent bleeding by causing blood clots to form. Also called platelets. [NIH] Thrombocytopenia: A decrease in the number of blood platelets. [NIH] Thrombocytosis: Increased numbers of platelets in the peripheral blood. [EU] 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]
Thrombopoietin: A humoral factor that controls blood platelet production through stimulation of megakaryocyte populations. Bone marrow megakaryocytes increase in both size and number in response to exposure to thrombopoietin. [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] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Thyroid Gland: A highly vascular endocrine gland consisting of two lobes, one on either side of the trachea, joined by a narrow isthmus; it produces the thyroid hormones which are concerned in regulating the metabolic rate of the body. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tissue Culture: Maintaining or growing of tissue, organ primordia, or the whole or part of an organ in vitro so as to preserve its architecture and/or function (Dorland, 28th ed). Tissue culture includes both organ culture and cell culture. [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] Total-body irradiation: Radiation therapy to the entire body. Usually followed by bone marrow or peripheral stem cell transplantation. [NIH]
Dictionary 239
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] 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] 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] 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] 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] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Treatment Outcome: Evaluation undertaken to assess the results or consequences of management and procedures used in combating disease in order to determine the efficacy, effectiveness, safety, practicability, etc., of these interventions in individual cases or series. [NIH]
Triglyceride: A lipid carried through the blood stream to tissues. Most of the body's fat tissue is in the form of triglycerides, stored for use as energy. Triglycerides are obtained primarily from fat in foods. [NIH] Trinucleotide Repeats: Microsatellite repeats consisting of three nucleotides dispersed in the euchromatic arms of chromosomes. [NIH] Troxacitabine: A drug being studied for use as an anticancer agent. [NIH] Tubulin: A microtubule subunit protein found in large quantities in mammalian brain. It has also been isolated from sperm flagella, cilia, and other sources. Structurally, the protein is a dimer with a molecular weight of approximately 120,000 and a sedimentation coefficient of 5.8S. It binds to colchicine, vincristine, and vinblastine. [NIH] Tumor marker: A substance sometimes found in an increased amount in the blood, other
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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 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] 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] Tunica: A rather vague term to denote the lining coat of hollow organs, tubes, or cavities. [NIH]
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] Ubiquitin: A highly conserved 76 amino acid-protein found in all eukaryotic cells. [NIH] Umbilical Arteries: Either of a pair of arteries originating from the internal iliac artery and passing through the umbilical cord to carry blood from the fetus to the placenta. [NIH] Umbilical Cord: The flexible structure, giving passage to the umbilical arteries and vein, which connects the embryo or fetus to the placenta. [NIH] Umbilical cord blood: Blood from the placenta (afterbirth) that contains high concentrations of stem cells needed to produce new blood cells. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]
Uric: A kidney stone that may result from a diet high in animal protein. When the body breaks down this protein, uric acid levels rise and can form stones. [NIH] Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urinate: To release urine from the bladder to the outside. [NIH] Urogenital: Pertaining to the urinary and genital apparatus; genitourinary. [EU] 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] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Varicose: The common ulcer in the lower third of the leg or near the ankle. [NIH] Varicose Ulcer: Ulcer due to varicose veins. Chronic venous insufficiency in the deep veins of the legs leads to shunting the venous return into the superficial veins, in which pressure and flow rate, as well as oxygen content, are increased. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU]
Dictionary 241
Vascular endothelial growth factor: VEGF. A substance made by cells that stimulates new blood vessel formation. [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] Venous: Of or pertaining to the veins. [EU] Venous blood: Blood that has given up its oxygen to the tissues and carries carbon dioxide back for gas exchange. [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] 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] Vinyl Chloride: A gas that has been used as an aerosol propellant and is the starting material for polyvinyl resins. Toxicity studies have shown various adverse effects, particularly the occurrence of liver neoplasms. [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] 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] 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] War: Hostile conflict between organized groups of people. [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]
Withdrawal: 1. A pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality
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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] Xanthoma: A tumour composed of lipid-laden foam cells, which are histiocytes containing cytoplasmic lipid material. Called also xanthelasma. [EU] Xenograft: The cells of one species transplanted to another species. [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] Zebrafish: A species of North American fishes of the family Cyprinidae. They are used in embryological studies and to study the effects of certain chemicals on development. [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]
243
INDEX A Abdominal, 187, 224 Aberrant, 13, 28, 58, 63, 90, 134, 144, 187, 225 Accelerated phase, 13, 22, 70, 105, 149, 154, 187 Acceptor, 187, 238 Acetylglucosamine, 85, 187 Actin, 122, 187, 221 Acute leukemia, 9, 19, 23, 24, 32, 40, 50, 54, 56, 109, 137, 141, 142, 150, 153, 187, 221, 241 Acute lymphoblastic leukemia, 9, 18, 40, 41, 55, 56, 59, 60, 64, 93, 142, 143, 152, 153, 187 Acute lymphocytic leukemia, 11, 52, 81, 147, 154, 187 Acute myelogenous leukemia, 42, 117, 137, 142, 151, 187 Acute myeloid leukemia, 17, 18, 55, 62, 142, 150, 152, 187, 228 Acute nonlymphocytic leukemia, 142, 187 Adaptability, 187, 195 Adenine, 187, 229 Adenosine, 140, 187, 192, 225 Adolescence, 37, 187, 224 Adoptive Transfer, 54, 57, 188 Adverse Effect, 188, 234, 241 Aerosol, 188, 241 Affinity, 29, 101, 188, 234 Age Groups, 137, 145, 188 Aged, 80 and Over, 188 Aggressiveness, 142, 188 Agonist, 188, 237 Algorithms, 188, 193 Alkaline, 184, 188, 194, 237 Alkaline Phosphatase, 184, 188 Alkaloid, 154, 188, 197, 210 Alkylating Agents, 37, 188, 194, 217 Alleles, 15, 188, 210 Allo, 117, 188 Allogeneic bone marrow transplantation, 25, 64, 68, 74, 83, 90, 91, 92, 94, 97, 103, 112, 117, 188 Allograft, 35, 188 Alopecia, 189, 199 Alpha Particles, 189, 230 Alternative medicine, 158, 189
Amine, 189, 210 Amino Acid Motifs, 189, 199 Amino Acid Sequence, 140, 189, 190, 198, 204, 207, 217 Amino Acids, 15, 140, 153, 189, 197, 199, 207, 224, 227, 228, 232, 233, 239 Amplification, 28, 61, 135, 189 Amputation, 106, 189, 236 Amyloid, 48, 189 Anaesthesia, 189, 213 Anal, 189, 221 Analog, 4, 100, 153, 189, 206 Analogous, 26, 189, 202, 239 Analytes, 189, 236 Anaphylatoxins, 189, 198 Anaplastic, 98, 190 Anatomical, 190, 233 Anemia, 135, 140, 141, 183, 190, 209, 221 Animal model, 11, 14, 24, 54, 190 Annealing, 190, 227 Anomalies, 29, 190, 237 Antecedent, 153, 190 Anthracycline, 190, 211 Anthrax, 10, 190 Antibacterial, 190, 235 Antibiotic, 190, 211, 235, 237 Antibodies, 12, 61, 135, 136, 142, 143, 147, 150, 190, 191, 192, 209, 211, 212, 220, 226, 230 Antibody, 12, 26, 28, 141, 145, 150, 188, 190, 194, 197, 204, 209, 210, 212, 213, 215, 220, 230, 234, 236, 242 Anticoagulant, 190, 228 Antifungal, 190, 205 Antigen-Antibody Complex, 190, 198 Antigen-presenting cell, 191, 201 Anti-inflammatory, 191, 199, 207, 227 Antimetabolite, 191, 192, 219 Antineoplastic, 37, 188, 191, 192, 194, 197, 199, 207, 211, 218, 219, 226, 241 Antineoplastic Agents, 37, 188, 191, 241 Antiproliferative, 71, 103, 191 Antiserum, 191, 192 Antiviral, 57, 191, 214, 224 Anus, 189, 191, 197, 214 Aplasia, 33, 78, 102, 191 Aplastic anemia, 6, 191 Apolipoproteins, 191, 206
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Applicability, 10, 46, 191 Aqueous, 191, 192, 200 Arachidonic Acid, 191, 216 Arsenic trioxide, 65, 88, 163, 191 Arterial, 191, 211, 215, 228 Arteriosclerosis, 191, 211 Aspiration, 79, 184, 192 Assay, 10, 12, 13, 16, 19, 25, 192 ATP, 153, 192, 202, 207, 225, 228, 238, 239 Autoantibodies, 25, 192 Autoantigens, 192 Autoimmune disease, 150, 192 Autoimmunity, 83, 192 Autologous bone marrow transplantation, 36, 118, 121, 192, 209 Autologous lymphocytes, 25, 192 Avidity, 54, 57, 69, 192 Azacitidine, 126, 127, 192 B Bacillus, 10, 190, 192 Bacteria, 143, 190, 192, 203, 219, 228, 230, 235, 239, 240 Bacterium, 10, 192 Base, 17, 19, 36, 42, 142, 187, 192, 200, 207, 215, 237 Basophils, 140, 192, 208 Benign, 11, 22, 30, 138, 145, 192, 195, 206, 208, 222, 230 Beta-pleated, 189, 192 Bile, 192, 210, 216 Biochemical, 10, 11, 21, 31, 34, 39, 74, 102, 134, 144, 188, 191, 193, 205, 225 Biogenesis, 51, 193 Biological response modifier, 37, 193, 214 Biological therapy, 193, 209 Biomolecular, 112, 193, 236 Biopsy, 76, 193 Biopsy specimen, 76, 193 Biosynthesis, 191, 193, 233 Biotechnology, 17, 20, 59, 62, 158, 169, 193 Bladder, 193, 198, 228, 240, 241 Blast Crisis, 9, 13, 22, 51, 60, 63, 67, 72, 77, 78, 79, 80, 82, 85, 88, 94, 95, 96, 97, 102, 104, 112, 123, 125, 126, 127, 136, 137, 142, 145, 149, 193 Blast phase, 23, 50, 85, 187, 193, 196 Blasts, 9, 22, 142, 193 Blood Cell Count, 193, 209 Blood Platelets, 193, 218, 238 Blood pressure, 193, 211, 220, 234 Blood vessel, 193, 195, 199, 203, 207, 217, 219, 225, 234, 238, 240, 241
Blood Volume, 193, 226 Blot, 135, 194, 212 Blotting, Western, 194, 212 Body Fluids, 194, 202, 234, 240 Bone Marrow Cells, 30, 55, 97, 147, 151, 194, 208, 218, 221, 225 Brachytherapy, 194, 214, 215, 230, 242 Breeding, 52, 194 Bronchial, 194, 210 Bryostatin-1, 19, 194 Busulfan, 35, 37, 68, 76, 162, 194 C Calcium, 60, 194, 198, 224, 234, 237 Calculi, 194, 208 Candidiasis, 194, 205 Capsules, 64, 194 Carbohydrate, 134, 194, 199, 227 Carboplatin, 117, 119, 194 Carcinogen, 194, 218 Carcinogenesis, 50, 195, 225 Carcinogenic, 144, 188, 195, 214, 223, 228, 240 Carcinoid, 98, 195 Carcinoma, 8, 85, 195, 241 Cardiac, 37, 195, 204, 211 Cardiovascular, 195, 216 Case report, 66, 73, 85, 86, 89, 98, 103, 104, 195 Caspase, 22, 195 Cause of Death, 134, 195 CDC2, 153, 195 Cell Adhesion, 11, 28, 49, 81, 195, 214 Cell Cycle, 7, 9, 22, 27, 49, 52, 195, 196, 199, 204 Cell Death, 8, 66, 77, 82, 191, 195, 204, 222 Cell Differentiation, 145, 195, 234, 235 Cell Division, 192, 195, 200, 204, 208, 214, 219, 220, 226 Cell Extracts, 12, 195 Cell Lineage, 31, 195 Cell membrane, 28, 145, 195, 201, 225 Cell motility, 11, 195 Cell proliferation, 11, 15, 20, 49, 60, 139, 192, 195, 234 Cell Size, 195, 205 Cell Survival, 15, 55, 195, 208 Central Nervous System, 38, 49, 196, 216 Character, 137, 196, 200 Chemokines, 28, 196 Chemotactic Factors, 196, 198 Chemotherapeutics, 147, 151, 196 Chimeras, 27, 196
245
Cholesterol, 192, 196, 206, 211, 237 Chromatin, 191, 196, 217 Chronic granulocytic leukemia, 140, 196 Chronic leukemia, 30, 51, 142, 196 Chronic phase chronic myelogenous leukemia, 99, 125, 196 Cirrhosis, 196, 209 CIS, 113, 196, 231 Cisplatin, 59, 79, 82, 196 C-kit receptor, 31, 136, 196, 235 Cladribine, 85, 197 Clinical Medicine, 145, 197, 227 Clinical Protocols, 46, 47, 197 Cloning, 34, 52, 136, 193, 197 Coagulation, 102, 193, 194, 197, 210, 238 Codon, 140, 197, 207 Cofactor, 197, 228, 238 Colchicine, 197, 239 Collagen, 197, 205, 208 Colloidal, 197, 203 Colon, 134, 197 Combination chemotherapy, 113, 121, 122, 124, 126, 197 Combination Therapy, 119, 197 Combinatorial, 20, 197 Complement, 49, 144, 151, 189, 197, 198, 207, 214, 215 Complementary and alternative medicine, 117, 130, 198 Complementary medicine, 117, 198 Complete remission, 9, 67, 71, 198, 231 Complete response, 138, 148, 198 Compliance, 38, 46, 198 Computational Biology, 169, 198 Concomitant, 21, 198 Conjugated, 28, 145, 151, 198 Connective Tissue, 194, 197, 198, 205, 217, 219, 232, 236, 237 Consensus Sequence, 78, 189, 198, 199 Conserved Sequence, 189, 199 Continuous infusion, 59, 126, 199 Contraceptive, 199, 218 Contraindications, ii, 199 Cooperative group, 38, 40, 43, 58, 199 Coordination, 16, 41, 44, 47, 199 Cornea, 199, 236 Corticosteroid, 199, 227 Cortisone, 199, 227 Cultured cells, 56, 199 Curative, 4, 22, 69, 199, 238 Cutaneous, 18, 71, 119, 190, 194, 199, 216 Cyclic, 113, 124, 199
Cyclin, 22, 49, 52, 60, 153, 199 Cyclophosphamide, 35, 37, 120, 199, 211, 217 Cyclosporine, 33, 37, 74, 113, 126, 200 Cysteine, 15, 196, 200 Cystine, 200 Cytarabine, 67, 119, 120, 121, 124, 127, 157, 200 Cytidine, 192, 200 Cytogenetics, 46, 51, 72, 79, 80, 90, 91, 92, 97, 104, 125, 138, 139, 142, 144, 200 Cytokine, 48, 53, 81, 113, 152, 200, 205 Cytomegalovirus, 89, 90, 200, 206 Cytomegalovirus Infections, 200, 206 Cytoplasm, 58, 60, 137, 153, 191, 192, 195, 200, 203, 217, 220, 228, 232 Cytosine, 68, 106, 107, 128, 200, 229 Cytoskeleton, 28, 200, 214 Cytostatic, 19, 200 Cytotoxic, 19, 33, 56, 124, 139, 151, 200, 212, 217, 230, 234 Cytotoxicity, 79, 108, 151, 196, 200, 215 D De novo, 53, 142, 200 Decarboxylation, 200, 210 Decitabine, 103, 200 Defense Mechanisms, 200, 214 Degenerative, 139, 144, 200, 232 Deletion, 51, 69, 72, 191, 200, 206 Denaturation, 200, 227 Dendrites, 201, 222 Dendritic, 20, 56, 57, 60, 72, 76, 82, 86, 105, 108, 201 Dendritic cell, 20, 56, 57, 60, 72, 76, 82, 86, 105, 108, 201 Deoxycytidine, 103, 201 Depolarization, 201, 234 Desensitization, 201, 212 Diabetes Mellitus, 201, 207, 209 Diagnostic procedure, 133, 158, 201 Diffusion, 201, 213 Digestion, 192, 201, 216, 236 Digestive system, 201, 220 Dinucleotide Repeats, 201, 219 Diploid, 123, 201, 226 Direct, iii, 17, 21, 32, 56, 147, 151, 161, 197, 201, 231 Disease Progression, 13, 63, 78, 94, 201 Disease-Free Survival, 39, 43, 201 Disparity, 32, 35, 201 Dissociation, 188, 201, 215 Distal, 136, 149, 202, 229
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Chronic Myelogenous Leukemia
DNA Topoisomerase, 202, 207 Dominance, 23, 71, 202 Dose-limiting, 22, 202 Dosimetry, 138, 144, 202 Drug Combinations, 16, 112, 121, 202 Drug Design, 20, 55, 163, 202 Drug Interactions, 162, 202 Drug Resistance, 10, 12, 13, 19, 45, 202 Drug Tolerance, 202, 238 Duct, 202, 204, 217, 232 Dyes, 189, 192, 202, 206 E Edema, 10, 107, 202, 217 Effector, 6, 8, 11, 31, 53, 198, 202, 215 Effector cell, 53, 202, 215 Efficacy, 9, 12, 13, 16, 18, 25, 33, 35, 46, 50, 57, 76, 92, 202, 203, 239 Effusion, 203, 217 Electrocoagulation, 197, 203 Electrons, 192, 203, 215, 218, 230, 236 Electrophoresis, 137, 203 Elementary Particles, 203, 218, 222, 229 Embryo, 195, 203, 213, 240 Embryogenesis, 203, 235 Enalapril, 38, 203 Encapsulated, 203, 216 Endogenous, 86, 192, 203, 209, 225, 228, 239 Endothelial cell, 95, 203, 238 Endotoxin, 203, 240 Enhancers, 59, 203 Environmental Exposure, 203, 223 Environmental Health, 168, 170, 203 Enzymatic, 10, 58, 194, 198, 203, 210, 227, 231 Eosinophil, 203, 208 Epigastric, 203, 224 Epinephrine, 204, 222, 240 Epitope, 32, 135, 204 Erythrocyte Indices, 193, 204 Erythrocytes, 190, 193, 194, 204, 224, 231 Erythroid Progenitor Cells, 204, 221 Erythropoiesis, 141, 204 Erythropoietin, 84, 204 Escalation, 75, 204 Esophagus, 201, 204, 236, 241 Estrogen, 60, 204, 233, 237 Estrogen receptor, 60, 204 Etoposide, 59, 119, 120, 126, 204 Eukaryotic Cells, 143, 195, 204, 213, 223, 240 Evaluable patients, 40, 204
Excitation, 146, 204, 205, 222 Exocrine, 204, 224 Exogenous, 203, 204, 209, 228 Exon, 11, 77, 136, 140, 148, 150, 153, 204 Exoribonucleases, 48, 205 Extensor, 205, 229 External-beam radiation, 205, 215, 230, 242 Extracellular, 141, 189, 198, 205, 214, 234, 237 Extracellular Matrix, 198, 205, 214 Extremity, 205, 215 F Family Planning, 169, 205 Fat, 16, 191, 194, 199, 205, 216, 234, 239 Femoral, 65, 205 Femur, 205 Ferritin, 101, 205 Fetus, 204, 205, 226, 227, 240 Fibroblasts, 205, 214 Fibronectin, 28, 205 Fibrosis, 75, 205, 233 Filgrastim, 83, 205 Flavopiridol, 22, 205 Flow Cytometry, 6, 22, 46, 58, 94, 141, 205, 212 Fluconazole, 68, 205 Fludarabine, 33, 35, 79, 105, 205 Fluorescence, 28, 51, 57, 63, 73, 79, 80, 96, 101, 104, 121, 205, 206 Fluorescent Dyes, 205, 206 Foam Cells, 206, 242 G Gamma Rays, 206, 221, 230 Ganciclovir, 57, 206 Gangrene, 81, 86, 206 Gas, 201, 206, 211, 221, 222, 241 Gastric, 206, 210 Gastrointestinal, 86, 106, 195, 204, 206, 216, 236, 240 Gastrointestinal stromal tumor, 86, 106, 206 Gastrointestinal tract, 206, 216, 240 Gemfibrozil, 113, 206 Gene Deletion, 63, 206 Gene Expression, 18, 23, 26, 28, 30, 206 Gene Rearrangement, 50, 98, 135, 142, 206 Gene Therapy, 6, 39, 118, 206 Genetic Code, 207, 222 Genetic Engineering, 193, 197, 207 Genetic Screening, 144, 207 Genetic testing, 207, 227
247
Genetics, 12, 17, 34, 46, 48, 54, 72, 79, 80, 90, 91, 92, 97, 104, 113, 125, 200, 202, 207, 212 Genistein, 124, 207 Genital, 207, 240 Genitourinary, 16, 207, 240 Genotype, 7, 32, 207, 225 Germline mutation, 56, 207, 210 Gestation, 27, 207, 226 Gland, 199, 207, 217, 224, 228, 233, 236, 238 Glomeruli, 207 Glomerulosclerosis, 89, 207 Glomerulus, 207 Glucocorticoid, 207, 227 Glucose, 201, 207, 209, 214 Glycine, 208, 222, 233 Glycoprotein, 100, 102, 204, 205, 208, 238, 240 Glycosidic, 208 Gout, 106, 197, 208 Governing Board, 208, 227 Gp120, 208, 224 Grade, 4, 98, 208 Graft, 4, 8, 14, 23, 26, 29, 32, 33, 35, 57, 68, 83, 108, 208, 213, 219, 220, 221 Graft Rejection, 23, 208, 213, 219, 220 Graft-versus-host disease, 4, 26, 32, 33, 35, 57, 68, 208, 221 Graft-versus-tumor, 33, 208 Granulocyte, 31, 83, 128, 140, 147, 205, 208 Granulocyte Colony-Stimulating Factor, 205, 208 Granulocyte-Macrophage ColonyStimulating Factor, 128, 208 Granuloma, 74, 208 Granuloma Annulare, 74, 208 Growth factors, 8, 19, 31, 208 Growth Inhibitors, 11, 209 H Habitual, 196, 209 Haploid, 209, 226 Haptens, 188, 209 Hematocrit, 193, 204, 209 Hematologic Diseases, 49, 209 Hematologic malignancies, 16, 18, 209 Hematologist, 49, 209 Hematopoiesis, 6, 7, 25, 37, 49, 51, 77, 102, 136, 209, 226 Hematopoietic growth factors, 48, 209 Hematopoietic Stem Cell Transplantation, 32, 33, 53, 56, 91, 104, 209
Hematopoietic Stem Cells, 25, 145, 149, 151, 209, 221 Hemin, 48, 209 Hemochromatosis, 141, 209 Hemoglobin, 190, 193, 204, 209 Hemoglobinopathies, 206, 209 Hemorrhage, 89, 203, 210 Hemostasis, 210, 214 Hepatic, 151, 210 Hereditary, 207, 208, 210, 232 Hereditary mutation, 207, 210 Heredity, 206, 207, 210 Heterodimers, 210, 214 Heterogeneity, 13, 18, 188, 210 Heterozygotes, 202, 210 Histamine, 85, 96, 190, 210 Histidine, 210 Histocompatibility, 210, 219 Homeobox, 63, 210 Homeostasis, 136, 210 Homoharringtonine, 120, 124, 125, 154, 163, 210 Homologous, 48, 112, 188, 206, 210, 221, 237 Homozygotes, 202, 210 Hormone, 188, 199, 204, 210, 232, 234, 238 Humoral, 26, 73, 208, 210, 238 Humour, 210 Hybrid, 140, 210, 211 Hybridization, 135, 210, 223 Hybridomas, 211, 214 Hydrogen, 187, 189, 192, 194, 200, 211, 220, 222, 223, 229 Hydrolysis, 196, 211, 225, 227, 228 Hydrophobic, 15, 211 Hydroxyurea, 66, 76, 81, 86, 122, 128, 211 Hyperlipoproteinemia, 211 Hyperplasia, 141, 211 Hypersensitivity, 201, 203, 211, 216, 232 Hypertension, 203, 211 Hyperthyroidism, 73, 211 Hypertriglyceridemia, 113, 211 Hypertrophy, 211 Hyperuricemia, 208, 211 I Idarubicin, 37, 99, 164, 211 Idiopathic, 141, 211 Idiopathic myelofibrosis, 141, 211 Idiotype, 151, 211 Ifosfamide, 59, 211 Immune response, 25, 108, 190, 191, 192, 199, 208, 209, 211, 212, 213, 236, 240, 241
248
Chronic Myelogenous Leukemia
Immune system, 53, 191, 192, 193, 203, 211, 212, 213, 216, 217, 240, 241 Immunity, 25, 53, 69, 212 Immunization, 188, 212, 213 Immunoblotting, 141, 212 Immunocompromised, 50, 212 Immunoconjugates, 147, 212 Immunodeficiency, 27, 212 Immunofluorescence, 11, 212 Immunogenetics, 32, 212 Immunogenic, 8, 53, 134, 140, 212 Immunoglobulins, 147, 212 Immunologic, 20, 29, 39, 188, 196, 212, 230 Immunology, 8, 25, 40, 41, 58, 59, 188, 206, 212 Immunophenotyping, 40, 212 Immunosuppressant, 188, 212, 219 Immunosuppression, 33, 212, 217 Immunosuppressive, 199, 207, 211, 212, 213 Immunosuppressive Agents, 212 Immunosuppressive therapy, 213 Immunotherapy, 14, 29, 53, 56, 57, 76, 81, 147, 150, 188, 193, 201, 213 Implant radiation, 213, 214, 215, 230, 242 In situ, 46, 51, 57, 63, 73, 79, 80, 96, 101, 104, 108, 121, 138, 144, 213 In Situ Hybridization, 57, 63, 73, 79, 80, 96, 101, 104, 108, 121, 138, 144, 213 Indolent, 11, 18, 148, 213 Indolent lymphoma, 18, 213 Induction, 6, 9, 15, 16, 19, 27, 52, 57, 66, 79, 88, 121, 151, 213 Induction therapy, 9, 213 Industrial Waste, 144, 213 Infancy, 37, 89, 149, 213 Infant, Newborn, 188, 213 Infantile, 90, 213 Infection, 32, 56, 73, 74, 89, 90, 190, 192, 193, 194, 196, 200, 208, 212, 213, 217, 232, 236, 241 Infiltration, 149, 213 Inflammation, 152, 191, 205, 208, 213, 216, 218, 226, 232, 237 Informed Consent, 38, 41, 43, 213 Infusion, 22, 25, 53, 57, 74, 214, 217 Ingestion, 190, 214, 219, 237 Initiation, 48, 68, 214, 239 Inorganic, 196, 214 Inositol, 7, 214 Insecticides, 214, 225 Insight, 26, 32, 214
Integrins, 28, 214 Interleukin-6, 83, 214 Internal Medicine, 7, 8, 22, 33, 53, 55, 113, 209, 214 Internal radiation, 214, 215, 230, 242 Interphase, 63, 73, 104, 138, 139, 144, 145, 214 Interstitial, 119, 194, 214, 215, 242 Intestines, 187, 201, 206, 214, 233 Intoxication, 215, 242 Intracellular, 10, 11, 15, 213, 214, 215, 234 Intrathecal, 215, 217 Intravascular, 102, 215 Intravenous, 9, 214, 215 Intrinsic, 188, 215 Invasive, 212, 215, 217 Ionization, 215 Ionizing, 138, 144, 189, 203, 215, 230 Ions, 192, 201, 211, 215 Irradiation, 3, 27, 33, 120, 215, 231, 242 K Kaposi, 91, 125, 215 Karyotype, 91, 92, 144, 215 Kb, 138, 144, 168, 215 Killer Cells, 215 Kinetic, 215 L Labile, 197, 215 Larva, 215, 219 Laser therapy, 3, 215 Latent, 15, 215 Leg Ulcer, 86, 215 Lesion, 208, 216 Lethal, 10, 15, 22, 31, 49, 145, 149, 216 Leucocyte, 203, 216, 217 Leukapheresis, 104, 216 Leukocyte Count, 147, 216 Leukocytosis, 140, 216, 226 Leukoencephalopathy, 101, 216 Leukotrienes, 83, 191, 216 Levo, 216, 218 Ligament, 216, 228 Ligands, 20, 214, 216, 236 Linkage, 216 Lipid, 11, 191, 206, 216, 239, 242 Liposomal, 68, 148, 216 Liver, 140, 187, 191, 192, 196, 199, 200, 201, 204, 208, 209, 210, 216, 226, 227, 241 Liver Neoplasms, 216, 241 Localization, 20, 34, 216 Localized, 93, 203, 208, 213, 216, 226 Locomotion, 216, 226
249
Loop, 55, 60, 216 Lupus, 216, 237 Lymph, 99, 203, 210, 217 Lymph node, 99, 217 Lymphadenopathy, 99, 217 Lymphatic, 213, 217, 219, 234, 235 Lymphatic system, 217, 234, 235 Lymphedema, 16, 217 Lymphoblastic, 12, 93, 122, 137, 142, 150, 217 Lymphoblasts, 41, 48, 187, 217 Lymphocyte Depletion, 212, 217 Lymphocytes, 25, 57, 77, 80, 86, 105, 140, 190, 192, 201, 211, 212, 216, 217, 221, 235, 241 Lymphocytic, 18, 142, 150, 196, 217 Lymphocytosis, 26, 217 Lymphoid, 42, 44, 56, 59, 60, 61, 93, 94, 95, 123, 127, 137, 142, 151, 190, 216, 217, 221 Lymphoproliferative, 39, 151, 197, 217 Lymphoproliferative Disorders, 151, 217 Lymphotoxin, 152, 217 M Macrophage, 31, 61, 83, 208, 217 Mafosfamide, 5, 217 Magnetic Resonance Imaging, 217, 218 Magnetic Resonance Spectroscopy, 20, 218 Maintenance therapy, 37, 218 Malignancy, 12, 35, 43, 52, 107, 134, 148, 218 Malignant tumor, 30, 218, 221, 223, 232 Mammary, 218, 237 Mastectomy, 16, 218 Mastication, 218 Masticatory, 146, 218 Maximum Tolerated Dose, 43, 202, 218 Mediate, 21, 54, 57, 61, 79, 152, 215, 218 MEDLINE, 169, 218 Medroxyprogesterone Acetate, 123, 218 Megakaryocytes, 142, 194, 218, 238 Melanin, 218, 225, 240 Melphalan, 37, 218 Memory, 80, 218 Meninges, 196, 218 Meningitis, 205, 218 Mental, iv, 4, 168, 170, 201, 218, 229, 232 Mental Processes, 201, 218, 229 Mentors, 32, 218 Mercury, 205, 218 Mesenchymal, 208, 219 Metabolic disorder, 208, 219
Metamorphosis, 147, 219, 223 Metaphase, 80, 138, 139, 144, 145, 219 Metaplasia, 97, 219 Metastasis, 85, 219 Metastatic, 118, 219, 233 Methanol, 146, 219 Methotrexate, 37, 41, 45, 81, 112, 122, 219 Methyltransferase, 15, 192, 219 Microbe, 219, 239 Microorganism, 197, 219, 241 Micro-organism, 209, 219 Microsatellite Repeats, 82, 201, 219 Migration, 28, 219 Minor Histocompatibility Antigens, 33, 219 Minor Histocompatibility Loci, 219 Mitochondrial Swelling, 220, 222 Mitosis, 191, 195, 220 Mitotic, 49, 145, 204, 220, 241 Mobility, 28, 220 Mobilization, 14, 122, 220 Modeling, 20, 202, 220 Monitor, 13, 220, 222 Monoclonal, 52, 134, 145, 147, 211, 212, 215, 220, 230, 242 Monoclonal antibodies, 52, 134, 147, 212, 220 Monocytes, 140, 206, 214, 220, 221 Mononuclear, 208, 220, 240 Morphology, 88, 144, 209, 220 Motility, 220 Mucosa, 3, 216, 220, 236 Mucositis, 3, 100, 220, 238 Multidrug resistance, 37, 124, 220 Multiple Myeloma, 25, 118, 221 Multivalent, 192, 221 Multivariate Analysis, 118, 221 Muscle Fibers, 221 Mutagen, 221 Mutagenic, 188, 221 Mycophenolate mofetil, 33, 221 Myelodysplasia, 147, 221 Myelodysplastic Syndromes, 150, 221 Myelofibrosis, 97, 129, 221, 226 Myeloid Cells, 59, 142, 145, 221 Myeloid Progenitor Cells, 31, 54, 60, 221 Myeloma, 23, 221 Myeloproliferative Disorders, 39, 66, 129, 138, 141, 221 Myelosuppression, 106, 221, 241 Myosin, 122, 221
250
Chronic Myelogenous Leukemia
N Natural killer cells, 24, 73, 221 Natural selection, 193, 221 NCI, 1, 9, 16, 167, 196, 221 Necrosis, 65, 82, 191, 217, 222 Neoplasia, 46, 49, 139, 144, 222 Neoplasm, 135, 147, 222, 232, 240 Nervous System, 196, 222, 236, 237 Neural, 151, 189, 210, 222 Neuroblastoma, 36, 39, 40, 42, 44, 48, 222 Neurology, 47, 59, 222 Neurons, 49, 201, 222, 237 Neurosurgery, 45, 47, 59, 222 Neurotoxicity, 222, 241 Neurotransmitter, 187, 208, 210, 222, 234, 236 Neutrons, 189, 215, 222, 230 Neutropenia, 35, 83, 222 Neutrophil, 71, 97, 222 Nitrogen, 188, 189, 199, 218, 222 Nuclear, 6, 15, 20, 51, 59, 88, 203, 204, 206, 222, 228 Nuclei, 104, 139, 189, 203, 206, 207, 218, 220, 222, 229 Nucleic acid, 28, 136, 138, 139, 143, 144, 148, 150, 200, 207, 211, 213, 222, 223, 229 Nucleic Acid Hybridization, 211, 223 Nucleic Acid Probes, 138, 139, 144, 223 Nurse Practitioners, 39, 95, 223 Nymph, 219, 223 O Ocular, 89, 223 Oncogene, 6, 8, 11, 16, 20, 28, 48, 50, 51, 56, 58, 61, 66, 69, 81, 108, 136, 139, 223, 235 Oncogenic, 8, 10, 11, 12, 15, 20, 27, 34, 54, 214, 223 Oncologist, 82, 223 Organ Culture, 223, 238 Organelles, 200, 220, 223 Osteogenic sarcoma, 223 Osteosarcoma, 41, 223 Outpatient, 25, 33, 223 Ovary, 223, 236 Overall survival, 4, 9, 32, 65, 223 Ovum, 207, 223 Oxidative metabolism, 216, 223 P P53 gene, 42, 80, 82, 223 Palliative, 224, 238 Pancreas, 93, 187, 201, 209, 224, 240 Pancytopenia, 23, 62, 224
Parathyroid, 77, 224, 237 Parathyroid Glands, 224 Parathyroid hormone, 77, 224 Partial remission, 71, 224, 231 Partial response, 224 Particle, 224, 239 Pathologic, 99, 191, 193, 211, 224, 229 Pathologic Processes, 191, 224 Pathophysiology, 17, 56, 141, 224 Pediatrics, 25, 29, 30, 36, 38, 39, 40, 42, 43, 44, 45, 46, 47, 58, 91, 122, 224 Pelvic, 224, 228 Peptide, 12, 29, 56, 139, 142, 224, 227, 228 Peptide T, 57, 224 Pericardial Effusion, 65, 224 Pericardium, 224, 237 Peripheral blood, 22, 25, 26, 29, 35, 37, 59, 60, 67, 73, 93, 101, 122, 140, 208, 209, 214, 224, 238 Peripheral stem cell transplantation, 224, 238 Peripheral stem cells, 208, 225 Pesticides, 144, 214, 225 Pharmacodynamics, 22, 46, 225 Pharmacokinetic, 9, 225 Pharmacologic, 5, 6, 9, 10, 39, 45, 225, 239 Phenotype, 11, 14, 18, 20, 21, 24, 48, 49, 54, 55, 58, 152, 206, 225 Phenyl, 153, 225 Phenylalanine, 225, 240 Philadelphia Chromosome, 63, 64, 113, 124, 225 Phospholipases, 225, 234 Phospholipids, 205, 214, 225 Phosphorus, 194, 224, 225 Phosphorylate, 26, 55, 225 Phosphorylated, 20, 60, 61, 136, 148, 225 Phosphorylating, 7, 225 Phosphorylation, 6, 7, 10, 12, 14, 16, 21, 22, 29, 55, 136, 141, 225, 228 Phosphotyrosine, 12, 20, 61, 225 Photocoagulation, 197, 225 Physiologic, 188, 193, 225, 230 Physiology, 10, 140, 209, 226 Pigment, 146, 226 Pilot Projects, 45, 226 Pilot study, 226 Placenta, 226, 240 Plant Growth Regulators, 209, 226 Plants, 139, 188, 194, 207, 220, 226, 235, 239
251
Plasma, 13, 42, 190, 193, 195, 205, 209, 210, 211, 216, 221, 226, 233 Plasma cells, 190, 221, 226 Platelet Activation, 226, 234 Platelets, 71, 141, 221, 224, 226, 238 Ploidy, 46, 94, 226 Pneumonia, 68, 119, 199, 226 Podophyllotoxin, 204, 226 Polyarthritis, 83, 226 Polycythemia Vera, 97, 129, 141, 226 Polyethylene, 106, 226 Polymerase, 57, 60, 82, 93, 101, 102, 135, 227 Polymerase Chain Reaction, 57, 60, 82, 93, 101, 102, 135, 227 Polypeptide, 189, 197, 199, 211, 227, 228, 242 Polysaccharide, 190, 227 Posterior, 189, 224, 227 Postnatal, 227, 235 Postsynaptic, 227, 234 Potentiation, 227, 234 Practicability, 227, 239 Practice Guidelines, 97, 170, 227 Preclinical, 22, 24, 54, 57, 227 Precursor, 48, 58, 96, 191, 199, 202, 203, 208, 225, 227, 240 Prednisolone, 126, 127, 128, 227 Prednisone, 123, 125, 126, 127, 227 Prenatal, 36, 139, 203, 207, 227 Prenatal Care, 36, 227 Probe, 51, 139, 227 Progeny, 6, 14, 137, 150, 227 Progression, 12, 13, 15, 18, 19, 21, 23, 50, 92, 141, 145, 149, 154, 190, 228 Progressive, 18, 22, 101, 149, 195, 196, 202, 204, 211, 222, 226, 228, 240 Progressive disease, 211, 228 Prokaryotic Cells, 143, 228 Promoter, 17, 112, 136, 150, 228 Promyelocytic leukemia, 9, 228 Prophylaxis, 228, 240 Prospective study, 96, 228 Prostate, 16, 142, 228, 240 Protease, 15, 197, 228 Protein Binding, 59, 228 Protein C, 48, 53, 148, 189, 191, 197, 205, 228 Protein Conformation, 189, 228 Protein S, 20, 105, 193, 199, 207, 228, 232, 238 Protein-Tyrosine Kinase, 50, 207, 228
Proteinuria, 207, 221, 228 Proteolytic, 48, 198, 228 Protocol, 18, 31, 36, 37, 38, 40, 42, 43, 45, 46, 122, 228 Protons, 189, 211, 215, 218, 229, 230 Protozoa, 219, 229, 235 Proximal, 202, 229 Pruritus, 119, 229 Psoriasis, 83, 103, 229 Psychiatric, 36, 229 Psychiatry, 229 Psychoactive, 229, 242 Psychology, 47, 201, 229 Public Policy, 169, 229 Publishing, 3, 59, 144, 229 Pulmonary, 74, 98, 146, 193, 216, 229 Pulse, 220, 229 Pupa, 219, 229 Purines, 229, 233 Putrefaction, 206, 229 Pyrimidines, 229, 233 Q Quality of Life, 229, 236 R Race, 215, 218, 219, 229, 230 Racemic, 218, 230 Radiation oncologist, 43, 223, 230 Radiation therapy, 42, 47, 185, 205, 214, 215, 230, 238, 242 Radioactive, 211, 213, 214, 215, 220, 222, 223, 230, 240, 242 Radioimmunotherapy, 212, 230 Radiolabeled, 194, 215, 230, 242 Radiology, 47, 106, 230 Radiotherapy, 42, 44, 118, 120, 147, 194, 215, 230, 235, 242 Randomized, 38, 46, 58, 203, 230 Randomized clinical trial, 46, 230 Reactive Oxygen Species, 96, 230 Recombinant, 53, 99, 135, 143, 152, 230, 241 Recombination, 206, 230 Rectum, 191, 197, 201, 206, 228, 231 Recurrence, 24, 135, 231 Red blood cells, 204, 211, 221, 231 Reductase, 219, 231 Refer, 1, 197, 216, 222, 230, 231, 239 Refraction, 231, 235 Refractory, 9, 19, 23, 37, 85, 117, 138, 147, 203, 231 Regeneration, 136, 231
252
Chronic Myelogenous Leukemia
Regimen, 3, 14, 22, 33, 35, 57, 65, 68, 120, 122, 197, 203, 231 Relapse, 30, 32, 35, 42, 43, 44, 50, 53, 59, 60, 74, 76, 82, 87, 91, 92, 93, 97, 135, 231 Remission, 25, 30, 50, 53, 56, 73, 78, 97, 113, 135, 154, 218, 231 Repopulation, 23, 231 Reproductive cells, 207, 210, 231 Research Personnel, 39, 231 Research Support, 17, 231 Residual disease, 13, 25, 29, 47, 72, 74, 101, 108, 135, 147, 231 Respiration, 220, 223, 231 Retina, 231, 232 Retinal, 201, 231 Retinoblastoma, 67, 231 Retinoid, 113, 232 Retinopathy, 102, 225, 232 Retroviral vector, 81, 118, 206, 232 Retrovirus, 8, 232 Reversion, 104, 232 Rhabdomyosarcoma, 45, 59, 232 Rheumatoid, 76, 232 Rheumatoid arthritis, 76, 232 Ribonuclease, 34, 48, 232 Ribonucleoside Diphosphate Reductase, 211, 232 Ribose, 187, 200, 232 Ribosome, 232, 239 Rigidity, 226, 232 Risk factor, 228, 232 Risk patient, 23, 232 Rod, 192, 232 Rodenticides, 225, 232 S Saliva, 232 Salivary, 146, 200, 201, 232 Salivary glands, 146, 200, 201, 232 Sarcoma, 37, 41, 59, 91, 125, 232, 234 Schizoid, 232, 241 Schizophrenia, 232, 233, 241 Schizotypal Personality Disorder, 232, 242 Sclerosis, 96, 192, 233 Screening, 36, 197, 207, 233 Secondary tumor, 219, 233 Secretion, 77, 87, 199, 210, 233 Sedimentation, 233, 239 Segmental, 89, 139, 144, 207, 233 Segmentation, 233 Selective estrogen receptor modulator, 233, 237 Semen, 228, 233
Semisynthetic, 204, 233 Septic, 65, 233 Sequence Homology, 224, 233 Sequencing, 227, 233 Serine, 6, 10, 233 Serum, 42, 53, 188, 189, 191, 197, 206, 217, 233, 240 Sex Characteristics, 187, 233 Shock, 48, 233, 239 Side effect, 147, 161, 163, 188, 193, 199, 202, 211, 221, 233, 236, 239, 241 Signal Transduction, 7, 10, 21, 22, 24, 53, 55, 131, 136, 214, 225, 234 Signs and Symptoms, 231, 234 Skeletal, 106, 221, 234 Skeleton, 187, 205, 234 Smooth muscle, 189, 206, 210, 234, 236 Sodium, 208, 234 Soft tissue, 59, 194, 234 Soft tissue sarcoma, 59, 234 Solid tumor, 12, 37, 38, 41, 46, 59, 234 Solvent, 219, 234 Somatic, 187, 203, 210, 220, 234, 237 Specialist, 4, 175, 234 Species, 52, 188, 192, 196, 197, 199, 204, 210, 215, 219, 220, 229, 230, 233, 234, 236, 239, 241, 242 Specificity, 12, 56, 188, 234 Spectrum, 24, 235 Sperm, 196, 207, 210, 231, 235, 239 Spinal cord, 196, 215, 218, 222, 235, 237 Spleen, 140, 183, 200, 217, 226, 235 Splenectomy, 121, 123, 235 Splenomegaly, 95, 140, 226, 235 Sporadic, 232, 235 Spores, 11, 235 Spotting, 31, 235 Squamous, 235, 241 Stabilization, 48, 235 Staging, 18, 235 Standard therapy, 154, 235 Statistically significant, 39, 235 Steel, 84, 235 Stem Cell Factor, 31, 196, 235 Stem Cells, 4, 5, 6, 23, 25, 35, 83, 90, 136, 151, 188, 204, 209, 221, 224, 225, 235, 240 Stereotactic, 37, 42, 235 Sterile, 224, 235 Sterility, 199, 235 Stimulant, 146, 210, 235 Stimulus, 202, 204, 236, 238
253
Stomach, 187, 201, 204, 206, 210, 214, 235, 236 Stool, 197, 236 Strand, 134, 227, 236 Stress, 38, 48, 184, 232, 236 Stroma, 14, 28, 61, 80, 236 Stromal, 14, 194, 236 Stromal Cells, 14, 194, 236 Stump, 106, 236 Subacute, 147, 213, 236 Subclinical, 213, 236 Subcutaneous, 25, 202, 236 Subspecies, 234, 236 Substance P, 233, 236 Substrate, 12, 20, 236 Support group, 185, 236 Supportive care, 45, 236 Suppression, 21, 29, 50, 199, 236 Surface Plasmon Resonance, 20, 236 Survival Rate, 223, 237 Sympathetic Nervous System, 222, 237 Symphysis, 228, 237 Symptomatic, 65, 237 Synaptic, 222, 234, 237 Synergistic, 7, 79, 105, 237 Systemic, 33, 68, 83, 99, 118, 162, 193, 194, 204, 213, 215, 227, 230, 237, 242 Systemic lupus erythematosus, 118, 237 T Tamoxifen, 16, 233, 237 Telomerase, 6, 50, 237 Telomere, 6, 237 Teratogenic, 144, 188, 237 Terminator, 197, 237 Testicular, 53, 237 Testis, 237 Tetany, 224, 237 Tetracycline, 55, 237 Therapeutics, 39, 46, 66, 118, 134, 162, 238 Thermal, 201, 222, 227, 238 Thigh, 205, 238 Threonine, 10, 224, 233, 238 Threshold, 30, 211, 238 Thrombin, 228, 238 Thrombocytes, 226, 238 Thrombocytopenia, 70, 89, 106, 238 Thrombocytosis, 129, 141, 238 Thrombomodulin, 228, 238 Thrombopoietin, 71, 78, 141, 238 Thrombosis, 214, 228, 238 Thymidine, 57, 238 Thymidine Kinase, 57, 238
Thyroid, 211, 224, 238, 240 Thyroid Gland, 211, 224, 238 Tissue Culture, 10, 238 Tolerance, 8, 25, 187, 238 Total-body irradiation, 120, 238 Toxic, iv, 13, 33, 57, 147, 188, 200, 201, 203, 212, 218, 219, 226, 239 Toxicity, 11, 13, 23, 33, 35, 37, 38, 43, 54, 56, 68, 147, 202, 211, 218, 219, 239, 241 Toxicology, 15, 170, 239 Toxin, 10, 203, 238, 239 Transcriptase, 30, 101, 232, 237, 239 Transcription Factors, 34, 58, 239 Transduction, 6, 10, 21, 24, 55, 56, 58, 234, 239 Transfection, 193, 206, 239 Translation, 48, 51, 53, 66, 239 Translational, 19, 29, 36, 57, 89, 239 Trauma, 222, 239 Treatment Outcome, 30, 239 Triglyceride, 211, 239 Trinucleotide Repeats, 219, 239 Troxacitabine, 100, 239 Tubulin, 42, 239 Tumor marker, 18, 239 Tumor Necrosis Factor, 152, 217, 240 Tumor suppressor gene, 30, 223, 240 Tumorigenic, 148, 240 Tumour, 240, 242 Tunica, 220, 240 U Ubiquitin, 11, 48, 58, 240 Umbilical Arteries, 240 Umbilical Cord, 14, 25, 240 Umbilical cord blood, 14, 25, 240 Urethra, 228, 240 Uric, 208, 211, 229, 240 Urinary, 194, 207, 240 Urinate, 240, 241 Urogenital, 207, 240 V Vaccination, 54, 72, 108, 240 Vaccine, 11, 228, 240 Vagina, 194, 235, 240 Varicose, 215, 240 Varicose Ulcer, 215, 240 Vascular, 87, 213, 226, 238, 240, 241 Vascular endothelial growth factor, 87, 241 Vasodilator, 210, 241 Vector, 239, 241 Vein, 215, 222, 240, 241
254
Chronic Myelogenous Leukemia
Venous, 193, 215, 216, 228, 240, 241 Venous blood, 193, 216, 241 Veterinary Medicine, 169, 241 Vinblastine, 16, 239, 241 Vinca Alkaloids, 16, 241 Vincristine, 16, 37, 123, 125, 126, 127, 239, 241 Vindesine, 123, 126, 127, 128, 241 Vinyl Chloride, 144, 241 Viral, 32, 50, 223, 232, 239, 240, 241 Virulence, 239, 241 Virus, 52, 57, 73, 203, 207, 208, 214, 232, 239, 241 Visceral, 18, 241 Vitamin A, 115, 214, 232, 241 Vitro, 5, 7, 9, 12, 14, 19, 22, 29, 31, 34, 37, 39, 50, 54, 55, 56, 57, 76, 88, 90, 102, 105, 112, 121, 124, 145, 152, 206, 213, 227, 238, 241
Vivo, 5, 6, 8, 9, 11, 12, 14, 16, 19, 21, 22, 25, 29, 31, 34, 39, 48, 49, 50, 54, 55, 56, 81, 102, 113, 119, 151, 206, 213, 217, 241 Void, 15, 241 W War, 33, 241 White blood cell, 28, 83, 140, 184, 187, 190, 192, 193, 196, 205, 208, 216, 217, 221, 222, 226, 241 Withdrawal, 104, 241 Wound Healing, 214, 242 X Xanthoma, 90, 242 Xenograft, 190, 242 X-ray, 206, 215, 221, 222, 230, 235, 242 X-ray therapy, 215, 242 Y Yeasts, 225, 242 Z Zebrafish, 11, 242 Zymogen, 228, 242
255
256
Chronic Myelogenous Leukemia
