Alternative Mechanisms of Multidrug Resistance in Cancer PDF
Preview Alternative Mechanisms of Multidrug Resistance in Cancer
Alternative Mechanisms of Multidrug Resistance in Cancer Cover: A schematic, simplified presentation of various cellular drug resistance mechanisms. By John A. Kellen and Patsy Cunningham. Alternative Mechanisms of Multidrug Resistance in Cancer JohnA. Kellen Editor Birkhauser Boston • Basel • Berlin John A. Kellen Sunnybrook Health Science Center University of Toronto Toronto, Canada M4N 3M5 Library of Congress Cataloging-in-Publication Data Mechanisms and reversal of multi drug resistance in cancer : the other alternatives / John A. Kellen, editor. p. cm. Includes bibliographical references and index. ISBN 0-8176-3775-3 (h : alk. paper). -- ISBN 3-7643-3775-3 (h : alk. paper). . 1. Drug resistance in cancer cells. 2. Multidrug resistance. I. Kellen, John A. [DNLM: 1. Neoplasms--drug therapy. 2. Drug Resistance, Multiple- -physiology. 3. Antineoplastic Agents, Combined--pharmacology. QZ RC271.C5M42 1995 95-1582 616.99'4061--dc20 CIP DNLMJDLC for Library of Congress Birkhiiuser $ ® © 1995 Birkhauser Boston Softcover reprint of the hardcover 1s t edition 1995 Copyright is not claimed for works of U.S. Government employees. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without prior permission of the copyright owner. Permission to photocopy for internal or personal use of specific clients is granted by Birkhauser Boston for libraries and other users registered with the Copyright Clearance Center (CCC), provided that the base fee of$6.00 per copy, plus $0.20 per page is paid directly to CCC, 222 Rosewood Drive, Danvers, MA 01923, U.S.A. Special requests should be addressed directly to Birkhauser Boston, 675 Massachusetts Avenue, Cambridge, MA 02139, U.S.A. Camera-ready text prepared by the editor. ISBN-13: 978-1-4615-9854-1 e-TSBN-13: 978-1-4615-9852-7 DOl: 10.1 007/978-1-4615-9852-7 CONTENTS Preface .................................! •••••••••••••••••••••••••••••• vii List of Contributors .................................................... xi 1. Mechanisms of Multidrug Resistance J.A. Kellen ...................................................... 1 2. The Role of Glutathione S-'Transferases in Drug Resistance W. T. Bellamy ................................................... 31 3. Pharmacology of Drug 'Transport in Multidrug Resistant Tumor Cells H.J. Broxterman and C.H. Versantvoort ......................... 67 4. The Multidrug Resistance-Associated Protein MRP D. Fan, D.R. Bielenberg, Y.F. Wang, R. Radinsky, and P.J. Beltran ................................................ 81 5. Topoisomerases in Multidrug Resistance T. Utsugi, C.E. Herzog, and D. Fan ............................. 95 6. Genotoxicity of Topoisomerase II Inhibitors-Consequences of Chemotherapy F. Gieseler ..................................................... 121 7. A Distinctive Multiple Drug Resistance Phenotype in Tumor Cells Exposed to X-Irradiation B. T. Hill ....................................................... 135 8. Taxoids and Multidrug Resistance R.A. Newman and D. Fan ...................................... 153 9. The Contribution of Protein Kinase C to Multiple Drug Resistance in Cancer C.A. 0 'Brian, N.E. Ward, K.P. Gupta, and K.R. Gravitt ....... 173 10. Bcl-2 and Chemoresistance in Cancer J.C. Reed ..................................................... 191 vi Contents 11. Molecular Interrelationships in Multidrug Resistance J.A. Kellen .. ................................................. 215 12. Platinum Resistance in Human Carcinomas H. Ishida, H. Kijima, Y. Ohta, M. Kashani-Sabet, and K. J. Scanlon ......... .................................... 225 Perspectives J.A. Kellen .......................................................... 265 Conclusions J.A. Kellen .......................................................... 275 Index ................................................................ 279 PREFACE Nullius in verba. .. Truth will be tested not by words. Horace (Epistles) Few read introductions except for book reviewers, who want to take a shortcut and avoid reading the book itself. However, tradition requires that the preface make public why the book was written at all (this is not supposed to include powerful reasons such as augmenting the ego of the editor and authors). Frequently, the inflationary tendency to publish in verbose length is in conflict with market forces and interest. No doubt, multidrug resistance is a "fashionable" topic, but there are many fashions displayed on the cat-walk of scientific literature. One can rationalize that the forces driving our concern with multi drug resistance reflect the frustration of pharmaceutical companies and oncologists alike: as soon as a new anticancer drug enters clinical trials, cancer cells start eluding extinction with their elaborate and successful mechanisms. Many grants have been awarded and spent, only to confirm the futility of our efforts to defeat this cellular Darwinism. Our medical and scientific training makes it hard, if not impossible, to accept that the survival of a malignant cell, alone or as part of a tissue, is part of the continuance of life. Since exposure to noxious and lethal substances is unavoidable, cells have been forced to develop a multitude of mechanisms to prevent entry or accelerate exit of such materials from intracellular space. The final result from these complex actions is a decrease of intracellular concentrations to tolerable levels, allowing survival of the cell. Cancer cells are no exception; of course, this becomes most undesirable when the cell is malignant and its good housekeeping wards off the effect of cytotoxic drugs. It is an accepted truism that once we understand the cause of an event, we may prevent, circumvent, or reverse it. Medicine is based on this gen- eral tenet. The phenomenon of cross-resistance, whether innate or selected by exposure to one or more drugs, is the result of numerous mechanisms operating in concert; they depend on the level and length of exposure, ge- netic make-up of the cancer cell, size of the cell population, characteristics of the inducing agent, level of oxygenation, intra- and extracellular pH and probably on many more unknown factors. We are only at the beginning of our insight into this complexity; for every complex question, there is almost certainly a simple answer that is almost always wrong. There are no simple answers for MDR. All biological systems are both capable to de- fend themselves by the production of toxic substances and possess age-old mechanisms for defending themselves against these. MDR is a problem created by a mixture of variables that affect the outcome of chemotherapy viii Preface in different and often unpredictable ways. For the clinical oncologist, resis- tance is synonymous with the fate of the individual patient: what happens to the tumor mass and how it responds to treatment. Increasing insight into the vulnerability of malignant cells has led to the design of perfectly tailored cytotoxic substances, expected to cause reasonably selective extinction of the cancer cell population. Yet, even the best of such fits allows a critical number of cells to escape and regrow in eventually fatal numbers, as the result of cumulative, cooperative cel- lular defenses. Perhaps the first stepping stone in our understanding of such defense mechanisms has been the recognition of P-glycoprotein as a general efflux pump. This may be o~e of the primordial instruments for turfing out unwanted guests, but it does not fulfill our expectations for a single "deus ex machina" which provides all the answers and solves all the problems. P-glycoprotein is considered by some as a "first line of defense," appearing very early in the hierarchy of defense mechanisms, as a normal response to foreign agents and hence inevitable in many, but not all tu- mors. Introduction of the apparently synonymous terminology: MDR for multidrug resistance and mdrl for the gene expressing P-glycoprotein, is causing some confusion; MDR in cancer can be caused by a multitude of mechanisms and is a vague term describing the ability of tumor cells to repair sublethal damage caused by structurally unrelated cytotoxic drugs. Acquired multidrug resistance is being extensively studied in rodent and human cell lines, with single or multistep selection, by one or more drugs or other inducers. In vitro conditions are ideal for "clean" experiments with a minimum of variables. Clinical studies are more difficult, if not impossible, to compare and evaluate since they differ in treatment proto- cols, demography as well as methodology and criteria for positivity of the MDR phenotype. MDR predominantly caused by P-glycoprotein has been coined as "classical," again a term which should be disputed. Binding to P-glyco- protein (as evidenced by photolabelling) is not always synonymous with transport across biomembranes, but reduced drug accumulation in non- Pgp-MDR cells is less well understood. Preoccupation with a single so- lution has led to the neglect of other explanations. Even more simplistic is the trend to use the term "atypical MDR" for resistance mechanisms involving Topoisomerase II only. Finally, there is a growing grab-bag filled with "non P-glycoprotein mediated" MDR which ranges from other mem- brane proteins belonging to the ATP-binding cassette (ABC) superfamily to a variety of detoxifying mechanisms, enzymatic and other. The cooperative effort represented by this book expressed our feel- ings that we have reached a critical mass of information: within the un- comfortable framework of inherent instability characteristic for the cancer cell, we must accept the continuously adapting and changing complexity of resistance. Some important and some perhaps less important factors have been examined and evaluated. At present, we can not predict which single Preface ix mechanism will playa leading role - if there is a universal leading role at all; only the passage of time will provide new perspectives. I had the good fortune to persuade many eminent scientists in the MDR scene to come forward with state of the art reviews in an apparently heterogeneous field. This heterogeneity should not come as a surprise, but as a warning. If clinical researchers wish to more effectively plan treatment with drugs and drug combinations able to circumvent defense mechanisms, they must learn to understand the molecular basis of drug resistance. The gap in our interpretation and application of data are evident and may direct the curious to further analytic and synthetic travail; comprehending the whole as more than the sum of its parts. To quote Galileo: We must look at what others have looked before and see it as no one has seen it before ... John A. Kellen August 1994 LIST OF CONTRIBUTORS William T. Bellamy, Ph.D., Arizona Health Science Center, Tucson, Arizona, USA Pedro J. Beltran, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA Diane R. Bielenberg, B.S., University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA Henk J. Broxterman, Ph.D. Academ. Ziekenhuis, VU Amsterdam, Amsterdam, The Netherlands Dominic Fan, Ph.D., University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA Frank Gieseler, M.D., Mediz. Poliklinik de Universitiit Wiirzburg, Wiirz- burg, Germany Karen R. Gravitt, M.Sc., University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA Krishna P. Gupta, Ph.D., University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA Cynthia E. Herzog, M.D., University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA Bridget T. Hill, Ph.D., Ctr. de Recherche Pierre Fabre, Castres, France Hironori Ishida, M.D., City of Hope Natl. Med. Ctr., Duarte, California, USA Mohamed Kashani-Sabet, M.D., City of Hope Natl. Med. Ctr., Duarte, California, USA John A. Kellen, M.D., Ph.D., Sunybrook Health Science Centre, Univer- sity of Toronto, Toronto, Canada Hiroshi Kijima, M.D., City of Hope Natl. Med. Ctr., Duarte, California, USA Robert A. Newman, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA Catherine A. O'Brian, Ph.D., University of Texas M.D. Anderson Can- cer Center, Houston, Texas, USA Yukinori Ohta, Ph.D., City of Hope Natl. Med. Ctr., Duarte, California, USA
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