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APOPTOSIS AND CANCER CHEMOTHERAPY CANCER DRUG DISCOVERY AND DEVELOPMENT Beverly A. Teicher, Series Editor 6. Signaling Networks and Cell Cycle Control: The Molecular Basis ofCancer and Other Diseases, edited by J. Silvio Gutkind, 1999 5. Apoptosis and Cancer Chemotherapy, edited by John A. Hickman and Caroline Dive, 1999 4. Antifolate Drugs in Cancer Therapy, edited by Ann L. Jackman, 1999 3. Antiangiogenic Agents in Cancer Therapy, edited by Beverly A. Teicher, 1999 2. Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval, edited by Beverly A. Teicher, 1997 1. Cancer Therapeutics: Experimental and Clinical Agents, edited by Beverly A. Teicher, 1997 APOPTOSIS AND CANCER CHEMOTHERAPY Edited by JOHN A. HICKMAN and CAROLINE DIVE University ofManchester, UK ~ SPRINGER SCIENCE+BUSINESS ~ MEDIA,LLC © 1999 Springer Science+Business Media New York Originally published by Humana Press Inc. in 1999 Softcover reprint of the hardcover 1st edition 1999 For additional copies, pricing for bulk purchases, and/or information about other Humana titles, contact Humana at the above address or at any of the following numbers: Tel.: 973-256- 1699; Fax: 973-256-8341; E-mail: [email protected] or visit our Website: http://humanapress.com All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise without written permission from the Publisher. All articles, comments, opinions, conclusions, or recommendations are those ofthe author(s), and do not necessarily reflect the views of the publisher. Cover illustration: From Fig. 1 in Chapter 14, "Discovery ofTNP-470 and Other Angiogenesis Inhibitors," by Donald E. Ingber, in Cancer Therapeutics: Experimental and Clinical Agents, Edited by Beverly A. Teicher, Springer Science+Business Media, LLC, 1997. Cover design by Patricia F. Cleary. This publication is printed on acid-free paper.@) ANSI Z39.48-1984 (American National Standards Institute) Permanence of Paper for Printed Library Materials. Photocopy Authorization Policy: Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Springer Science+Business Media, LLC, provided that the base fee of US$IO.OOpercopy. plus US $00.25 per page, is paid directly to the Copyright Clearance Center at 222 Rosewood Drive, Danvers, MA 01923. For those organizations that have been granted a photocopy license from the CCC, a separate system ofpayment has been arranged and is acceptable to Springer Science+Business Media, LLC, The fee code for users of the Transactional Reporting Service is: [0-89603-743-6/99 $10.00 + $00.25]. 10 9 8 7 6 5 4 3 2 I Library of Congress Cataloging-in-Publication Data Apoptosis and cancer chemotherapy/edited by John A. Hickman and Caroline Dive. p. cm.--{Cancer drug discovery and development; 5) Includes bibliographical references and index. ISBN 978-1-61737-165-3 ISBN 978-1-59259-720-8 (eBook) DOI 10.1007/978-1-59259-720-8 I. Cancer-Chemotherapy. 2. Apoptosis. 3. Carcinogenesis. I. Hickman, John A. II. Dive, Caroline. Ill. Series. [DNLM: I. Neoplasms---drug therapy. 2. Neoplasms-physiopathology. 3. Apoptosis---drug effects. 4. Apoptosis-physiology. 5. Drug resistance, neoplasm. QZ 267 A6435 1999] RC27l.C5A69 1999 616.99'4061~c21 DNLMIDLC for Library of Congress 99-12556 CIP FOREWORD The past few years have witnessed an astonishing international effort that established the role of some 20 new molecules in apoptosis and added activation or suppression of apoptosis to the accepted biological functions of a great many others already familiar in cancer biology. Some of these molecules are receptors, transducing cytokine-mediated signals; others appear to intensify or diminish the risk that a compro­ mised cell will fire its apoptosis effector mechanism. All are of interest as potential targets for tumor therapy, and some may prove to be control points influenced in the pathogenesis of cancer and other diseases as diverse as viral infection, neurodegenerative disorders, and stroke. Sometimes, in the midst of these developments, a kind of euphoria ap­ pears to have gripped the research community, with the expectation that apoptosis will afford explanations to many unsolved questions in cellu­ lar regulation. This book, in a series of thoughtful and provocative ar­ ticles--some from established leaders in the field, and others from younger scientists--seeks to redress the balance. One central issue is the role of apoptosis in defining the response of authentic tumor populations to chemotherapeutic agents. It is easy to construct experiments in which large differences appear in the initiation of apoptosis in populations of tumor cells exposed in vitro to a variety of potential therapies. But it is not always justifiable to interpret these results as indicating tumor resistance or sensitivity in the therapeutic sense. Clonogenic assays, applied to the same populations, sometimes produce different answers, presumably because they address a different end point (1,2). Rather than enumerating the cells that die (a process sensitive in the experimental context to the kinetics of death) they iden­ tify those cells with the capacity to survive and replicate, even in the austere conditions of low-density culture. The clonogenic cells often represent a tiny fraction ofthe original population, not readily measured by the techniques used to enumerate cell kill, but potentially highly significant. Nonetheless, when such clonogenic cells are studied in de­ tail, a high proportion bears mutations that are the fingerprints of re­ paired DNA damage (3,4). These fingerprints clearly indicate the transient presence ofDNA damage ofa type known to activate apoptosis. The question therefore remains how such long-term surviving cells sus­ tained such damage without becoming committed to death. v vi Foreword This question is only part of another, more general one. Although the molecular interactions of the terminal effector pathway of apoptosis have now been described in great detail, we know surprisingly little of the mechanisms coupling DNA damage to the activation of the pathway in the first place. New reagents are becoming available that indicate that critical damage-signaling molecules, such as p53, may become phos­ phorylated, perhaps at sites that are specific to their particular types of DNA injury. But it is also clear that the cellular context in which these changes take place greatly influences the outcome of such signaling. Thus, in hepatocytes damaged by ultraviolet light the unequivocal, im­ mediate p53 activation is coupled to cell-cycle arrest (5,6), whereas in some other cell types the same immediate injury and p53 activation lead to apoptosis. Moreover, powerful p53-independent death mechanisms are present in some cell types but not others. And, in the tissue context, these signaling and activation pathways might be profoundly influenced by local paracrine factors (7), which in tumors may emanate from adja­ cent normal or neoplastic cells, including the vascular stroma and infil­ trating lymphocytes. New questions are also suggested from the profusion of new signaling, modulating, and effector molecules now implicated in apoptosis. How re­ dundant are the dozen odd members of the caspase family? Are caspases activated in different cellular locations, and if so does this have a biological meaning? There are many beautiful studies implicating the mitochondria as a source ofcaspase activation, but it is already probable that other intracel­ lular sources may in appropriate circumstances be just as significant, includ­ ing the cell membrane (unequivocally a source of ceramide following irradiation) or the nucleus. Should we be searching for activation mecha­ nisms centered on the cytoskeleton and the endoplasmic reticulum also? Some provocative but now quite long-established data indicate that apoptosis-suppressormolecules, such as bcl-2, can have radically different effects when targeted to different intracellular membranes (8). Finally, cell biology has a trick of producing entirely new options, at times when these are least expected. The caspase cascade appears to afford a highly satisfactory explanation for the long-described cluster ofstructural events, involving coordinate changes in cell surface, nucleus, cytosol, and cytoskeleton, that led long ago to the identification ofapoptosis on morpho­ logical grounds. But it is not clear that caspase activation is the only means whereby these changes may be affected, nor even that other styles and modes of "programmed" cell death may not exist. It is with questions such as these that this book is concerned. Andrew H. Wyllie Foreword vii REFERENCES 1. Brunet CL, Gunby RH, Benson RSP, Hickman JA, Watson AJM, Brady G. Commitment to cell death measured by loss of clonogenicity is sepa­ rable from the appearance of apoptotic markers. Cell Death Different. 1998; 5: 107-113. 2. Longthome VL, Williams GT. Caspase activity is required for commit­ ment to fas-mediated apoptosis. EMBO J. 1997; 16: 3805-3812. 3. Griffiths SD, Clarke AR, Healy LE, Ross G, Ford AM, Hooper ML, Wyllie AH, Greaves M. Absence of p53 promotes propagation of mutant cells following genotoxic damage. Oncogene 1997; 14: 523-531. 4. Corbet SW, Clarke AR, Gledhill S, Wyllie AH. p53-dependent and inde­ pendent links between DNA damage, apoptosis and mutation frequency in ES cells. Oncogene 1998;

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