COX-2
Progress in Experimental Tumor Research Vol. 37 Series Editor Joseph R. Bertino, New Brunswick, N.J. Basel Freiburg Paris London New York Bangalore Bangkok Singapore Tokyo Sydney
COX-2 A New Target for Cancer Prevention and Treatment Volume Editors Andrew J. Dannenberg, New York, N.Y. Raymond N. DuBois, Nashville, Tenn. 32 figures, 6 in color and 20 tables, 2003 Basel Freiburg Paris London New York Bangalore Bangkok Singapore Tokyo Sydney
Progress in Experimental Tumor Research Founded 1960 by F. Homburger, Cambridge, Mass. Andrew J. Dannenberg Raymond N. DuBois Department of Medicine Department of Medicine Weill Medical College of Cornell Vanderbilt University Medical Center University 1161 21st Ave. South 525 East 68th Street Nashville, TN 37232-2279 (USA) New York, NY 10021 (USA) Library of Congress Cataloging-in-Publication Data Cox-2 : a new target for cancer prevention and treatment / volume editor, Joseph R. Bertino. p. ; cm. (Progress in experimental tumor research ; vol. 37) Includes bibliographical references and indexes. ISBN 3 8055 7536 X (hard cover : alk. paper) 1. Cyclooxygenase 2 Inhibitors Therapeutic use. 2. Cancer Chemotherapy. I. Bertino, Joseph R. II. Series. [DNLM: 1. Neoplasms drug therapy. 2. Cyclooxygenase Inhibitors therapeutic use. QZ 267 C877 2003] RC271.C78C69 2003 616.99 4052 dc21 2003044688 Bibliographic Indices. This publication is listed in bibliographic services, including Current Contents and Index Medicus. Drug Dosage. The authors and the publisher have exerted every effort to ensure that durg selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Copyright 2003 by S. Karger AG, P.O. Box, CH 4009 Basel (Switzerland) www.karger.com Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel ISBN 3 8055 7536 X
Contents VII Preface 1 Epidemiology of Non-Steroidal Anti-Inflammatory Drugs and Cancer Baron, J.A. (Lebanon, N.H.) 25 Pharmacology of COX-2 Inhibitors Isakson, P.C. (Peapack, N.J.) 52 Regulation of COX-2 Expression in Human Cancers Dixon, D.A. (Nashville, Tenn.) 72 Cyclooxygenase-2 and Skin Carcinogenesis Fürstenberger, G.; Marks, F.; Müller-Decker, K. (Heidelberg) 90 The Role of COX-2 in Breast and Cervical Cancer Dannenberg, A.J.; Howe, L.R. (New York, N.Y.) 107 Cyclooxygenase-2: A Target for the Prevention and Treatment of Cancers of the Upper Digestive Tract Altorki, N.K.; Subbaramaiah, K.; Dannenberg, A.J. (New York, N.Y.) 124 Cyclooxygenase-2 and Colorectal Cancer DuBois, R.N. (Nashville, Tenn.) 138 Cyclooxygenase-2 in Lung Cancer Dubinett, S.M.; Sharma, S.; Huang, M.; Dohadwala, M.; Pold, M.; Mao, J.T. (Los Angeles, Calif.) 163 COX-2 Inhibitors and Other NSAIDs in Bladder and Prostate Cancer Sabichi, A.L.; Lippman, S.M. (Houston, Tex.)
179 Therapeutic Potential of Selective Cyclooxygenase-2 Inhibitors in the Management of Tumor Angiogenesis Gately, S. (Lake Forest, Ill.); Kerbel, R. (Toronto) 193 Potential for Combined Modality Therapy of Cyclooxygenase Inhibitors and Radiation Saha, D.; Choy, H. (Nashville, Tenn.) 210 Non-Steroidal Anti-Inflammatory and Cyclooxygenase-2-Selective Inhibitors in Clinical Cancer Prevention Trials Hawk, E.T.; Viner, J.L.; Umar, A. (Bethesda, Md.) 243 Chemotherapy with Cyclooxygenase-2 Inhibitors in the Treatment of Malignant Disease: Pre-Clinical Rationale and Preliminary Results of Clinical Trials Blanke, C.D. (Portland, Oreg.); Masferrer, J.L. (Chesterfield, Mo.) 261 Role of COX-Independent Targets of NSAIDs and Related Compounds in Cancer Prevention and Treatment Soh, J.-W.; Weinstein, I.B. (New York, N.Y.) 284 Author Index 285 Subject Index Contents VI
Preface Over the last decade, cancer biologists have shifted their emphasis from developing global inhibitors of cell growth (cytotoxic agents) to specifically targeting molecular pathways known to be involved in cell transformation. One of the best examples of the potential success for this kind of strategy is the development of the drug, Gleevec, which inhibits the Bcr-Abl tyrosine kinase enzyme which is known to be involved in the pathogenesis of Philadelphia chromosome-positive (Ph ) chronic myeloid leukemia. Hence, a number of investigators have focused their efforts on evaluating the usefulness of targeting specific molecules in key signaling pathways in the hope that this would inhibit tumor growth. The cyclooxygenase-2 (COX-2) enzyme has been utilized as a target for the treatment of patients with chronic inflammatory diseases, such as rheumatoid arthritis. In these diseases, there is a long history of the use of nonsteroidal anti-inflammatory agents (NSAIDs) which typically inhibit both COX-1 and -2. Work over the past 5 years has shown that a significant portion of the gastrointestinal toxicity from NSAIDs use arises from inhibition of COX-1. With the development of new agents (celecoxib, rofecoxib and valdecoxib) which selectively inhibit the COX-2 enzyme, an improved GI safety profile was obtained with equivalent efficacy. Numerous investigators have found increased levels of COX-2 in both pre-malignant and malignant tissues. Recently, two different groups have shown directly that expressing the COX-2 gene in breast or skin tissue leads to a dramatic increase in risk for breast or skin carcinoma. Furthermore, animals engineered to be COX-2 deficient are protected against developing both intestinal and skin tumors. VII
This book represents an up-to-date review of the entire field of COX-2 cancer biology. We have been able to solicit the world s experts in this area of research and bring all of their expertise together in this volume. Indeed, this is a very fast-paced field and it has been difficult to keep up with the most current developments. We have included a review of the key issues in cancer biology where a link to the COX-2 pathway has been described. We have also provided two chapters reviewing the clinical trials underway and those planned in the near future testing the efficacy of selective COX-2 inhibitors for prevention and/or treatment of cancer. The selective COX-2 inhibitors have shown promise when given in combination with other agents and as a radiation-sensitizer for cancer treatment, however, their ultimate use will not be clear until the clinical trials underway have been completed and carefully analyzed. Andrew J. Dannenberg Raymond N. DuBois Preface VIII