Anticancer drug development guide : preclinical screening, clinical trials, and approval PDF
Preview Anticancer drug development guide : preclinical screening, clinical trials, and approval
CANCER DRUG DISCOVERY AND DEVELOPMENT Anticancer Drug Development Guide Preclinical Screening, Clinical Trials, and Approval SECOND EDITION Edited by Beverly A. Teicher Paul A. Andrews ANTICANCER DRUG DEVELOPMENT GUIDE Teicher228-2_FM_Final 1 12/03/2003, 4:26 PM CANCER DRUG DISCOVERY AND DEVELOPMENT Beverly A. Teicher, Series Editor Proteasome Inhibitors in Cancer Therapy, edited by Julian Adams, 2004 Nucleic Acid Therapeutics in Cancer, edited by Alan M. Gewirtz, 2004 Cancer Chemoprevention, Volume 1: Promising Cancer Chemopreventive Agents, edited by Gary J. Kelloff, Ernest T. Hawk, and Caroline C. Sigman, 2004 DNA Repair in Cancer Therapy, edited by Lawrence C. Panasci and Moulay A. Alaoui- Jamali, 2004 Hematopoietic Growth Factors in Oncology: Basic Science and Clinical Therapeutics, edited by George Morstyn, MaryAnn Foote, and Graham J. Lieschke, 2004 Handbook of Anticancer Pharmacokinetics and Pharmacodynamics, edited by William D. Figg and Howard L. 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Furr, 2002 Tumor Models in Cancer Research, edited by Beverly A. Teicher, 2002 Tumor Suppressor Genes in Human Cancer, edited by David E. Fisher, 2001 Matrix Metalloproteinase Inhibitors in Cancer Therapy, edited by Neil J. Clendeninn and Krzysztof Appelt, 2001 Farnesyltransferase Inhibitors in Cancer, edited by Saïd M. Sebti and Andrew D. Hamilton, 2001 Platinum-Based Drugs in Cancer Therapy, edited by Lloyd R. Kelland and Nicholas P. Farrell, 2000 Apoptosis and Cancer Chemotherapy, edited by John A. Hickman and Caroline Dive, 1999 Signaling Networks and Cell Cycle Control: The Molecular Basis of Cancer and Other Diseases, edited by J. Silvio Gutkind, 1999 Antifolate Drugs in Cancer Therapy, edited by Ann L. Jackman, 1999 Antiangiogenic Agents in Cancer Therapy, edited by Beverly A. Teicher, 1999 Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval, edited by Beverly A. Teicher, 1997 Cancer Therapeutics: Experimental and Clinical Agents, edited by Beverly A. Teicher, 1997 Teicher228-2_FM_Final 2 12/03/2003, 4:26 PM ANTICANCER DRUG DEVELOPMENT GUIDE PRECLINICAL SCREENING, CLINICAL TRIALS, AND APPROVAL SECOND EDITION Edited by BEVERLY A. TEICHER, PhD Vice President and Director of Oncology Portfolio Genzyme Corporation Framingham, MA PAUL A. ANDREWS, PhD Senior Director, Preclinical Sciences Aton Pharma Inc. Tarrytown, NY HUMANA PRESS TOTOWA, NEW JERSEY Teicher228-2_FM_Final 3 12/03/2003, 4:26 PM © 2004 Humana Press Inc. 999 Riverview Drive, Suite 208 Totowa, New Jersey 07512 www.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. Due diligence has been taken by the publishers, editors, and authors of this book to assure the accuracy of the information published and to describe generally accepted practices. The contributors herein have carefully checked to ensure that the drug selections and dosages set forth in this text are accurate and in accord with the standards accepted at the time of publication. Notwithstanding, as new research, changes in government regulations, and knowledge from clinical experience relating to drug therapy and drug reactions constantly occurs, the reader is advised to check the product information provided by the manufacturer of each drug for any change in dosages or for additional warnings and contraindications. This is of utmost importance when the recommended drug herein is a new or infrequently used drug. It is the responsibility of the treating physician to determine dosages and treatment strategies for individual patients. Further it is the responsibility of the health care provider to ascertain the Food and Drug Administration status of each drug or device used in their clinical practice. The publisher, editors, and authors are not responsible for errors or omissions or for any consequences from the application of the information presented in this book and make no warranty, express or implied, with respect to the contents in this publication. All articles, comments, opinions, conclusions, or recommendations are those of the author(s), and do not necessarily reflect the views of the publisher. Cover design by Patricia F. Cleary. Cover illustration: Effect of TNP470 (NSC 642492) and Taxol (NSC 125973) on chick aortic ring assay (Fig. 8, Chapter 8; see full caption on p.163 and discussion on p. 162). This publication is printed on acid-free paper. ∞ ANSI Z39.48-1984 (American National Standards Institute)Permanence of Paper for Printed Library Materials 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; Email: For the beautiful ones Emily and Joseph Katie and Matt Teicher228-2_FM_Final 5 12/03/2003, 4:26 PM Teicher228-2_FM_Final 6 12/03/2003, 4:26 PM PREFACE This unique volume traces the critically important pathway by which a “molecule” becomes an “anticancer agent.” The recognition following World War I that the administration of toxic chemicals such as nitrogen mustards in a controlled manner could shrink malignant tumor masses for relatively substantial periods of time gave great impetus to the search for molecules that would be lethal to specific cancer cells. We are still actively engaged in that search today. The question is how to discover these “anticancer” molecules. Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval, Second Edition describes the evolution to the present of preclinical screening methods. The National Cancer Institute’s high-throughput, in vitro disease-specific screen with 60 or more human tumor cell lines is used to search for molecules with novel mechanisms of action or activity against specific phenotypes. The Human Tumor Colony-Forming Assay (HTCA) uses fresh tumor biopsies as sources of cells that more nearly resemble the human disease. There is no doubt that the greatest successes of traditional chemotherapy have been in the leukemias and lymphomas. Since the earliest widely used in vivo drug screening models were the murine L1210 and P388 leukemias, the community came to assume that these murine tumor models were appropriate to the discovery of “antileukemia” agents, but that other tumor models would be needed to discover drugs active against solid tumors. Several solid tumor models were developed in mice that are still widely used today and have the advantage of growing a tumor in a syngeneic host. In the meantime, a cohort of immunodeficient mice was developed, including nude, beige, and SCID mice, allowing the growth of human tumor cell lines and human tumor biopsies as xenografts in the mice. Through the great advances in our knowledge of intracellular communication by secreted growth factors, cytokines, chemokines, and small molecules, the importance of the normal cellular environment, both stromal and organal, to the growth of malignant tumors has come to the fore. Now preclinical tumors in which malignant cells are implanted into the organ of origin, that is, in the orthotopic site, add this additional level of sophistication to drug discovery. In addition, new endpoints for preclinical testing, such as quantified tumor cell killing and detection of tumor cells in sanctuary sites, have been developed. Of the hundreds of thousands of molecules passing through the in vitro screens, few reach clinical testing. In the United States, the FDA must grant permission to enter new investigational agents into human testing, whether the clinical testing is sponsored by an academic investigator, the NCI, or the pharmaceutical industry. Patient safety is the foremost concern. Nonclinical safety testing programs need to be carefully designed to allow identification of potential hazards so that they can be appropriately monitored and so that safe starting doses can be selected. The ongoing costs and timelines for toxicology studies need to be realistically factored into overall development plans so that clinical testing is not unnecessarily delayed. The phase I clinical trial allows the initial study of a candidate therapeutic’s pharmacokinetics, pharmacodynamics, toxicity profile, and tolerated dose. In phase II clinical trials, the goal becomes demonstration of disease- vii Teicher228-2_FM_Final 7 12/03/2003, 4:26 PM viii Preface specific activity. In phase III clinical trials, statistically significant clinical benefit in well-designed and adequate clinical trials is required for success and FDA marketing approval. Phase III trial designs and statistical plans need to be appropriate relative to the current standard therapy for the intended indication. Poorly conceived and poorly executed clinical development can sabotage promising agents with recognizable activity. Much of the world’s community of physicians and investigators now participate in clinical trials of potential new anticancer agents; however, the century-old goal of discovering molecules that control the growth and spread of malignancies as well as being viable as therapeutics in humans remains elusive. The systems for finding molecules to manage malignancy are in place worldwide and our knowledge of cell growth and regulation is increasing daily; thus, one must remain optimistic of success in cancer drug discovery. This volume provides a guide for navigating the treacherous path from molecule discovery to a commercial therapy. This development path is mined with ample opportunity for failure. For anticancer drug development programs to succeed, promising compounds need to be expeditiously and intelligently selected; toxicology programs need to be thorough, relevant, timely, and informative; clinical development needs to be focused and executed with the highest scientific and administrative integrity; and FDA regulations and guidance have to be understood and followed. It is our hope that Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval, Second Edition will help all those engaged in developing new treatments for this dread disease to avoid the pitfalls that await. Our friends, colleagues, and family members who are burdened with a diagnosis of cancer await your successes. Beverly A. Teicher, PhD Paul A. Andrews, PhD Teicher228-2_FM_Final 8 12/03/2003, 4:26 PM CONTENTS Preface ......................................................................................................................... vii Contributors ................................................................................................................... xi Value-Added eBook/PDA .......................................................................................... xiv Part I: In Vitro Methods 1 High-Volume Screening ....................................................................................... 3 Michel Pagé 2 High-Throughput Screening in Industry ............................................................ 23 Michael D. Boisclair, David A. Egan, Kety Huberman, and Ralph Infantino 3 The NCI Human Tumor Cell Line (60-Cell) Screen: Concept, Implementation, and Applications .................................................. 41 Michael R. Boyd 4 Human Tumor Screening ................................................................................... 63 Axel-R. Hanauske, Susan G. Hilsenbeck, and Daniel D. Von Hoff Part II: In Vivo Methods 5 Murine L1210 and P388 Leukemias .................................................................. 79 William R. Waud 6 In Vivo Methods for Screening and Preclinical Testing: Use of Rodent Solid Tumors for Drug Discovery .......................................... 99 Thomas Corbett, Lisa Polin, Patricia LoRusso, Fred Valeriote, Chiab Panchapor, Susan Pugh, Kathryn White, Juiwanna Knight, Lisa Demchik, Julie Jones, Lynne Jones, and Loretta Lisow 7 Human Tumor Xenograft Models in NCI Drug Development ....................... 125 Michael C. Alley, Melinda G. Hollingshead, Donald J. Dykes, and William R. Waud 8 NCI Specialized Procedures in Preclinical Drug Evaluations ........................ 153 Melinda G. Hollingshead, Michael C. Alley, Gurmeet Kaur, Christine M. Pacula-Cox, and Sherman F. Stinson 9 Patient-Like Orthotopic Metastatic Models of Human Cancer ....................... 183 Robert M. Hoffman 10 Preclinical Models for Combination Therapy ................................................. 213 Beverly A. Teicher 11 Models for Biomarkers and Minimal Residual Tumor ................................... 243 Beverly A. Teicher ix Teicher228-2_FM_Final 9 12/03/2003, 4:26 PM
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