SEEDS OF DESTRUCTION THE SCIENCE REPORT ON CANCER RESEARCH
SEEDS OF
DESTRUCTION THE SCIENCE REPORT ON CANCER RESEARCH THOMAS H. MAUGH II AND JEAN L. MARX PLENUM PRESS. NEW YORK AND LONDON AMERICAN ASSOCIATION FOR THE ADVANCEMENT OF SCIENCE
Library of Congress Cataloging in Publication Data Maugh, Thomas H Seeds of destruction. "Part of the material... originally appeared as a series in the Research News section of Science, the Journal of the American Association for the Advancement of Science." Bibliography: p. Includes index. 1. Cancer. 2. Carcinogenesis. I. Marx, Jean L., joint author. II. Science. III. Title. [DNLM: 1. Neoplasms-Popular works. 2. Research-Popular works. QZ201 M449s] RC261.M434 616.9'94 75-15860 ISBN 978-1-4684-8564-6 ISBN 978-1-4684-8562-2 (ebook) DOl 10.1007/978-1-4684-8562-2 Part of the material in this book originally appeared as a series in the Research News section of SCIENCE, the Journal of the American Association for the Advancement of Science. The authors are members of the Research News staff of SCIENCE. 1975 American Association for the Advancement of Science Softcover reprint of the hardcover I 5t edition 1975 Plenum Press, New York is a division of Plenum Publishing Corporation 227 West 17th Street, New York, N.Y. 10011 United Kingdom edition published by Plenum Press, London A Division of Plenum Publishing Company, Ltd. Davis House (4th Floor), 8 Scrubs Lane, Harlesden, London, NWlO 6SE, England 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
Preface There is little prospect of an immediate cure for cancer. The seeds of destruction seem to be sown within all of us, and there is no consensus about how these seeds develop into tumors or about what can be done to halt that development. Indeed, it is often difficult to find a consensus about any aspect of cancer research. The sharply conflicting views of investigators in different subdisciplines has been most aptly summarized by Charles Heidelberger of the McArdle Laboratory for Cancer Research, who argues that "the mechanism of cancer is a mirror into which each man looks and sees himself." This is true despite the fact that large infusions of money and manpower now come to the aid of cancer research. In late 1974, Betty Ford and Margaretta (Happy) Rockefeller underwent surgery for breast cancer. The extensive publicity surrounding these mastectomies provoked a great deal of interest in the subject of cancer, particularly breast cancer. Newspaper and television stories associated with the operations gave their audiences some insight into the nature of cancer and cancer research, but they provided only a glimpse of the sweeping changes that the directions of cancer research have undergone in the last few years. In large part, these changes simply reflect the natural progression of research, but there is little question that that progression was sharply accelerated by the National Cancer Act of 1971, which initiated what politicians then termed a "crusade against cancer." As a result of that act, the budget of the National Cancer Institute (NCI) more than tripled, from $190 million in 1970 to more than $600 million in 1975. Other sources will probably add half again as much. In v
vi PREFACE 1973, the last year for which complete figures are available, NCI's budget of $431 million accounted for some 58 percent of the $752 million available for cancer research and support. Other Federal agencies contributed $90 million, and state and local agencies provided $96 million. Voluntary agencies, primarily the American Cancer Society, contributed $95 million. Private research institutions and industry contributed about $22 million and $17 million, respectively. If the level of support from these other sources remains more or less constant, as is expected, the resources available for cancer programs in 1975 will total more than $920 million-making cancer the best-funded area of biological research in this country. Meanwhile, in biology there has been increasing emphasis on the study of mammalian cells, rather than on bacteria and other simpler organisms. Hence, with the increased cancer funding and the nearstagnation in support for most other types of biological research, many new investigators have been attracted to the study of cancer. A recent estimate from the National Institutes of Health indicates that some 7.7 percent of the total U.S. biomedical manpower pool-more than 7250 scientists-are working on projects that can be directly related to cancer and many more are working on projects that are peripherally related. The effect of these stimuli has been to produce distinct changes in emphasis within many of the subdisciplines of cancer research. In viral carcinogenesis research, for example, there has been a subtle shift from efforts to isolate a tangible human cancer virus to more sophisticated attempts to detect biochemical traces of such viruses in human tumors. In chemical carcinogenesis research, there has been a more marked shift away from simple screening and identification of possible carcinogens to a detailed examination of the interaction of chemical and cell. Investigation of the biochemistry of cancer has increasingly been focused on the role of cellular membranes in tumorigenesis and on the identification of tumor antigens that might permit earlier detection and more precise quantification of the disease. And there has been a strong trend in cancer therapy away from reliance on any single tool (such as surgery, irradiation, or drugs) toward a combined-modality approach and a renewed interest in stimulation of the body's own immune defenses. While no cure is on the horizon and no agreement has been reached on the likely cause or causes of cancer, there has been progress, and there
PREFACE vii is the promise of much more to come. This book assesses the status of cancer research and examines some of the areas where progress has been most apparent. While it cannot pretend to be either comprehensive or exhaustive, the book focuses on what appears to be some of the most interesting and significant developments in the drive to understand the molecular biology of cancer. The authors would like to thank Allen L. Hammond and Van R. Potter for their assistance in preparing two of the chapters, Fanny Groom for doing much of the typing, and their colleagues on the staff of Science for their enthusiasm and assistance. They would also like to thank Emmanuel Farber, Bernard Roizman, Elizabeth C. Miller, and Herbert Rapp for reviewing parts of the glossary. May 1,1975 THOMAS H. MAUGH II JEANL.MARx
Contents Preface v List of Illustrations List of Tables xiii Xl I II Cancer Etiology 1 What Is Cancer? How Does It Kill? 3 2 Chemical Carcinogenesis: A Long- Neglected Field Blossoms 8 3 Viral Carcinogenesis: Role of DNA Viruses 23 4 RNA Viruses: The Age of Innocence Ends 37 5 Tumor Immunology: The Host's Response to Cancer 53 Cancer Biochemistry 6 A Mystery Wrapped in an Enigma 69 7 Biochemistry of Cancer Cells: Focus on the Cell Surface 74 8 Fetal Antigens: A Biochemical Assay for Cancer? 88 ix
x CONTENTS III Cancer Therapy 9 Trends in Cancer Therapy 97 10 Radiation Therapy: Potential for High Energy Particles 100 11 Chemotherapy: Now a Promising Weapon 111 12 Immunotherapy: New Strategies for Cancer Therapy 130 13 After Cancer Therapy: Rehabilitating the Patient 142 IV Specific Cancers 14 The Organ Site Approach to Cancer Research 151 15 Breast Cancer Research: Problems and Progress 155 16 Leukemia: Much Is Known, but the Picture Is Still Confused 167 Appendix 181 Glossary 192 Selected Readings 239 Index 241
List of Illustrations Figure 1. Percent of cancer incidence by site and sex 4 Figure 2. Percent of cancer deaths by site and sex 4 Figure 3. 2-Acetylaminofluorene and benzo[a]pyrene and their activated forms 3 Figure 4. The presumed routes for activation of some carcinogens 15 Figure 5. One mechanism for action of carcinogenic alkylating agents 16 Figure 6. Schematic representation of the structure of herpes simplex viruses 24 Figure 7. Electron micrographs showing different views of the HSV I virion 25 Figure 8. Electron micrographs of oncornaviruses 40 Figure 9. A schematic representation of the oncogene hypothesis 46 Figure ZO. One method by which the protovirus can realign chromosomes within a cell to produce oncogenic information 49 Figure 11. Virus replication and cell transformation by RNA tumor viruses 50 Figure 12. Electron micrographs of a T lymphocyte and a B lymphocyte 57 Figure 13. Schematic representation of the blocking phenomenon 59 Figure 14. Figure 15. Figure 16. Transformation of a normal cell to a tumor cell results in expression of new tumor antigens 62 One possible simplified mechanism for feedback control of genetic expression 72 Morphological differences between normal and malignant fibroblasts 77 xi
xii LIST OF ILLUSTRA TIONS Figure 17. Current version of the fluid mosaic model of cell membrane structure 78 Figure 18. A schematic representation of antigens which have been identified to exist on rodent tumor cells 90 Figure 19. Energy transfer as a function of depth for several types of radiation 104 Figure 20. A typical experimental setup for generating pions 109 Figure 21. The mechanism of action of several antitumor agents 116 Figure 22. Chemotherapeutic agents interfere at different phases of the mitotic cycle 117 Figure 23. Treatment of melanoma metastases with BCG 132 Figure 24. Guinea pig model used for investigating immunotherapy 134 Figure 25. Xeroradiogram showing carcinoma of the breast 162 Figure 26. Thermograms of a normal breast and a cancerous breast 163 Figure 27. One type of laminar air flow bedroom 180 Figure 28. Geographical distribution of estimated U.S. cancer deaths, 1974 181 Figure 29. Male cancer death rates by site, United States, 1930-1969 182 Figure 30. Female cancer death rates by site, United States, 1930-1969 182
List of Tables Table 1. Some chemicals that are recognized to be carcinogens in humans 8 Table 2. Typical carcinoembryonic antigen (CEA) concentrations in patients with various diseases 93 Table 3. The susceptibility of certain tumors to chemotherapeutic agents 112 Table 4. Availability of data about effects of certain chemotherapeutic agents on selected tumors 124 Table 5. Estimated number of new cases and deaths for selected cancers, 1974 152 Table 6. The evolution of leukemia therapy at St. Jude Children's Research Hospital in Memphis 176 Table 7. Relation of cancer to other leading causes of death in the United States, 1969 183 Table 8. Estimated cancer deaths and new cases by sex and site, 1973 184 Table 9. Percentage of patients with various types of cancer who survive for 3 or 5 years 186 Table 10. Age-adjusted death rates per 100,000 population for selected cancer sites for 39 countries, 1966-1967 188 Table 11. A condensed outline of the National Cancer Program 190 Table 12. The seven warning signals of cancer 191 xiii