FUNDAMENTALS OF ONCOLOGY FOURTH EDITION, REVISED AND EXPANDED Henry C. Pitot McArdle Laboratory for Cancer Research University of Wisconsin Medical School Madison, Wisconsin With a Contribution by Daniel D. Loeb McArdle Laboratory for Cancer Research University of Wisconsin Medical School Madison, Wisconsin Marcel Dekker, Inc. New York Basel • TM Copyright ©2002 by Marcel Dekker,Inc. All Rights Reserved. ISBN: 0-8247-0650-1 This book is printed on acid-free paper. Headquarters Marcel Dekker, Inc. 270 Madison Avenue, New York, NY 10016 tel: 212-696-9000; fax: 212-685-4540 Eastern Hemisphere Distribution Marcel Dekker AG Hutgasse 4, Postfach 812, CH-4001 Basel, Switzerland tel: 41-61-261-8482; fax: 41-61-261-8896 World Wide Web http://www.dekker.com The publisher offers discounts on this book when ordered in bulk quantities. For more information, write to Special Sales/Professional Marketing at the headquarters address above. Copyright © 2002 by Marcel Dekker, Inc. All Rights Reserved. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and re- trieval system, without permission in writing from the publisher. Current printing (last digit): 10 9 8 7 6 5 4 3 2 1 PRINTED IN THE UNITED STATES OF AMERICA To Mary Julie and Beth Anita Jeanne Cathy Henry Michelle Lisa Patrice Mom, Dad, and Big Anita I am a cancer cell. Of my earliest ancestry no evidence remains. When the earth’s first creatures stirred the ancient seas, when the Pharaohs wrought the pyramids, when the medieval scribes laboriously recorded their philosophies, I was there. The ingenious Virchow, who recognized my stamp, marshaled the forces of science against me. Malicious, relentless, insidious I am, full of destruction, ripe for carnage, yet in my enduring frame I carry the secret of life. Study me, and you will bring into the light of day precious urns of wisdom long buried in the tomb of ignorance. For you I shall tell a wondrous tale of the beginning of things that are and are to be. Study me, know me, and you will hold the world in fief. Neglect me, and as surely as the fingers of the dawn grasp first the temples of the East, I will strike you dead. Preface to the Fourth Edition It has been some 15 years since the third edition of this text was published. The original purpose of the book was to replace notes in a course, “Introduction to Experimental Oncology,” which has been given in the Department of Oncology at the University of Wisconsin–Madison for more than 25 years. The course has evolved from being primarily directed towards graduate students to one that includes more than 80% undergraduates, usually juniors and seniors in various sci- ences. The course has always been offered for two credits, but with the enormous increase in information in the field of oncology, it will likely be increased to three credits. In this revision, four new chapters have been added and the other chapters significantly expanded. The genetics of neoplasia is now covered in two chapters, as is the stage of progres- sion. Discussion of carcinogenesis in humans has also been expanded to two full chapters in addition to the chapter on the evaluation of risk of carcinogenic environmental agents. Finally, another chapter has been added in the area of host–tumor relationships, covering endocrine and stromal responses. Of necessity, the glossary has been somewhat expanded, as have the number of figures and tables. (We are very grateful to the authors and publishers who gave us permission to incorporate their work in this text. In addition, for instructors wishing to use this text in classes in oncology, we have developed an extended series of slide illustrations that may be found at our web site: http://mcardle.oncology.wisc.edu/pitot.+ Click on “Courses” and scroll down to “Oncology 401.”) As in the third edition, I have again cited references in the text. Although some of the third edition’s references have been retained because of their usefulness, a larger number of new refer- ences have been added since the last edition than were in the third edition itself. Still, this funda- mental text is not exhaustive in its treatment of the literature (although some students may think it is), but it presents reasonably representative samples of each of the topics and areas covered. My sincere apologies are extended to any colleagues whose work was not specifically cited. If there are other subjects in the field of oncology that should be covered in a basic text such as this, I would certainly appreciate receiving such information. I would like to express my sincere appreciation to my colleague Dr. Daniel Loeb, who, after some arm-twisting, agreed to write the vast majority of Chapter 4, on viruses and cancer. This field has become much more complex since the third edition, and I felt need of an expert in the area. I am also grateful to other colleagues who read and made critical comments on the manuscript, especially Drs. Norman Drinkwater, the late Dr. James Miller, and Bill Sugden of the McArdle Laboratory; Dr. Lynn Allen-Hoffmann of the Department of Pathology at the Uni- v vi Preface to the Fourth Edition versity of Wisconsin–Madison; my son, Dr. Henry C. Pitot IV, and his colleagues in the Depart- ment of Oncology of the Mayo Clinic, Rochester, Minnesota; and Dr. Peter Duesberg of the University of California, Berkeley. In particular, I express my deepest thanks to Dr. Ilse Riegel for her invaluable help in editing and correcting the manuscript throughout all its stages. Our special appreciation and thanks go to Mrs. Mary Jo Markham and Mrs. Kristen Adler for their patient, enduring, and expert transcribing and typing of the manuscript and indexing the entire book. A special thanks is given to my colleague Dr. Yi-hua Xu, who aided us immensely in developing and digitizing figures. Perhaps the greatest debt of gratitude in developing the fourth edition of this text is owed my wife and our children, who have endured the constant “working on the book” that kept me from spending more time with them. As the final corrections were being made to the text, our oldest daughter was diagnosed with metastatic breast cancer. Several years ago she gave me a small blackboard on which was written, “A teacher affects eternity; they can never tell where their influence stops.” I can only hope and pray that these words are prophetic and that this text may play a small role in the ultimate control of cancer. Henry C. Pitot Preface to the Third Edition Since the manuscript for the second edition of this text was completed, information regarding the science of oncology, in the human and the experimental animal as well as in the plant king- dom, has expanded in an astounding manner. The prediction of an earlier reviewer that this test would require constant updating has proven true many times over. Furthermore, for the sake of our students—the prime motivation for writing this text—a reasonably succinct survey of the field of experimental oncology and its applications to humans continues to be of primary impor- tance in our basic instructional program. In this revision of the text, a number of new chapters have been added. A new Chapter 5, concerned with hereditary factors in the causation of cancer, has been included. The discussion of human cancer has been divided into two chapters: Chapter 9 is concerned with the direct known causes and Chapter 10 with the scientific and societal considerations of human cancer. Finally, the chapter on the biochemistry of neoplasia (Chapter 10 in the second edition) has also been divided into two chapters, one dealing with the biochemistry of the neoplastic transforma- tion in vivo (Chapter 12), the other with the biochemistry and molecular biology of the neoplas- tic transformation in vitro (Chapter 13). At the suggestion of one of the reviewers of the second edition, we have cited the refer- ences in the text for the convenience of the reader. This has the disadvantage of a somewhat more formal presentation, but we hope that it will be useful to the student who wishes to study the field of experimental oncology in greater depth. This fundamental text is not exhaustive in its treatment of the literature but presents representative examples of each of the topics and areas covered. My apologies to any colleagues whose work was not specifically cited. If anyone feels strongly that additional references are needed, please communicate your suggestions to the author. Again I would like to express my sincere appreciation to my colleagues at the McArdle Laboratory who read and made critical comments on the manuscript, especially Doctors Nor- man Drinkwater, Janet Mertz, James and Elizabeth Miller, Gerald C. Mueller, Van R Potter, Rex Risser, Jeffrey Ross, Bill Sugden, and Howard M. Temin, and to Dr. Paul Carbone of the vii viii Preface to the Third Edition Wisconsin Clinical Cancer Center. In particular I would like to express my thanks to Dr. Ilse Riegel and Bette Sheehan for their invaluable help in editing and correcting the manuscript throughout all of its stages and my appreciation to Mary Jo Markham and Karen Denk for their patient and expert transcribing and typing. Finally, my thanks are extended to Carol Dizack for her expert artistry in drawing the figures added to this edition of the text and to Terrill P. Stewart for his photographic skills. Henry C. Pitot Preface to the Second Edition In the few short years since the publication of the first edition of this text, a number of signifi- cant facts have been uncovered in the science of oncology. Many of these findings have been incorporated into the teaching of our basic course in experimental oncology through additional notes and lectures, and the revision of this text became a clear necessity. In this revision we have maintained the same format as in the first edition but have altered the contents of most of the chapters, adding both figures and tables. In addition, the pathogenesis of cancer and the natural history of cancer in vivo have been divided into Chapters 6 and 8 re- spectively. Finally, Chapter 13 has been added to present some aspects of the basis for cancer chemotherapy. Although this chapter is not an attempt to discuss the various treatment modali- ties used in cancer therapy, the subject matter does introduce the student to the experimental basis for chemotherapy and also briefly discusses the methodology and rationale for the chemi- cal therapies used today. We have continued to utilize illustrative slides to supplement the lectures and text. Lec- tures by several of my clinical colleagues on the diagnosis, therapy, and psychosocial aspects of cancer continue to be significant components of our course. Again I would like to express my sincere appreciation to a number of my colleagues at the McArdle Laboratory, especially Doctors Roswell Boutwell, James and Elizabeth Miller, Van R. Potter, Rex Risser, Bill Sugden, and Howard Temin, as well as others who have read and made critical comments on the manuscript. In particular, I would like to express my thanks to Dr. Ilse Riegel and Ms. Bette Sheehan for their invaluable help in collating, editing, and correcting the manuscript throughout all of its stages, and my appreciation to Ms. Karen Denk for her patient and expert typing. Finally, my thanks are again extended to Mr. John L. Shane for his continued artistic aid in drawing the new figures for this text. Henry C. Pitot ix