Chemical Induction of Cancer. Structural Bases and Biological Mechanisms

498 Pages·1968·8.036 MB·English

by  Joseph C. Arcos, Mary F. Argus and George Wolf (Auth.)

CHEMICAL
INDUCTION OF
CANCER
Structural Bases
and Biological Mechanisms
JOSEPH C.ARCOS
TULANE UNIVERSITY SCHOOL OF MEDICINE
NEW ORLEANS, LOUISIANA
MARY F.ARGUS
TULANE UNIVERSITY SCHOOL OF MEDICINE
NEW ORLEANS, LOUISIANA
GEORGE WOLF
DEPARTMENT OF NUTRITION AND FOOD SCIENCE
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
CAMBRIDGE, MASSACHUSETTS
VOLUME I
1968
ACADEMIC PRESS New York San Francisco London
A Subsidiary of Harcourt Brace Jovanovich, Publishers
The first edition of "Chemical Induction of Cancer,"
by George Wolf, was published in 1952 by
Harvard University Press, Cambridge, Massachusetts,
and Casse 11 and Company Ltd., London.
COPYRIGHT © 1968, BY ACADEMIC PRESS INC.
ALL RIGHTS RESERVED.
NO PART OF THIS BOOK MAY BE REPRODUCED IN ANY FORM,
BY PHOTOSTAT, MICROFILM, OR ANY OTHER MEANS, WITHOUT
WRITTEN PERMISSION FROM THE PUBLISHERS.
ACADEMIC PRESS INC.
111 Fifth Avenue, New York, New York 10003
United Kingdom Edition published by
ACADEMIC PRESS, INC. (LONDON) LTD.
24/28 Oval Road. London NW1
LIBRARY OF CONGRESS CATALOG CARD NUMBER: 66-30118
PRINTED IN THE UNITED STATES OF AMERICA
Dedicated to those whose teaching
and inspiration made a lasting mark :
GEORGE BÄRSONY
SAMUEL BORBÉLY
NGUYEN PH. BUU-HOI
AUGUSTE CHAGNON
LÉON DENIVELLE
EMERICH EGRI
ANDRÉ ETIENNE
SR. MARY FINBAR, O.S.F.
CHARLES HEIDELBERGER
ANTOINE LACASSAGNE
ELIZABETH C. MILLER
JAMES A. MILLER
SIR KARL POPPER
FRANCIS E. RAY
SIR ROBERT ROBINSON
SR. IGNATIUS SANCHE, S.C.
LADISLAU VON VARGHA
General Plan
Volume I
1. Introduction
1.1 Some Specific Bibliographie Tools of Chemical Oncology
PART I. Molecular Architecture and the Physical Bases of Molecular Forces
2. Some Fundamentals of Organic Chemistry: Structural Concepts
2.1 Alkanes. Isomerism. Substitution Reactions. The Tetrahedral Carbon Atom
2.2 Alkenes and Alkynes. Chemical Properties of Double and Triple Bonds
2.3 Some Important Functional Groups and Their Reactions
2.4 Benzene and the Aromatic Character
3. The Nature of Intra- and Intermodular Forces
3.1 The Nature of Valence
3.2 Resonance
3.3 Secondary Valence Forces
3.4 Parameters of Molecular Geometry and Stability
PART II. The Nature of Tumors. Concepts and Techniques of Testing Chemical Agents for
Carcinogenic Activity
4. General Characteristics of Tumors and the Testing of Carcinogens
4.1 General Characteristics of Tumors
4.2 Some Aspects of the Pathology of Induced Tumors
4.3 Testing Procedures
Author Index
Subject Index
Volume II
PART III. Structure-Activity Relationships of Chemical Carcinogens. Effect of Chemical
Reactivity, Molecular Geometry, and Metabolism on Carcinogenic Activity
5. Structure-Activity Relationships
5.1 Conjugated Aromatic Systems
5.2 Nonconjugated Organic Compounds
5.3 Naturally Occurring Carcinogens
5.4 Films and Other Implanted Foreign Bodies; Soluble High Polymers. Sarcomatogenic
Effect of Topical Osmotic Disturbances
5.5 Inorganic Carcinogens
PART IV. Cross-Reactions between Carcinogens: Anti- and Cocarcinogenesis. Influence of
Exogeneous Factors and Biological Parameters on Carcinogenic Activity
6. Cross-Reactions between Carcinogens and the Effect of Noncarcinogenic Chemicals on
Carcinogenic Activity
6.1 Synergism and Antagonism
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viii General Plan
6.2 Anti- and Cocarcinogenesis
7. Biological and Other Parameters Which Influence Tumor Induction by Chemical Carcino-
gens
7.1 The Effect of Diet on Tumor Induction
7.2 The Effect of Animal Age on Tumor Induction
7.3 The Effect of Hormones on Tumor Induction
7.4 The Effect of Sex on Tumor Induction
7.5 The Effect of Radiations on Tumor Induction
7.6 The Effect of Trauma on Tumor Induction
Author Index
Subject Index
Volume III
PART V. Cell Structure and Function. Effect of Carcinogens on Living Tissues. Mechanisms of
Biological Action
8. Fundamentals of Cell Structure and Function
8.1 Structure of Proteins
8.2 Structure of Nucleic Acids
8.3 Fine Morphology, and Division of Function in Cells: General Aspects
8.4 Some Essential Facets of Cell Metabolism : Pathways and Mechanisms of Energy Produc-
tion. Templates and Macromolecular Synthesis. Cellular Information Transfer
8.5 The Concept of Feedback
8.6 Control and Integration of Function: The Cell as a Multiple Macromolecular Feedback
System
9. Effect of Carcinogens on Tissues. Mechanisms of Action
9.1 Brief Review of the Theories of Carcinogenesis
9.2 Subcellular Distribution of Carcinogens and Their Covalent Binding to Proteins and
Nucleic Acids. The Enzyme Deletion Hypothesis
9.3 Effects on the Steric Conformation of Biological Macromolecules
9.4 Alterations of Enzyme Function : A Bird's-Eye View
9.5 Alterations of Cell Organelles and of Templates of Macromolecular Synthesis
9.6 Cross-Linking, Aging and Carcinogenesis. Loss of Feedback Regulatory Channels. Clonal
Selection. Microevolution of Tumors
APPENDIX I. Inhibition of Tumor Growth and Possibilities of Tumor Chemotherapy
APPENDIX II. Some Biological Effects of Chemical Carcinogens Other Than Tumorigenesis
APPENDIX III. Some Future Avenues of Chemical Oncology
Author Index
Subject Index
Foreword
The years since the first edition of this book have seen many remarkable
advances in biology. Studies on the chemical basis for gene action, the
synthesis of important cellular macromolecules such as proteins and nucleic
acids, and the ultrastructure of cell organelles together with relatively simple
methods for cell culture are providing a new foundation for our understand-
ing of cell behavior. As anticipated, these concepts and tools are leading to
rapid progress in the nature and mechanism of interaction of chemical
carcinogens and cell components.
Coincident with these developments has been a new awareness of the
possible importance of chemicals as carcinogens in man's environment. It is
becoming increasingly evident that not only our external physical environ-
ment but also foods and food contaminants contain potent compounds which
may play an important role in the genesis of cancer in man.
These considerations make a second edition of this book both timely and
significant. By presenting an up-to-date survey of the role of chemicals in the
genesis of cancer, the authors offer an opportunity for all who are interested
in cancer to familiarize themselves with the latest advances in this important
area of cancer research and environmental medicine. However, the authors
have made an additional important contribution in presenting and stressing
the multifaceted nature of the problem at hand. Although it is commonplace
to hear expressed the need in cancer research for a multidisciplinary approach,
too much of the research being done today is still highly oriented along
classical disciplines, without much interdisciplinary interaction. In fact, one
of the impediments to progress in several phases of the study of cancer is the
restricted nature of the outlook and background of the investigator. By
virtue of their own varied experiences and interests, the authors have been
able to encompass in this edition many of the major scientific fields which are
relevant to the problem. The presentation of morphologic, chemical, and
metabolic aspects of chemical carcinogenesis in a single work is both re-
freshing and encouraging.
The majority of changes in the cell's environment leading to disease,
including the presence of carcinogenic chemicals, evoke many cellular
chemical responses. Some of these are no doubt the consequence of specific
chemical interactions with cell components. Since these reactions frequently
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x I Foreword
involve more than one class of cellular macromolecules, some selection for
relevance to the neoplastic process will have to be made. The discrimination
between the significant and the insignificant reactions will be dependent upon
the use of ingenious biological approaches in close association with the
chemical. The reader is offered in this edition the opportunity to acquire
some of the conceptual framework upon which the intelligent selection of the
relevant from the irrelevant may be made. This contribution alone makes
this work recommended reading for those interested in understanding the
nature and causation of cancer.
March, 1968 EMMANUEL FÄRBER
Department of Pathology
University of Pittsburgh School of Medicine
Pittsburgh, Pennsylvania
Foreword
to the First Edition
All who are actively engaged upon the experimental study of cancer, and
especially upon the elucidation of its chemical causation, are well aware of a
strong demand for some comprehensive, authoritative, yet not over-
elaborate description of developments in this field, which would be of value
at once to the general medical and scientific reader and to the interested
layman. It is a matter for regret that the very pace of discovery has hindered
the satisfaction of this need, by leading too many of us, in the excitement of
the chase, to neglect our duty of more general exposition. Not only those to
whom this book is primarily addressed, but his immediate colleagues in the
field of cancer research also, are accordingly under a special debt to Dr. Wolf
for providing, in short compass and eminently readable form, this unified
and lucid account. That he is well qualified to do so is shown by his own
contributions, made both in this country and in the United States.
A great part of the relevant work carried out in the past thirty years has
been concerned with the discovery of chemical agents, both naturally
occurring and purely synthetic, having the capacity to induce cancer under
experimental conditions. Dr. Wolf has done ample justice to this important
field, as also to the related problems of chemical constitution and biological
action. At the same time his book reflects the change of emphasis of the past
few years, as a result of which much more attention is being devoted to
mechanisms of action, for example through studies of the chemical reactivity
and metabolic fate of carcinogens, the contributions of the French school,
and the discovery and significance of carcinogenic activity in many nitrogen
mustards and other biological alkylating agents. All these advances are now
leading to very greatly increased confidence that the elucidation of the
carcinogenic process will in fact lead, as had been hoped, to the means of its
chemical or enzymatic control. Dr. Wolf's book therefore appears at an
appropriate moment in the development of the subject, and is warmly to be
commended as an admirable summary of the main experimental facts, for its
balanced interpretation, and as a source not only of information but of
stimulus as well. It will perhaps be specially welcomed by those wishing to
acquaint themselves, without too great difficulty, with a field of research
which, if it has of necessity developed along highly specialized lines, is never-
theless of the utmost importance towards the ultimate solution of the greatest
problem confronting medicine. No other subject quite combines, in the same
degree, the thrill of discovery and the prospect of bénéficient application. So
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xii I Foreword to the First Edition
far as concerns the experimental reproduction of the disease and the
understanding of the biological process involved, no more useful or more
succinct general account can be recommended than that in the pages which
follow.
May, 1952 ALEXANDER HADDOW
Chester Beatty Research Institute,
The Royal Cancer Hospital,
{Institute of Cancer Research, University of London),
London, S.W.3.
Preface
The final aim of cancer research or oncology is to elucidate the cause of the
disease and, hence, find a rational basis for its therapy and prevention. The
problem has become complex, however, and its roots have spread into many
areas of scientific investigation. A most important approach to oncology is
chemical: studies of the chemical induction of cancer, of the chemical nature
of tumors and of tumor-host relationships, and of investigations on the
chemo- and immunotherapy of tumors.
The modern era of chemical oncology opened with the identification and
syntheses in the 1930's of well-defined organic compounds that produced
tumors at will and with some degree of specificity with respect to tissue,
animal strain, and species. By means of the different tumor-inducing
(carcinogenic) compounds—precision tools in the hands of the biologist,
pathologist, and biochemist—one can interfere with the normal life of cells
and turn them into tumor cells (carcinogenesis). It is now well established
that chemical carcinogens interact with various vital cell components : pro-
teins and nucleic acids. As a result of these interactions gradual change takes
place in the molecular organization and chemical functioning of the cells in
the target tissue, leading ultimately to uncontrolled growth and the emergence
of malignant tumors. The nature of this change, its relation to the carcinogen
and to the emergence of spontaneous cancer (the disease), is the problem of
the chemical induction of cancer.
The idea of writing a second edition of Wolf's "Chemical Induction of
Cancer" was conceived at the completion of an extensive review article on the
"Molecular Geometry and Mechanisms of Action of Chemical Carcinogens,"
which appeared in 1962 in "Progress in Drug Research." This and other
review articles and books which appeared on chemical carcinogenesis in
recent years were addressed mainly to the specialist and assumed a thorough
familiarity with the component terminologies. Yet the cancer problem, apart
from its clinical aspects, is so closely related to the fundamental questions
of growth control and differentiation that it presents a challenging interest for
all students of biology. Actually, the study of the chemical induction of
tumors has become a widely traveled crossroad for many scientific and
technological disciplines such as biochemistry, organic chemistry, pharma-
cology, toxicology, industrial and preventive medicine, pathology, cytology,
biophysics, quantum mechanics, cybernetics, and air and water pollution
and food additive testing and evaluation studies. Moreover, aside from the
difficulties of a complex and multicentric terminology, the voluminous
literature on the structure-activity relationships, testing procedures, and
xiii