ADVANCES IN CANCER RESEARCH Volume I1 This Page Intentionally Left Blank ADVANCES IN CANCER RESEARCH EDITED BY JESSE P. GREENSTEIN National Cancer Institute, US. Public Health Service, Bethesda, Maryland ALEXANDER HADDOW Chester Beatty Research Institute, Royal Cancer Hospital, London, England Volume I I ACADEMIC PRESS INC., PUBLISHERS NEW YORK, N.Y. 1954 COPYRIGHT 1954, BY ACADEMIC PRESS INC. 125 East 23rd Street, New York 10, N.Y. 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. Library of Congress Catalog Card Number: 52-13360 PHINTED IN THE UNITED STATES OF AMERICA CONTRIBUTORS TO VOLUME II PETER ALEXANDER, Chester Beatty Research Institute, Royal Cancer Hospital, London, and Chemistry Department, Imperial College, London, England G. M. BADaER, Chemistry Department, University of Adelaide, Australia JEANNE C. BATEMAN, Warwick Memorial Clinic, George Washington I . BERENBLUM, Department of Experimental Biology, The Weizmann AUSTIN M. BRUES, Division of Biological and Medical Research, Argonne .JAMES CRAIGIE, Imperial Cancer Research Fund, London, England LEONARD D. FENNINQER, National Cancer Institute, National Institutes M. GU~CRIN, Institut de Recherches sur le Cancer, Vzllejuif (Seine), France CALVIN T. KLOPP, Warwick Memorial Clinic, George Washington Uni- I,. W. LAW, National Cancer Institute, National Institutes of Health, G. BURROUQHS MIDER, National Cancer Institute, National Institutes of C. OBERLINQ, Institut de Recherches sur le Cancer, VilZejuif (Seine) , France C. CHESTER STOCK, Division of Experimental Chemotherapy, Sloan- University Medical School, Washington, D.C. Institute of Science, Rehovoth, Israel National Laboratory, Lemont, Illinois of Health, Bethesda, Maryland versity Medical School, Washington, D.C. Bethesda, Maryland Health, Bethesda, Maryland Kettering Institute for Cancer Research, New York V This Page Intentionally Left Blank PREFACE In the year which has elapsed since the publication of Volume I of Advances in Cancer Research, the editors have been gratified by the favor- able reception accorded to it, equally by their fellow workers and by the scientific press. This they regard not only as a general encouragement of the new enterprise but also as a reflection of the value, certainly no less in this than in any other scientific field, of the authoritative review. Since their aim is not only to consolidate the venture but, so far as is possible, to improve it, they take the present opportunity of welcoming sugges- tions to this end, whether concerned with particular topics or aspects which most merit inclusion, or with policy as a whole. In the current volume, the central theme of carcinogenesis again finds a prominent place, as, for example, in the review of carcinogenesis and tumor pathogenesis by Dr. I. Berenblum, whose own work has elucidated so many of the factors involved; and in that of Dr. G. M. Badger, who, not only as a pupil of Professor J. W. Cook at the Royal Cancer Hospital in London and at the University of Glasgow, but also by virtue of his own contributions subsequently, is especially qualified to deal with the relationships of chemical constitution and carcinogenic activity. Although the list of chemical carcinogens is doubtless still incomplete, and much may still be learned from the chemical interrelationships of those already known, within the past few years a new emphasis has inevitably been given to problems of their mode of action, involving a shift of interest toward those macromolecular receptors with which, it would appear, they most probably combine. This development has been greatly stimulated by the discovery of carcinogenic activity in a whole range of “biological alkylating agents,’’ the reactions of which, among other carcinogens, are dealt with in a contribution by Dr. P. Alexander. So far at least as their biological end-results are concerned, many of these alkylating agents may very reasonably be described as “radiomimetic,” lending special signifi- cance to the facts, first that the earliest experimentally induced tumors owed their origin to ionizing radiations, and, second, that the total of carcinogenic agents has been greatly increased, through the wealth of radioisotopes accruing from the atomic energy programs of the past ten years; these, and their practical bearings, are considered in a contribution by Dr. A. M. Brues. From its beginnings, research into the etiology of cancer has been vii viii PREFACE enlivened by the controversy between those who subscribe to the impor- tance of a process of infection-especially by viral agents-and those others who believe the reverse. Even though many must judge the anti- thesis to be a false one, the issue in reality is still undecided; contributions which throw light upon it include a vigorous review by Dr. C. Oberling and Dr. M. Guerin, a survey of genetic studies by Dr. L. W. Law, and an account, by Dr. J. Craigie, of the survival and preservation of tumors in the frozen state-the last including details not merely of great theoreti- cal interest but of much practical value as well. Apart altogether from etiology and pathogenesis, increased note has been paid of recent years to the systemic and nutritional consequences of tumor growth once established, and the review by Dr. L. D. Fenninger and Dr. G. Burroughs Mider, on energy and nitrogen metabolism, is of special interest for its relevance to the disease in man. The same applies in marked degree to the contribution of Dr. C. Chester Stock on experi- mental cancer chemotherapy, and that of Dr. C. T. Klopp and Dr. Jeanne C. Bateman on the clinical use of the nitrogen mustards. Admitted that the chemotherapeutic agents of the future are likely to be very different in their nature, specificity, and potency from those at present used, it is a matter of no little consequence that limited gains continue to be recorded, and that the harvest of benefit grows, even if slowly, from year to year. It is our ambition, and hope, that these volumes may serve not merely as an annual chronicle of progress, but as a recurring stimulus to the work ahead. THE EDITORS February, i 954 CONTENTS CONTRIBUTORS TO VOLUME 11 . . . . . . . . . . . . . . . . . . . . . . . PREFAC~ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vil The Reactions of Carcinogens with Macromolecules BY PETER ALEXANDER, Chester Beatty Research Institute. Royal Cancer Hospital. London. and Chemistry Departmentl Imperial College. London. England V I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 4 42 55 62 65 I1 . Biological Alkylating Agents . . . . . . . . . . . . . . . . . . . . IV . Polycyclic Hydrocarbons . . . . . . . . . . . . . . . . . . . . . . I11 . Ionizing Radiations . . . . . . . . . . . . . . . . . . . . . . . . V . Compounde Containing Amino Groups . . . . . . . . . . . . . . . . VI . Carcinogenic Polymers . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 Chemical Constitution and Carcinogenic Activity BY G . M . BADQER. Chemistry Department. University of Adelaide. Australia I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 73 I1 . Historical . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74 I11 . Polycyclic Aromatic Hydrocarbons . . . . . . . . . . . . . . . . . . 80 IV . Aeo Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . 112 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 Carcinogenesis and Tumor Pathogenesis BY I . BERENBLUM~ Department of Experimental Biology. The Weizmann Institute of Science, Rehovoth. Israel I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . 129 I1 . Nature of Response to Carcinogenic Action . . . . . . . . . . . . . 130 I11 . Genetic Factors Influencing Carcinogenesis . . . . . . . . . . . . . . 139 IV . Influence of Age. Sex. and Hormonal Factors . . . . . . . . . . . . . 142 V . Dietary Factors Influencing Carcinogenesis . . . . . . . . . . . . . . . 144 VI . Effect of Solvents on Carcinogenesis . . . . . . . . . . . . . . . . . 147 VII . Irritation and Carcinogenesis . . . . . . . . . . . . . . . . . . . . 151 VIII . Initiating and Promoting Action as Independent Stages of Carcinogenesis 155 IX . Histogenesis of Preneoplasia . . . . . . . . . . . . . . . . . . . . 159 X . General Discussion . . . . . . . . . . . . . . . . . . . . . . . . 163 Referencee . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164 Ionizing Radiations and Cancer BY AUSTIN M . BRUES. Division of Biological and Medical Research. Argonne National Laboratory, Lemont. Illinois I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 177 I1 . Basis of Radiation Effects . . . . . . . . . . . . . . . . . . . . 178 I11 . Radiation Carcinogenesis . . . . . . . . . . . . . . . . . . . . . 179 IV . Mechanism of Carcinogenesis . . . . . . . . . . . . . . . . . . . . 182 V . The Mutation Hypothesis . . . . . . . . . . . . . . . . . . . . . 184 ix