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Ernst Schering Research Foundation Workshop 1 0
Nongenotoxic Carcinogenesis
Ernst Schering Research Foundation Workshop
Editors: Gunter Stock Ursula-F. Habenicht
Vol. 3 Excitatory Amino Acids and Second Messenger Systems Editors: V. I. Teichberg, L. Turski
Vol. 4 Spermatogenesis- Fertilization - Contraception Editors: E. Nieschlag, U.-F. Habenicht
Vol. 5 Sex Steroids and the Cardiovascular System Editors: P. Ramwell, G. Rubanyi, E. Schillinger
Vol. 6 Transgenic Animals as Model Systems for Human Diseases Editors: E. F. Wagner, F. Theuring
Vol. 7 Basic Mechanisms Controlling Term and Preterm Birth Editors: K. Chwalisz, R. E. Garfield
Vol. 8 Health Care 2010 Editors: C. Bezold, K. Knabner
Vol. 9 Sex Steroids and Bone Editors: R. Ziegler, J. Pfeilschifter, M. Brautigam
Vol. 10 Nongenotoxic Carcinogenesis Editors: A. Cockburn, L. Smith
Ernst Schering Research Foundation Workshop 10
Nongenotoxic Carcinogenesis A. Cockburn, L. Smith Editors
With 24 Figures
Springer-Verlag Berlin Heidelberg GmbH
ISBN 978-3-662-03024-0 ISBN 978-3-662-03022-6 (eBook) DOI 10.1007/978-3-662-03022-6
This work is subject to copyright. AII rights are reserved, whether the whole or part of the material is concemed, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law.
© Springer-Verlag Berlin Heidelberg 1994 Originally published by Springer-Verlag Berlin Heidelberg New York in 1994 Softcover reprint of the hardcover l st edition 1994
The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protecti ve laws and regulations and therefore free for general use.
Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature.
Typesetting: Data conversion by Springer-Verlag
21/3130--54321 0- Printed on acid-free paper
Preface
"What is a nongenotoxic carcinogen?" This question recurred throughout the Ernst Schering Research Foundation Workshop on nongenotoxic carcinogenesis, underlining the complexity of the topic. The clarity of the view that all carcinogens act by mutating DNA, originally advocated by Bruce Ames nearly 20 years ago, has been clouded by the increasing numbers of compounds which are not genotoxic but which nevertheless can cause cancer. There is an urgent need to increase our understanding of these compounds so that their risks can be evaluated realistically and decisions made from a position of knowledge and strength, rather than in fear of the unknown.
A nongenotoxic carcinogen can be defined as a compound which causes cancer, but which does not cause damage to DNA as its primary biological activity. This negative definition covers a range of carcinogens acting through a variety of mechanisms. Such chemicals often produce tumours only in a single organ species, and there are a few common locations which are affected most often. For example, in male rats, certain carcinogens bind to az11 globulin to form a complex which accumulates in the kidney tubular cells, which is followed by necrosis and compensatory cell proliferation leading the neoplasia. Other common mechanisms include hormonal imbalance resulting in thyroid tumours or peroxisome proliferation resulting in liver cancer. These and other examples are studied in some detail in the papers of this book.
Cancer is now widely thought to be a multistage process, and some of the stages of this process are examined, from DNA damage by the free radicals, through the progressive genetic and biochemical changes involved in the cells, to the influence of control mechanisms such as
VI Preface
growth factors and tumour suppressor genes, the interactions of genes with hormones, and the importance of inherited genetic susceptibility to certain cancers. A prime reason for studying nongenotoxic carcinogens is to enable sensible decisions to be made regarding their risks for humans. The majority of known human carcinogens are genotoxic, and it is relatively straightforward for this class of carcinogen to take steps to ensure human safety. For nongenotoxic carcinogens, in contrast, much more information is needed on issues such as species specificity, threshold effects, and mechanisms of action before rational, safe levels for humans can be set using appropriate safety margins. This has implications both for the design of studies to assess the hazards of chemicals and for the decisions made based on the results of these studies.
At the workshop communication was cultivated between scientists in different disciplines, helping to crystallise scientific opinion on this issue - which is critical to the introduction of new and useful chemicals without jeopardising human safety. We hope that the publication of this book will continue to stimulate discussion and debate on this crucial topic.
Andrew Cockburn Lewis Sinith Elaine Aggintin
Table of Contents
1 Nongenotoxic Chemical Carcinogens: Evidence for Multiple Mechanisms R. W. Tennant .......... . 1
2 Oxidative Damage and Carcinogenesis P. Amstad, R. Ghosh, G. Shah, Y. Oya, and P. Cerutti 17
3 DNA Damage by Free Radicals. Mechanism, Meaning and Measurement B. Halliwell . . . . . . . . . . . . . . .
4 U2u-Globulin Mediated Male Rat Kidney Carcinogenesis
31
J. A. Swenberg . . . . . . . . . . . . . . . . . . . . . 63
5 Nongenotoxic Mechanisms in Thyroid Carcinogenesis G. Thomas . . . . . . . . . . . . . . . . . . . . . . . 79
6 Nongenotoxic Carcinogenesis in the Liver R. Schulte-Hermann, W. Bursch, B. Grasl-Kraupp, W. Huber, and W. Parzefall . . . . . . . . . . . . . . . . . 109
7 Compensatory Cell Proliferation, Mitogen-Induced Liver Growth and Hepatocarcinogenesis in the Rat G. M. Ledda-Columbano and A. Columbano . . . . . . . . 121
VIII Table of Contents
8 The Role of Genotoxic and Nongenotoxic Agents in Multistage Carcinogenesis of Mouse Skin A. Balmain, C. J. Kemp, P. A. Burns, R. Bremner, S. Bryson, M. Clarke, S. Williamson and K. Brown . . . . . 141
9 Liver Tumor Promotion and Breast Cancer Chemoprevention: Common Mechanisms R. L. Jirtle . . . . . . . . . . . . . . . . .... 157
10 Peroxisome Proliferation and Hepatocarcinogenesis B. G. Lake ..................... .
11 Peroxisome Proliferators Mimic an Endogenous Inducer and Inactivate a Transcriptional Repressor in Bacillus megqterium
. . 173
N. English, V. Hughes, and C. R. Wolf . . . . . . . . . . 201
12 The Interaction of Genes and Hormones in Murine Hepatocarcinogenesis N. R. Drinkwater ....................... 219
13 Evaluating Carcinogenic Risks C. L. Berry ......... . 231
Subject Index 239
List of Contributors
P. Amstad Department of Carcinogenesis, Swiss Institute for Experimental Cancer Research, Ch. Boveresses 155, 1066 Epalinges/Lausanne, Switzerland
A. Balmain CRC Beatson Laboratories, Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 IBD, UK
C. L. Berry Department of Morbid Anatomy, The Royal London Hospital, London, E1 lBB, UK
R. Bremner The Hospital for Sick Children, 555 University Avenue, Toronto Ontario, M5G 1X8, Canada
K. Brown CRC Beatson Laboratories, Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 IBD, UK
S. Bryson CRC Beatson Laboratories, Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 lBD, UK
P. A. Burns Jack Birch Unit for Environmental Carcinogenesis, Department of Biology, University of York, Heslington, York YOI 5DD, UK
X List of Contributors
W. Bursch Institut ftir Tumorbiologie-Krebsforschung, Borschkegasse 8a, 1090 Wien, Austria
P. Cerutti Department of Carcinogenesis, Swiss Institute for Experimental Cancer Research, Ch. Boveresses 155, 1066 Epalinges/Lausanne, Switzerland
M. Clarke CRC Beatson Laboratories, Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 IBD, UK
A. Columbano lstituto di Patologia Sperimentale, School of Medicine, University of Cagliari, Cagliari, Italy
N. R. Drinkwater McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, 1400 University Avenue, Madison, WI 53706, USA
N. English Imperial Cancer Research Fund, Molecular Pharmacology Unit, Biomedical Research Centre, Ninewells Hospital & Medical School, Dundee DDI 9SY, Scotland, UK
R. Ghosh Department of Carcinogenesis, Swiss Institute for Experimental Cancer Research, Ch. Boveresses 155, 1066 Epalinges/Lausanne, Switzerland
B. Grasl-Kraupp lnstitut ftir Tumorbiologie-Krebsforschung, Borschkegasse 8a, 1090 Wien, Austria
B. Halliwell Pharmacology Group, King's College, Manresa Road, London SW3 6LX, UK
W.Huber lnstitut fi.ir Tumorbiologie-Krebsforschung, Borschkegasse 8a, 1090 Wien, Austria
List of Contributors
V. Hughes Imperial Cancer Research Fund, Molecular Pharmacology Unit, Biomedical Research Centre, Ninewells Hospital & Medical School, Dundee DDI 9SY, Scotland, UK
R. L. Jirtle Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, UK
C. J. Kemp CRC Beatson Laboratories, Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 IBD, UK
B. G. Lake BIBRA Toxicology International, Woodmansterne Road, Carshalton, Surrey SM5 4DS, UK
G. M. Ledda-Columbano
XI
Istituto di Patologia Sperimentale, School of Medicine, University of Cagliari, Cagliari, Italy
F. Oberhammer Institut fiir Tumorbiologie-Krebsforschung, Borschkegasse Sa, 1090 Wien, Austria
Y. Oya Department of Carcinogenesis, Swiss Institute for Experimental Cancer Research, Ch. Boveresses 155, 1066 Epalinges/Lausanne, Switzerland
W. Parzefall Institut fiir Tumorbiologie-Krebsforschung, Borschkegasse Sa, 1090 Wien, Austria
R. Schulte-Hermann Institut fi.ir Tumorbiologie-Krebsforschung, Borschkegasse Sa, 1090 Wien, Austria
G. Shah Department of Carcinogenesis, Swiss Institute for Experimental Cancer Research, Ch. Boveresses 155, 1066 Epalinges!Lausanne, Switzerland
XII List of Contributors
J. A. Swenberg Departments of Environmental Sciences and Engineering, Pathology
and Curriculum in Toxicology, The University of North Carolina at Chapel
Hill, Chapel Hill, NC 27599, USA
R. W. Tennant Chief, Laboratory of Environmental Carcinogenesis and Mutagenesis,
National Institute of Environmental Health Sciences, P.O. Box 12233,
Research Triangle Park, NC 27709, USA
G. Thomas Department of Histopathology, University of Cambridge, Addenbrooke's
Hospital, Hills Road, Cambridge CB2 2QQ, UK
S. Williamson CRC Beatson Laboratories, Beatson Institute for Cancer Research,
Garscube Estate, Switchback Road, Bearsden, Glasgow G61 IBD, UK
C. R. Wolf Imperial Cancer Research Fund, Molecular Pharmacology Unit, Biomedical Research Centre, Ninewells Hospital & Medical School, Dundee DDI 9SY, Scotland, UK