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

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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