Metal Compounds in Cancer Therapy

Metals in Health and Disease The inorganic elements account for less than 1 % of the atoms in the human body, yet they are vital constituents of many of the biochemical processes and physiological functions of living organisms. Metals and their compounds play many diverse roles in biological systems, both as structural and functional components. Biology has evolved homeostatic mechanisms for those metals which are essential for life. Many metals are toxic however, including excess quantities of those that are considered essential, and thus can be causative agents of disease. Conversely, inorganic compounds have been used as medicines since the earliest days of civilization. The therapeutic use of gold can be traced back to the Chinese in 2500 BC and mercury salts to Hippocrates in 400 Be. Erlich introduced metals into twentieth century medicine using the arsenical, salvarsan, for the treatment of syphilis. Inorganic pharmaceuticals, such as platinum, gold, lithium and bismuth compounds for the treatment of cancer, arthritis, depression and ulcers respectively, are now a major part of the modern pharmacopoeia.

This series will explore the multi-functional role of metals in health and disease. An integrated and multi-disciplinary approach is used to discuss the relevant biological activity of metals. Each volume will provide an in-depth study of a selected subject area, bringing together and evaluat­ing published data. The series is aimed primarily at graduates, post­graduates and researchers. It will be of interest to a wide variety of readers including toxicologists, pharmacologists, pharmaceutical and medicinal chemists, food scientists and nutritionists, veterinary scientists, clin­icians, biochemists and environmental and occupational health scien­tists.

Metal Compounds in Cancer Therapy

Edited by

Simon P. Fricker Johnson Matthey Technology Centre

Reading UK

SPRINGER-SCIENCE+BUSINESS MEDIA, B.V.

First edition 1994

© 1994 Springer Science+Business Media Dordrecht Originally published by Chapman & Hall in 1994 Softcover reprint of the hardcover 18t edition 1994

Typeset in 10/12 pt Palatino by Type Study, Scarborough

ISBN 978-94-010-4545-2 ISBN 978-94-011-1252-9 (eBook) DOI 10.1007/978-94-011-1252-9

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(3 Printed on permanent acid-free text paper, manufactured in accordance with ANSIINISO Z39.48-1992 and ANSIINISO Z39.48-1984 (Permanence of Paper)

To my wife Meta

Contents

List of contributors xi Preface xlli

1 Introduction 1 Simon P. Fricker 1.1 The discovery of cisplatin 1 1.2 Cancer - the target 3 1.3 The role of metals in cancer therapy 10 1.4 The search for new drugs 15 1.5 The way forward 23

Appendix 25 References 27

2 Platinum anticancer drugs 32 Lloyd R. Kelland 2.1 Introduction 32 2.2 Platinum chemistry 32 2.3 Mechanism of action 33 2.4 Platinum pharmacology 36 2.5 Platinum toxicology 37 2.6 The clinical impact of platinum-based anticancer drugs 38 2.7 The search for new platinum-based anticancer drugs 39 2.8 Summary 41

References 41

3 Gold 46 C. Frank Shaw III 3.1 Introduction 46 3.2 Gold chemistry 47 3.3 Gold biochemistry and pharmacology 50 3.4 Antitumour activity of auranofin and analogues 52 3.5 [(J.-Bis(diphenylphosphine)ethane]digold species 56 3.6 Bis[I,2-bis(diphenylphosphino)ethane]gold(I) and

related complexes, [Au(P-Ph]+ 57 3.7 Gold complexes of known antitumour agents 58

Vlll Contents

3.8 Other active compounds 3.9 Cisplatin analogues 3.10 Conclusions

Acknowledgement References

59 59 60 61 61

4 Ruthenium compounds in cancer therapy 65 Gianni Sava 4.1 Introduction 65 4.2 Chemical properties relevant to tumour treatment 66 4.3 Effects on cancer growth 71 4.4 Conclusions 87

Acknowledgement 88 References 88

5 Rhodium, iridium and palladium compounds as experimental anticancer drugs 92 Robert G. Buckley 5.1 Introduction 92 5.2 Rhodium 94 5.3 Iridium 100 5.4 Palladium 100 5.5 Comments 105

References 105

6 Organometallic titanium, vanadium, niobium, molybdenum and rhenium complexes - early transition metal anti tumour drugs 109 Petra Kopf-Maier and Hartmut Kopf 6.1 Introduction 109 6.2 Antitumour activity of titanocene and vanadocene

dichlorides, two neutral organometallic complexes of early transition metals 111

6.3 Antitumour activity of ionic titanocene complexes, another type of organometallic early transition metal compound 121

6.4 Toxicological and pharmacokinetic properties of neutral titanocene and vanadocene dichloride complexes 126

6.5 Phase I clinical trial with titanocene dichloride 136 6.6 Antitumour activity of ionic niobocene, molybdenocene

and rhenocene complexes, newly developed organometallic early transition metal complexes 138

6.7 Antitumour activity of inorganic bis(J3-diketonato)-titanium complexes in preclinical and phase I clinical ~~ ill

Contents IX

6.8 Summary and outlook 143 Acknowledgements 143 References 143

7 Antitumour activity of tin compounds 147 Alan J. Crowe 7.1 Introduction 147 7.2 Early anti tumour studies involving metal derivatives 150 7.3 Tin analogues of cisplatin 151 7.4 Other in vivo studies involving tin compounds 156 7.5 In vitro studies using tin derivatives 159 7.6 Mode of action 166 7.7 The use of tin derivatives in the photodynamic therapy

of cancer 168 7.8 Concluding remarks 171

Acknowledgements 172 References 172

8 Gallium compounds in cancer therapy 180 Philippe Callery 8.1 Introduction 180 8.2 In vitro studies 180 8.3 In vivo studies 185 8.4 Clinical studies 189

References 191

9 Bleomycin and metal interactions 198 John M. C. Gutteridge 9.1 Introduction 198 9.2 The activation of oxygen to reactive intermediates by

transition metal ions 200 9.3 Binding of metal ions to bleomycin 202 9.4 Binding of bleomycin to DNA 205 9.5 The antitumour activity of bleomycin 205 9.6 Bleomycin used as a biological tool to detect and measure

low molecular mass iron in body fluids 207 Acknowledgements 211 References 211

10 The in vivo use of metallic radioisotopes in cancer detection and imaging 215 D. J. Hnatowich 10.1 Introduction 215 10.2 Tumour imaging applications of simple chelates 218

x Contents

10.3 Tumour imaging and therapeutic applications of bifunctional chelates 221

10.4 Radioisotopes 223 10.5 Novel pretargeting approaches 236 10.6 Conclusions 241

References 241

Index 248

Contributors

Robert G. Buckley, Johnson Matthey Technology Centre, Blount's Court, Sonning Common, Reading, Berkshire, RG49NH, UK.

Philippe Collery, Departement des Maladies Respiratoire, Hopital Maison Blanche, Centre Hospitalier Universitaire, 51092 Reims Cedex, France.

Alan J. Crowe, International Tin Research Institute, Kingston Lane, Uxbridge, UK.

Simon P. Fricker, Johnson Matthey Technology Centre, Blount's Court, Sonning Common, Reading, Berkshire, RG49NH, UK.

John M. C. Gutteridge, Department of Anaesthesia and Intensive Care, Oxygen Chemistry Laboratory, Royal Brompton Hospital and National Heart and Lung Institute, Sydney Street, London, SW36NP, UK.

Donald J. Hnatowich, Department of Nuclear Medicine, University of Massachusetts Medical Center, Worcester, Massachusetts, USA.

Lloyd R. Kelland, Section of Drug Development, The Institute of Cancer Research, 15 Cotswold Road, Belmont, Sutton, Surrey, SM25NG, UK.

Hartmut Kopf, Institut fiir Anorganische und Analytische Chemie, Technische UniversWit Berlin, StrafSe des 17 Juni 135,0-10623 Berlin 12, Germany.

Petra Kopf-Maier, Institut fiir Anatomie, Freie Universitat Berlin, Konigen-Luise-StrafSe 15, 0-14195 Berlin 33, Germany.

Gianni Sava, Institute of Pharmacology and Pharmacognosy, School of Pharmacy, University of Trieste, via L. Giorgieri 7, 34127 Trieste, Italy.

C. Frank Shaw III, Department of Chemistry, The University of Wisconsin-Milwaukee, PO Box 413, Milwaukee, WI 53201, USA.

Preface

The discovery of the antitumour activity of cisplatin in 1965 and its subsequent introduction into clinical trials in 1971 was the catalyst for a major international research effort investigating the potential of metal compounds in cancer therapy. Cisplatin now occupies an important place in the armamentarium of the oncologist due to its effectiveness in the treatment of testicular cancer. A second generation analogue, carbo­platin, offers reduced toxicity together with therapeutic activity, which gives it a place in the front-line therapy of genitourinary cancers. These and other successes have encouraged the search for novel metal-based drugs for cancer therapy.

Research has shown that metal compounds have potential for activity not only as cytotoxic antitumour agents, but also in areas such as adjuvant therapy, diagnosis and immunotherapy. The aim of this book is to review and describe the major achievements and developments arising from this international research effort. The contributing authors come from labora­tories throughout Europe and America and represent the many disci­plines characteristic of this research, such as clinical research, pharmacology, tumour biology and inorganic medicinal chemistry.

Chapter 1 gives an overview of the field and sets it in the context of recent advances in tumour biology. The current clinical status of the platinum drugs cisplatin and carboplatin is described in Chapter 2, together with a review of recent research on new platinum compounds and current knowledge of the molecular mechanism of these powerful drugs. Gold compounds have a long history as pharmaceutical agents and Chapter 3 describes the major research effort into the evaluation of gold compounds for tumour therapy. The platinum group metals have been the focus of much attention. The potential for ruthenium is discussed in Chapter 4, in particular the unique antimetastatic properties of ruthenium dimethylsulphoxide complexes. To complete the picture, Chapter 5 gives a medicinal chemist's view of the properties of rhodium, iridium and palladium. Chapter 6 on the early transition metals describes the progression of a titanium compound, titanocene, from the experi­mental stage, through preclinical pharmacology and toxicology and into clinical trials. In discussing the work on tin complexes, Chapter 7 gives a comprehensive description of the medicinal chemistry process. Chapter 8

XIV Preface

reviews the biological properties of ionic gallium and describes recent clinical developments with gallium nitrate. Chapter 9 describes the biochemical mechanism for the metal-mediated antitumour activity of the antibiotic bleomycin. The exploitation of radionuclides presents a unique role for metals in the management of cancer and Chapter 10 completes the book by reviewing the in vivo use of metal radioisotopes for therapy and diagnosis.

The search for new and improved metal-based agents for cancer therapy is a vital and dynamic area of research. The platinum drugs are in the front line in the fight against cancer, with other metal-based agents undergoing clinical evaluation. The advances in tumour biology are motivating the development of novel agents with potentially unique modes of action. There are many exciting future possibilities for metal compounds in cancer therapy. It is hoped that this volume will appeal to all those with an interest in medical research and drug discovery, particularly pharmacologists, oncologists, tumour biologists and med­icinal chemists.

Simon P. Fricker