Anticancer Therapeutics Anticancer Therapeutics Edite d b y S otir is Missa ilidis © 2008 John Wiley & Sons, L td. ISBN: 978-0-470-72303-6 Anticancer Therapeutics Edited by Sotiris Missailidis The Open University, UK A John Wiley & Sons, Ltd., Publication This edition first published 2008 © 2008 by John Wiley & Sons, Ltd Wiley-Blackwell is an imprint of John Wiley & Sons, formed by the merger of Wiley’s global Scientific, Technical and Medical business with Blackwell Publishing. 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Antineoplastic agents. I. Missailidis, Sotiris. [DNLM: 1. Antineoplastic Agents – therapeutic use. 2. Drug Design. 3. Neoplasms – drug therapy. QZ 267 A6287 2008] RC271.C5.A6728 2008 616.9904061 – dc22 200802409 ISBN 978-0-470-72303-6 A catalogue record for this book is available from the British Library. Typeset in 10/12 Times by Laserwords Private Limited, Chennai, India Printed and bound in Singapore by Markono Pte. Ltd First printing 2008 To Mary and all those who may have benefited by these new drug developments Contents Forward xiii Acknowledgements xv List of contributors xvii SECTION I: Development of Anticancer Therapeutics 1 1 Exploring the Potential of Natural Products in Cancer Treatment 3 Fotini N. Lamari and Paul Cordopatis 1.1 Introduction 3 1.2 Sources 4 1.3 Different Approaches to the Search for Bioactive Natural Products 6 1.4 Methodologies of Lead Compound or New Drug Identification 10 1.5 Chemoprevention – A New Area for Natural Product Research 13 1.6 Concluding Remarks 13 2 Combinatorial Approaches to Anticancer Drug Design 17 Sotiris Missailidis 2.1 Introduction 17 2.2 Combinatorial Approaches for Small Molecule Drug Design 17 2.3 Display Technologies 21 2.4 Aptamer Selection 23 2.5 Conclusions 27 3 Rational Approaches to Anticancer Drug Design/in silico Drug Development 29 Stefano Alcaro, Anna Artese and Francesco Ortuso 3.1 Introduction 29 3.2 Approaches to the Drug Discovery Process in Anticancer Research 31 viii CONTENTS 3.3 Ligand-based Examples 32 3.4 Structure-based Examples 36 3.5 Conclusions 44 SECTION II: Anticancer Therapeutics 47 4 Introduction to Anticancer Therapeutics 49 Teni Boulikas 4.1 Problems in cancer 49 4.2 Cancer treatments 51 4.3 Classification of chemotherapy drugs 53 5 Platinum Drugs 55 Teni Boulikas, Alexandros Pantos, Evagelos Bellis and Petros Christofis 5.1 Cisplatin 55 5.2 Lipoplatin 57 5.3 Carboplatin 61 5.4 Oxaliplatin 62 5.5 Lipoxal 62 5.6 New Platinum Compounds 64 5.7 Cisplatin Resistance and Chemotherapy 70 6 Antimicrotubule Agents 79 Iain Brown, Jay N Sangrithi-Wallace and Andrew C Schofield 6.1 Taxanes 79 6.2 Vinca Alkaloids 82 6.3 Mechanisms of Resistance to Antimicrotubule Agents 86 7 Antimetabolites in Cancer Therapy 91 Jessica Scaife and David Kerr 7.1 Introduction 91 7.2 Folate Antagonists 92 7.3 Pyrimidine Antagonists 96 7.4 Purine Antagonists 104 7.5 Summary 109 8 Antitumour Antibiotics 111 Manuel M. Paz 8.1 Introduction 111 CONTENTS ix 8.2 Actinomycin 111 8.3 Mitomycin C 112 8.4 Bleomycin 115 8.5 Anthracyclines 118 8.6 Trabectedin (Ecteinascidin, ET-743) 121 8.7 Camptothecins 123 8.8 Podophyllotoxins 124 9 Alkylating Agents 133 Ana Paula Francisco, Maria de Jesus Perry, Rui Moreira and Eduarda Mendes 9.1 Introduction 133 9.2 Nitrogen Mustards 133 9.3 Methylmelamines and Ethylenimines 140 9.4 Methylhydrazine Derivatives 141 9.5 Alkylsulfonates 143 9.6 Nitrosoureas 144 9.7 Triazenes 149 10 Hormone Therapies 159 George C. Zografos, Nikolaos V. Michalopoulos and Flora Zagouri 10.1 Introduction 159 10.2 Oestrogen Receptor Targeted Therapeutics 160 10.3 Progesterone-Targeted Therapy 174 10.4 Neuroendocrine Tumours 176 11 Photodynamic Therapy of Cancer 187 K. Eszter Borbas and Dorothée Lahaye 11.1 Introduction 187 11.2 Photosensitizers 196 11.3 Outlook 212 11.4 Acknowledgement 212 12 Target-directed Drug Discovery 223 Tracey D. Bradshaw 12.1 Introduction 223 12.2 Tyrosine Kinases – Role and Significance in Cancer 226 12.3 Targeted Therapy for the Treatment of Non-small Cell Lung Cancer (NSCLC) 226 12.4 Targeted Therapy for the Treatment of Chronic Myeloid Leukaemia 229 12.5 Targeted Therapy for the Treatment of Breast Cancer 230 12.6 Angiogenesis 231 x CONTENTS 12.7 Targeting Cell Cycling 235 12.8 Targeting Apoptosis 237 12.9 Targeting mTOR 237 12.10 The Future of Molecularly Targeted Therapy 238 13 Tumour Hypoxia: Malignant Mediator 245 Jill L. O’Donnell, Aoife M. Shannon, David Bouchier-Hayes 13.1 Introduction 245 13.2 Hypoxia Inducible Factor-1 and Hypoxia 246 13.3 HIF-1α Post-translational Changes 247 13.4 How Genetics Can Modify HIF 248 13.5 How Tumours Overcome Hypoxia with HIF-1 249 13.6 HIF-1 Therapeutics 252 13.7 Conclusion 255 14 Resistance to Chemotherapy Drugs 263 Robert O’Connor and Laura Breen 14.1 Introduction 263 14.2 What are the Factors Limiting the Efficacy of Cancer Chemotherapy Treatment? 263 14.3 A Classification of the Important Chemotherapy Resistance Mechanisms 265 14.4 Illustrative Mechanisms of Pharmacokinetic Resistance 267 14.5 Illustrative Mechanisms of Pharmacodynamic Resistance 273 14.6 Conclusion 277 15 Cancer Immunotherapy 283 Maria Belimezi 15.1 The Molecular Basis of Cancer Immunotherapy and Gene Immunotherapy of Cancer 283 15.2 Recombinant Monoclonal Antibodies 284 15.3 Cell Immunotherapy 292 15.4 Cancer Vaccines 296 16 Gene Therapy 305 Maria Belimezi, Teni Boulikas and Michael L. Roberts 16.1 The Concept of Gene Therapy 305 16.2 Steps for Successful Gene Therapy 306 16.3 Retroviruses in Cancer Gene Therapy 307 16.4 Adenoviruses in Cancer Gene Therapy 308 16.5 Gene Therapy of Cancer 310 CONTENTS xi 16.6 Cancer Immunotherapy with Cytokine Genes 311 16.7 IL-12 in Cancer Immunotherapy 311 16.8 Viruses able to Kill Cancer Cells 314 17 Antisense Agents 317 Huma Khan and Sotiris Missailidis 17.1 Introduction 317 17.2 Traditional Antisense Oligonucleotides (ASOs) 318 17.3 Ribozymes and DNAzymes 320 17.4 RNA Interference and siRNAs 321 17.5 Shortcomings of Antisense Therapeutics 322 17.6 Antisense Agents in Clinical Trials 324 17.7 Concluding Remarks 329 18 Aptamers as Anticancer Agents 331 Vaidehi Makwana, Suzanne Simmons and Sotiris Missailidis 18.1 Introduction 331 18.2 Aptamers in Cancer 332 18.3 Final comments 341 SECTION III: Other Aspects in Anticancer Therapeutic Development 347 19 Treatment of Cancer in Conjunction with Other Agents 349 Gary Robert Smith 19.1 Introduction 349 19.2 Non-steroidal Anti-inflammatory Drugs 353 19.3 Angiotensin-converting Enzyme (ACE) Inhibitors and Angiotensin Receptor Blockade 358 19.4 Partners in Crime – Dealing with Co-infections 362 19.5 Discussion 363 20 Clinical Trials in Oncology 365 Tim Friede, Janet Dunn and Nigel Stallard 20.1 Clinical Trials 365 20.2 Early-Phase (Phase I and Phase II) Clinical Trials in Oncology 368 20.3 Confirmatory (Phase III) Trials in Oncology 371 20.4 Further Issues in Clinical Trials in Oncology 374