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

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

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

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

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

21 Representative Cancers, Treatment and Market 377
Teni Boulikas and Nassos Alevizopoulos

21.1 Lung Cancer 377

21.2 Breast Cancer 378

21.3 Prostate Cancer 378

21.4 Colorectal Cancer 379

21.5 Ovarian Cancer 380

21.6 Pancreatic Cancer 380

21.7 Gastric Cancer 381

21.8 Combination Chemotherapy 382

21.9 The Pharmaceutical World of Anticancer Drugs 383

22 Future Trends in Cancer Therapeutics 387
Sotiris Missailidis

22.1 Introduction 387

22.2 Personalized Medicines 388

22.3 Delivery Systems 390

22.4 Closing Remarks 391

Index 393