Anticancer Therapeutics

Written by the winner of the 2008 Mike Price Fellowship

"This volume provides a comprehensive overview of the wealth
of information now available in this important and fast-moving
subject." Anticancer Research, November - December
2008

This book provides a clear introduction to the area, with an
overview of the various drug design and development approaches for
cancer therapeutics and their progress in today's
multidisciplinary approach to cancer treatment.

Clearly structured throughout, the book not only provides
information on currently used molecular treatment approaches, but
also describes the various agents that are currently at various
stages of development and clinical trials, thus making them the
drugs of tomorrow.

The book goes on to present current therapeutic regimes
including their indications and side effects, as well as their
position in the international market in terms of sales and
development costs. Furthermore, coverage of our advancement in the
understanding of cancer biology and how this has driven the drug
discovery process is clearly discussed. Modern drug discovery
aspects, through genomic, proteomic and metabolomic approaches are
referred to as well as combinatorial chemistry techniques and
discovery of chemotherapeutic agents from plant extracts, re-use of
old drugs and drugs from other indications, or de novo
rational drug design.

Including contributions from leading experts in the field, this
book provides the reader with a complete overview of the various
types of therapeutic agents, current and emerging, as well as other
aspects associated with anticancer therapy, drug design, resistance
and clinical trials in oncology.

Autorentext
Dr Sotiris Missailidis. Department of Chemistry and Analytical Sciences, The Open University, Milton Keynes, UK.

Zusammenfassung
Written by the winner of the 2008 Mike Price Fellowship "This volume provides a comprehensive overview of the wealth of information now available in this important and fast-moving subject." Anticancer Research, November - December 2008

This book provides a clear introduction to the area, with an overview of the various drug design and development approaches for cancer therapeutics and their progress in today's multidisciplinary approach to cancer treatment.

Clearly structured throughout, the book not only provides information on currently used molecular treatment approaches, but also describes the various agents that are currently at various stages of development and clinical trials, thus making them the drugs of tomorrow.

The book goes on to present current therapeutic regimes including their indications and side effects, as well as their position in the international market in terms of sales and development costs. Furthermore, coverage of our advancement in the understanding of cancer biology and how this has driven the drug discovery process is clearly discussed. Modern drug discovery aspects, through genomic, proteomic and metabolomic approaches are referred to as well as combinatorial chemistry techniques and discovery of chemotherapeutic agents from plant extracts, re-use of old drugs and drugs from other indications, or de novo rational drug design.

Including contributions from leading experts in the field, this book provides the reader with a complete overview of the various types of therapeutic agents, current and emerging, as well as other aspects associated with anticancer therapy, drug design, resistance and clinical trials in oncology.

Inhalt

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

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 f...