Contents

Preface ix

Abbreviations xi

1. Introduction 1

1. Some General Remarks About Cancer and Cancer Chemotherapy 1

2. A Brief Account of the Role of Chemistry in Cancer Chemotherapy 3

3. Natural Products in Cancer Chemotherapy 5

4. A Brief Comment About Cancer Nanotechnology 6

5. Conclusion 7 References 7

2. Antimetabolites 9

1. Introduction 10

2. Inhibitors of the Biosynthesis of Uridylic Acid 10

3. Inhibitors of the Biosynthesis of 2'-Deoxyribonucleotides by

Ribonucleotide Reductase (RNR) 11

4. Inhibitors of the Biosynthesis of Thymidilic Acid 18

5. Inhibitors of Dihydrofolate Reductase (DHFR) 32

6. Inhibitors of the De Novo Purine Biosynthesis Pathway 36

7. Inhibitors of Adenosine Deaminase 42

8. Inhibitors of Late Stages in DNA Synthesis 45

9. Antimetabolite Enzymes 50 References 51

3. Anticancer Drugs That Inhibit Hormone Action 53

1. Introduction 54

2. Estrogens and Their Involvement in Carcinogenesis 54

3. Antiestrogens as Antitumor Drugs 58

4. Aromatase Inhibitors 65

5. Steroid Sulfatase Inhibitors 73

6. Androgen-Related Antitumor Agents 75

7. Regulation of Steroidal Hormone Synthesis as a Target for Antitumor Drugs 79

8. Miscellaneous Steroid Hormone-Related Anticancer Therapy 85

9. Compounds Acting on Other Proteins of the Nuclear Receptor Superfamily: Retinoids 86

References 90

4. Anticancer Drugs Acting via Radical Species, Photosensitizers and

Photodynamic Therapy of Cancer 93

1. Introduction: Radicals and Other Reactive Oxygen Species 93

2. Biological Effects of ROS 95

3. Anthracyclines and Their Analogs 102

4. Mitoxantrone and Related Quinones 112

5. Actinomycin D 114

6. Chartreusin, Elsamicin A, and Related Compounds 116

7. Bleomycins 116

8. Enediyne Antibiotics 122

9. Tirapazamine 126

10. Penclomedine 128

11. Radiosensitizers 129

12. Photodynamic Therapy of Cancer 132 References 135

5. DNA Alkylating Agents 139

1. Introduction 139

2. Nitrogen Mustards 141

3. Aziridines (Ethyleneimines) 154

4. Epoxides 158

5. Methanesulfonates 159

6. Nitrosoureas 160

7. Triazenes 165

8. Methylhydrazines 166

9. 1,3,5-Triazines: Hexamethylmelamine and Trimelamol 168

10. Platinum Complexes 169

11. Miscellaneous Alkylating and Acylating Antitumor Agents 173 References 174

6. Alkylating and Non-Alkylating Compounds Interacting with the

DNA Minor Groove 177

1. Introduction 177

2. Netropsin, Distamycin, and Related Compounds 178

3. Mitomycins 182

4. Tetrahydroisoquinoline Alkaloids 189

5. Cyclopropylindole Alkylating Agents 193

6. Pyrrolo[1,4]Benzodiazepines 195 References 196

7. DNA Intercalators and Topoisomerase Inhibitors 199

1. DNA Intercalation and Its Consequences 200

2. Monofunctional Intercalating Agents 201

3. Bifunctional Intercalating Agents 206

4. DNA Topoisomerases 209

5. Topoisomerase II Poisons 213

6. Topoisomerase II Catalytic Inhibitors 218

7. Specific Topoisomerase I Inhibitors 220 References 225

8. Anticancer Drugs Targeting Tubulin and Microtubules 229

1. Introduction 229

2. Drugs That Inhibit Microtubule Polymerization at High Concentrations 231

3. Microtubule-Stabilizing Agents: Compounds Binding at the Taxane Site 237

4. Miscellaneous Anticancer Drugs Acting on Novel Sites on Tubuline 245

5. Antivascular Effects of Microtubule-Targeted Agents 245

6. Mitotic Kinesin Inhibitors 246 References 247

9. Drugs That Inhibit Signalling Pathways for Tumor Cell

Growth and Proliferation 251

1. Introduction: The Role of Protein Kinases in Cancer 252

2. Signalling Pathways Related to Kinases 254

3. Inhibitors of Tyrosine Kinases (TKs) 254

4. Inhibitors of Serine-Threonine Kinases 275

5. Inhibitors of the RAS-RAF-MEK Signalling Pathway and Farnesyl Transferase 286

6. Inhibitors of Farnesyldiphosphate Synthase and Geranylgeranyldiphosphate Synthase 295

7. Anticancer Drugs Acting on Apoptotic Signalling Pathways 296

8. Inhibitors of Heat-Shock Proteins (HSP 90) 299 References 302

10. Other Approaches to Targeted Therapy 307

1. Proteasome Inhibitors 307

2. Antiangiogenic Agents Unrelated to Kinase Signaling 312

3. Epigenetic Therapy of Cancer 323

4. Inhibitors of Other DNA-Associated Enzymes 337

5. Therapy Directed at Other Targets 341 References 347

11. Drug Targeting in Anticancer Chemotherapy 351

1. Introduction 351

2. Prodrug-Based Anticancer Drug Targeting: Small-Molecule Prodrugs 352

3. Polymer-Protein Conjugates 368

4. Macromolecular Small-Drug Carrier Systems 369

5. Polymer-Directed Enzyme Prodrug Therapy (PDEPT) 377

6. Folate Receptor-Targeted Chemotherapy and Immunotherapy of Cancer 378

7. Liposomes and Nanoparticles in Anticancer Drug Targeting 380 References 383

12. Drugs That Modulate Resistance to Antitumor Agents 387

1. ATP-Binding Cassette Efflux Pumps in Anticancer Drug Resistance 388

2. Glutathione and Glutathione-S-Transferase in Anticancer Drug Resistance 397

3. Chemosensitizers Targeting DNA-Repair Systems 401

4. Antitumor Drug Resistance Related to Extracellular pH: Tumor-Associated Carbonic Anhydrase as an Anticancer Target 412

References 414

13. Cancer Chemoprevention 417

1. Introduction 417

2. Ligands for Nuclear Receptors in Cancer Chemoprevention 418

3. Anti-Inflammatory Agents and Antioxidants in Cancer Chemoprevention 421

4. Chromatin Modifiers in Cancer Chemoprevention 425

5. Miscellaneous Agents for Chemoprevention 426

6. Cancer Vaccines 428 References 428

Index 431

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