Cancer Chemotherapy

Preface xi About the Companion Website xiii 1 Cancer Epidemiology 1 1.1 Cancer Incidence and Mortality 1 1.2 Childhood Cancer 4 1.3 Global Epidemiology 5 1.4 Cancer Survival Rates 8 1.5 Summary and Conclusions 12 Further Reading 12 2 Cancer Histopathology 13 2.1 Cancer Morphology, Phenotype, and Nomenclature 14 2.2 Apoptosis 16 2.3 Necrosis 22 2.4 Autophagy and Others 23 2.5 Summary and Conclusions 24 Further Reading 25 3 Carcinogenesis 27 3.1 Initiation 27 3.2 Promotion 29 3.3 Progression and Environmental Carcinogenesis 30 3.4 Cell Cycle 31 3.5 Summary and Conclusions 33 Further Reading 33 4 Molecular Biology of Cancer 35 4.1 Oncogenes: Disruptors and Instigators 36 4.2 Cellular Oncogenes 39 4.3 Viral Oncogenes 41 4.4 Altered Oncogenic Products 42 4.5 Biological Carcinogens 44 4.6 Tumor Suppressor Genes 46 4.7 Familial Cancers and Cancer Syndromes 50 4.8 Summary and Conclusions 52 Further Reading 52 5 Cancer Metastasis 53 5.1 Detachment from the Primary Tumor 54 5.2 Migration of Cancer Cells from Primary Tumor 55 5.3 Intravasation of Tumor Cells into Vessels 57 5.4 Metastatic Transport 60 5.5 Extravasation 61 5.6 Growth of the Metastatic Tumor Mass 63 5.6.1 Cancer Dormancy 63 5.6.2 Extracellular Matrix of the Tumor Microenvironment 64 5.6.3 Seed and Soil 65 5.7 Summary and Conclusions 66 Further Reading 67 6 Health Professionals and Cancer Treatment 69 6.1 Pathology 69 6.2 Radiology 70 6.3 Biopsies 72 6.4 Surgical Treatment 73 6.5 Oncology Pharmacy 74 6.6 Oncology Nursing 75 6.7 Artificial Intelligence and Healthcare 75 6.8 Summary and Conclusions 75 Further Reading 76 7 Principles of Cancer Chemotherapy 77 7.1 Staging, Treatment, and Monitoring 77 7.2 General Types of Chemotherapy 79 7.3 Biomarker Uses and Limitations 82 7.4 Pharmacogenetics, Pharmacogenomics, Pharmacokinetics, Pharmacodynamics, and Personalized Medicine 86 7.5 Summary and Conclusions 87 Further Reading 88 8 Cytotoxic Compounds 89 8.1 Alkylating Agents 89 8.2 Intercalating Agents 94 8.3 Topoisomerase Blockers 104 8.4 Tubulin Disruptors 109 8.5 Summary and Conclusions 113 Further Reading 113 9 Antimetabolites and Hormonal Blockers 115 9.1 Nucleic Acid Analogs 115 9.2 Folate Analogs 118 9.3 Amino Acid Blockers 120 9.4 Hormone Modulators 121 9.5 Estrogen Antagonists 124 9.6 Aromatase Inhibitors 127 9.7 Antiandrogens 127 9.8 Endocrine Therapy 128 9.9 Summary and Conclusions 129 Further Reading 130 10 Cancer Research 131 10.1 Gel Electrophoresis Methods 131 10.2 Polymerase Chain Reaction 132 10.3 Molecular Cloning 133 10.4 Enzyme-Linked Immunosorbent Assay, Immunohistochemistry, and Immunofluorescence 134 10.5 Mass Spectroscopy and Proteomics 135 10.6 Genomics, Transcriptomics, and Metabolomics 136 10.7 Microarrays 137 10.8 Cell Culture and Exogenous Expression Strategies 138 10.9 Protein Expression and Targeting 141 10.9.1 Targeting RNA. 143 10.9.2 Targeting the Genome 145 10.10 Animal Models 147 10.11 Delivery Systems 149 10.12 Resources 151 10.13 Summary and Conclusions 152 Further Reading 153 11 Clinical Trials 155 11.1 Clinical Trial Design 158 11.2 Clinical Trials Governance and Quality Assurance 161 11.3 Clinical Trial Ethics 166 11.4 Clinical Trial Study Schema 168 11.5 Measurement of Clinical Endpoints, Response, and Outcomes 169 11.6 Local and National Organization of Clinical Trials 169 11.7 Summary and Conclusions 173 Further Reading 174 12 Tumor Hypoxia 175 12.1 Effects of Hypoxia on Chemotherapy 177 12.2 Energy Reprogramming and the Warburg Effect 178 12.3 Hypoxia-Inducible Factor 181 12.4 Lactate Dehydrogenase and Carbonic Anhydrase 183 12.5 Hypoxic Vascularization and Imaging 185 12.6 Bioreductive Drugs 189 12.7 Summary and Conclusions 192 Further Reading 192 13 Antiangiogenic and Antivascular Agents 193 13.1 History of Antiangiogenic Chemotherapy 193 13.2 Endogenous Integrin Blockers 195 13.3 Matrix Metalloproteinase Inhibitors 197 13.4 Synthetic Integrin Blockers 202 13.5 The Return of Thalidomide 204 13.6 Vascular Disrupting Agents 205 13.7 Antiangiogenic Antibodies 207 13.8 Summary and Conclusions 210 Further Reading 210 14 Protein Kinase and Ras Blockers 211 14.1 Signal Transduction 211 14.2 Receptor Tyrosine Kinase Blockers 214 14.3 Nonreceptor Tyrosine Kinase Blockers 216 14.4 Receptor Serine/Threonine Kinase Blockers 220 14.5 Nonreceptor Serine/Threonine and Multiple Kinase Blockers 223 14.6 Ras and PLC Blockers 226 14.7 Summary and Conclusions 228 Further Reading 228 15 Modulating Global Gene and Protein Expression 231 15.1 Stress Protein Inhibitors 231 15.2 Proteasome Inhibitors 234 15.3 Ubiquitin Ligase Inhibitors 237 15.4 Histone Deacetylase Inhibitors 238 15.5 DNA Methylation Inhibitors 241 15.6 Summary and Conclusions 242 Further Reading 243 16 Stem Cells – Telomerase, Wnt, Hedgehog, Notch, and Galectins 245 16.1 Telomerase Blockers 246 16.2 Wnt Blockers 250 16.3 Hedgehog Blockers 252 16.4 Notch Blockers 254 16.5 Galectin Blockers 257 16.6 Summary and Conclusions 258 Further Reading 258 17 Immunotherapy and Oncolytic Viruses 261 17.1 Immunization 264 17.2 Immune Checkpoint Blockers 266 17.3 Chimeric Antigen Receptor T-Cells 268 17.4 Oncolytic Viruses 270 17.5 Summary and Conclusions 275 Further Reading 275 18 Pharmaceutical Problems in Cancer Chemotherapy 277 18.1 Manifestation of Toxicity 277 18.2 Regimen-Related Toxicity 282 18.3 Secondary Malignancies 283 18.4 Drug Resistance 284 18.4.1 Multiple Drug Resistance 284 18.4.2 Enhanced DNA Repair 286 18.4.3 Alteration of Drug Targets 287 18.5 Pharmaceutical Complications 287 18.5.1 Extravasation 288 18.5.2 Local and National Extravasation Guidelines 290 18.6 Phlebitis and Venous Irritation 290 18.7 Health and Safety 291 18.8 National Guidance on the Safe Administration of Intrathecal Chemotherapy 291 Further Reading 292 Index 295