Cancer Chemotherapy Basic Science to the Clinic

Provides a clear and accessible summary of all stages and aspects of the discovery, design, development, validation and clinical use of anticancer drugs

This new edition provides an update on the current state of the art of cancer chemotherapy and clinical practice and presents new pipeline anticancer agents and promising therapeutic strategies that are emerging alongside new breakthroughs in cancer biology. Its unique approach enables students to gain an understanding of the pathological, physiological, and molecular processes governing malignancy, while also introducing the role of health professionals and scientists in the research and treatment of cancer.

Invaluable for its clarity and accessibility, Cancer Chemotherapy: Basic Science to the Clinic, 2nd Edition offers complete coverage of the scientific and clinical aspects of the creation, development, and administration of drugs or drug regimens used in the treatment of the disease. Chapters look at: cancer epidemiology and histopathology; carcinogenesis; current research; tumor hypoxia; antiangiogenic and antivascular agents; protein kinase and Ras blockers; new targets associated with development such as Hedgehog and Wnt signaling; stem cells; immunotherapy and oncolytic viruses; and more.

• Presents a clear, accessible, and comprehensive approach to cancer chemotherapy from basic science to clinical practice
• Offers a major update that reflects the latest developments in personalized chemotherapy
• Provides in-depth coverage of advances in biomarker diagnostics
• Includes new chapters/sections on bioinformatics and the ‘omic sciences’; pharmaceutical strategies used to achieve tumor-selective drug delivery; and cancer cell autophagy
• Combines descriptions of both clinical protocol and explanations of the drug design process in one self-contained book
• Features numerous diagrams and illustrations to enhance reader understanding

Aimed at upper undergraduate, graduate, and medical students, Cancer Chemotherapy: Basic Science to the Clinic, 2nd Edition is also an excellent reference for health professional, especially clinicians specializing in Clinical Oncology, and their patients who want to gain an understanding of cancer and available treatment options.

GARY S. GOLDBERG, PhD, is an Associate Professor at the School of Osteopathic Medicine, Rowan University, Stratford, NJ, USA.

RACHEL AIRLEY, MRes, PhD, MRPharmS, FHEA, is a Community Pharmacist and former Lecturer in Pharmacology and Cancer Sciences, Manchester, UK.

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

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