Table of Contents
Preface vii
Acknowledgments xi
1 Introduction 1
1.1 What is cancer? 2
1.2 Evidence suggests that cancer is a genetic disease at the cellular level 4
1.3 Influential factors in human carcinogenesis 9
1.4 Principles of conventional cancer therapies 12
1.5 Clinical trials 14
1.6 The role of molecular targets in cancer therapies 15
2 DNA structure and stability: mutations versus repair 21
2.1 Gene structure-two parts of a gene: the regulatory region and the coding region 22
2.2 Mutations 23
2.3 Carcinogenic agents 24
2.4 DNA repair and predispositions to cancer 36
Therapeutic strategies 39
2.5 Conventional therapies: chemotherapy and radiation therapy 39
3 Regulation of gene expression 47
3.1 Transcription factors and transcriptional regulation 47
3.2 Chromatin structure 54
3.3 Epigenetic regulation of transcription 55
3.4 Evidence of a role for epigenetics in carcinogenesis 58
3.5 Telomeres and telomerase 60
Therapeutic strategies 64
3.6 Epigenomic and histonomic drugs 64
3.7 Telomerase inhibitors 65
4 Growth factor signaling and oncogenes 69
4.1 Epidermal growth factor signaling: an important paradigm 70
4.2 Oncogenes 78
Therapeutic strategies 86
4.3 Kinase inhibitors 87
4.4 RAS-directed therapies 91
5 The cell cycle 95
5.1 Cyclins and cyclin-dependent kinases (cdks) 96
5.2 Mechanisms of cdk regulation 99
5.3 Progression through the G[subscript 1] checkpoint 101
5.4 The G[subscript 2] checkpoint 103
5.5 The mitotic checkpoint 104
5.6 The cell cycle and cancer 106
Therapeutic strategies 108
5.7 Cyclin-dependent kinase inhibitors 109
5.8 Other cell cycle kinase targets 109
5.9 Inhibitors of themitotic spindle 110
6 Growth inhibition and tumor suppressor genes 113
6.1 Definitions of tumor suppressor genes 113
6.2 The retinoblastoma gene 117
6.3 Mutations in the RB pathway and cancer 118
6.4 The p53 pathway 119
6.5 Mutations in the p53 pathway and cancer 127
6.6 Interaction of DNA viral protein products with RB and p53 129
Therapeutic strategies 130
6.7 Targeting of the p53 pathway 130
7 Apoptosis 137
7.1 Molecular mechanisms of apoptosis 139
7.2 Apoptosis and cancer 148
7.3 Apoptosis and chemotherapy 152
Therapeutic strategies 154
7.4 Apoptotic drugs 154
8 Stem cells and differentiation 161
8.1 Stem cells and cancer 162
8.2 Differentiation and the regulation of transcription 171
Therapeutic strategies 176
8.3 Inhibitors of the Wnt pathway 177
8.4 Inhibitors of the Hh pathway 178
8.5 Leukemia and differentiation therapies 180
9 Metastasis 185
9.1 Steps of metastasis 186
9.2 Tools of cell migration: cell adhesion molecules, integrins, and proteases 186
9.3 Intravasation 189
9.4 Transport 191
9.5 Extravasation 191
9.6 Metastatic colonization 192
9.7 The angiogenic switch 194
9.8 Parallels between early development and metastasis 199
9.9 Other means of tumor neovascularization 200
Therapeutic strategies 201
9.10 Metalloproteinase inhibitors (MPIs) 201
9.11 Anti-angiogenic therapy and vascular targeting 202
9.12 Targeting several steps of metastasis at once 207
10 Infections and inflammation 211
10.1 Identifying infectious agents as carcinogens 212
10.2 Inflammation and cancer 217
Therapeutic strategies 223
10.3 A national vaccination program against Hepatitis B virus in Taiwan 224
10.4 Eradication of H. pylori and the relationship to prevention of gastric cancer 225
10.5 Cancer vaccines to prevent cervical cancer 225
10.6 Inhibition of inflammation 227
11 Nutrients, hormones, and gene interactions 231
11.1 Causative factors 233
11.2 Preventative factors: microconstituents of fruits and vegetables 237
11.3 Metabolic changes in tumor cells 242
11.4 Genetic polymorphisms and diet 244
11.5 Vitamin D: a link between nutrients and hormone action 245
11.6 Hormones and cancer 247
Therapeutic strategies 251
11.7 'Enhanced' foods and dietary supplements for chemoprevention 251
11.8 Drugs that target energy pathways 252
11.9 Drugs that target estrogen 252
12 The cancer industry: drug development and clinical trial design 259
12.1 Strategies of drug development 259
12.2 Development of imatinib 263
12.3 Second-generation therapeutics 265
12.4 Pharmacogenomics 266
12.5 Improved clinical trial design 267
12.6 A career in cancer research 270
13 Cancer in the future: focus on diagnostics and immunotherapy 275
13.1 Cancer vaccines 276
13.2 Microarrays and expression profiling 283
13.3 Diagnostics and prognostics 285
13.4 Imaging 287
13.5 Cancer research bioinformatics 288
13.6 Cancer nanotechnology 289
13.7 Treating cancer symptoms 291
13.8 Are we making progress? 291
Appendix 1 Cell Cycle Regulation 297
Appendix 2 Centers for Cancer Research 298
Glossary 302
Index 311
Color Plates
