Vitamin D and Cancer (eBook)

Candace S. Johnson, Donald L. Trump (Herausgeber)

eBook Download: PDF

2010 | 2011
XI, 342 Seiten
Springer New York (Verlag)
978-1-4419-7188-3 (ISBN)

Infos

Substantial data indicate the broad importance of vitamin D-based signaling in normal human physiology and the broad effects of vitamin D deficiency. Vitamin D may play a role not only in the control of bone and mineral metabolism, but also appears to be involved in immune function, cardiovascular health, thrombosis and vasculogenesis and neuromuscular function. Considerable epidemiologic data demonstrate that low vitamin D serum levels occur very commonly in normal adult populations and that vitamin D deficiency is associated with an enhanced risk of cancer death from lung, prostate, head & neck, colorectal and other gastrointestinal cancers. In addition, preclinical data provide evidence that calcitriol and other active analogues of calcitriol have anti-proliferative, pro-differentiative, pro-apoptotic and anti-angiogenic activity in numerous in-vitro and in-vivo models. It is quite clear that, while it requires high exposure to calcitriol to induce these effects, such exposure can be readily achieved when high dose intermittent therapy is given.

Inhalt

Vitamin D and Cancer 3
Preface 5
Vitamin D Analogues as Antineoplastics: A Prologue Long Overdue? 5
Contents 7
Contributors 9
Chapter 1: Vitamin D: Synthesis and Catabolism – Considerations for Cancer Causation and Therapy 13
1.1 Introduction 14
1.1.1 1,25-(OH)2D3 Synthesis 15
1.2 Regulation of 1,25-(OH)2D3 Synthesis in Extrarenal Cells 16
1.2.1 Expression of CYP27B1 and of VDR During Hyperproliferation and Tumor Progression 17
1.2.2 Expression of CYP24A1 During Hyperproliferation and Tumor Progression 18
1.2.3 Regulation of CYP27B1 and CYP24A1 Expression by Sex Hormones 19
1.2.4 Regulation of CYP27B1 and of CYP24A1 Expression by Splicing Mechanisms and Polymorphisms 21
1.2.5 Epigenetic Regulation of CYP27B1 and of CYP24A1 Expression 22
1.3 Regulation of CYP27B1 and of CYP24A1 Expression by Nutrition 25
1.3.1 Regulation of Vitamin D Metabolism in the Gut Mucosa by Calcium 25
1.3.2 Regulation of the Vitamin D System by Phytoestrogens 26
1.3.3 Effect of Folate on CYP24A1 Expression 27
1.4 Can Regulation of Vitamin D Hydroxylases Be Implemented for Therapy? 28
1.5 Conclusion 29
References 30
Chapter 2: The Molecular Cancer Biology of the VDR 37
2.1 Choreography of VDR Signaling 38
2.1.1 General Findings for VDR Transcriptional Actions 38
2.1.2 VDR Signal Specificity 40
2.1.3 Vitamin D Response Elements 42
2.2 Integrated VDR Actions 44
2.2.1 Lessons from Murine Models 44
2.2.2 Self-renewing Epithelial Systems 45
2.3 VDR Transcriptional Networks in Malignancy 46
2.3.1 Cell Cycle Arrest 47
2.3.2 Sensing DNA Damage 48
2.3.3 Programmed Cell Death 49
2.4 Mechanisms of Resistance Toward the VDR 50
2.4.1 Reduced Local Availability of 1a,25(OH)2D3 50
2.4.2 Dominant Signal Transduction Events 50
2.4.3 Genetic Resistance 51
2.4.4 Epigenetic Resistance 52
2.5 Toward an Integrated Understanding of the VDR 53
References 55
Chapter 3: Anti-inflammatory Activity of Calcitriol in Cancer 65
3.1 Introduction 66
3.2 Inflammation and Cancer 66
3.3 Anti-inflammatory Effects of Calcitriol 67
3.3.1 Regulation of Prostaglandin Metabolism and Signaling 67
3.3.1.1 COX-2 68
3.3.1.2 15-PGDH 69
3.3.1.3 PG Receptors 69
3.3.1.4 Calcitriol Effects on the PG Pathway in Prostate Cells 70
3.3.1.5 Combination of Calcitriol and NSAIDs as a Therapeutic Approach in PCa 70
3.3.2 Induction of MKP5 and Inhibition of Stress-Activated Kinase Signaling 72
3.3.3 Inhibition of NFkB Activation and Signaling 73
3.4 The Role of Anti-inflammatory Effects of Calcitriol in Cancer Prevention and Treatment 75
3.4.1 Calcitriol and Prostate Cancer Chemoprevention 75
3.5 Summary and Conclusions 76
References 76
Chapter 4: The Epidemiology of Vitamin D and Cancer Risk 84
4.1 Introduction 85
4.2 Overview of Study Designs 86
4.2.1 Prospective Studies of Circulating 25(OH) Vitamin D and Cancer Risk 86
4.2.2 Studies of Vitamin D Intake 86
4.2.3 Studies of Predicted 25(OH)D Level 87
4.2.4 Case–Control and Cohort Studies of Sun Exposure 88
4.2.5 Randomized Trials 88
4.3 Colorectal Cancer 89
4.3.1 25(OH)D Level 89
4.3.2 Predicted 25(OH)D Level 90
4.3.3 Dietary Intake 90
4.3.4 Sun Exposure 91
4.3.5 Vitamin D and Colorectal Adenoma 91
4.3.6 Randomized Controlled Trial 92
4.4 Prostate Cancer 92
4.4.1 25(OH) Vitamin D 92
4.4.2 Predicted 25(OH)D Level 93
4.4.3 Vitamin D Intake 93
4.4.4 Sun Exposure 93
4.5 Breast Cancer 95
4.5.1 25(OH)D Level 95
4.5.2 Vitamin D Intake 95
4.5.3 Sun Exposure 96
4.6 Pancreatic Cancer 97
4.6.1 25(OH)D Level 97
4.6.2 Predicted 25(OH)D 97
4.6.3 Vitamin D Intake 97
4.7 Ovarian Cancer 98
4.7.1 25(OH)D Level 98
4.7.2 Sun Exposure 98
4.8 Esophageal and Gastric Cancers 98
4.8.1 25(OH)D Level 98
4.9 Non-Hodgkin Lymphoma 99
4.9.1 Sun Exposure 99
4.10 Total Cancer 100
4.10.1 Circulating 25(OH)D 100
4.10.2 Predicted 25(OH)D 101
4.10.3 Randomized Trials (RCT) 101
4.11 Summary 102
References 103
Chapter 5: Vitamin D and Angiogenesis 109
5.1 Overview of Angiogenesis 110
5.1.1 Angiogenesis Process 110
5.1.2 Endogenous Activators and Inhibitors 111
5.1.3 Therapeutic Angiogenesis Inhibitors 112
5.2 Vitamin D Effects on Angiogenesis 113
5.2.1 VDR Expression in Cells of Vasculature 113
5.2.2 Effect on Endothelial Cells 113
5.2.3 Effect on Angiogenesis Models 114
5.2.4 Potential Mechanisms for the Effects of Vitamin D on Angiogenesis 115
5.2.5 Effect on VSMC 116
References 117
Chapter 6: Vitamin D: Cardiovascular Function and Disease 125
6.1 Introduction 126
6.2 1950s to 1970s: Adverse Vascular Effects from Vitamin D 126
6.2.1 Vascular Lesions from Vitamin D Intoxication 126
6.2.2 Early Epidemiological Studies 128
6.2.2.1 Dietary Vitamin D and Cardiovascular Disease 128
6.2.2.2 25-Hydroxyvitamin D and Myocardial Infarction 129
6.2.2.3 25-Hydroxyvitamin D and Serum Cholesterol 130
6.3 1980s to 1990s: Vitamin D May Protect Against Cardiovascular Disease 130
6.3.1 Hypothesis 130
6.3.2 Animal Studies 131
6.3.3 Human Studies 132
6.3.3.1 Blood Pressure 132
6.3.3.2 Cardiac Function 133
6.3.3.3 Calcification 134
6.3.4 Summary 134
6.4 2000s: Increasing Evidence of a Beneficial Cardiovascular Effect 135
6.4.1 Studies in Hemodialysis Patients 135
6.4.2 Studies in Healthy Populations 136
6.4.2.1 Cardiovascular Disease 136
6.4.2.2 Blood Pressure 137
6.4.3 Studies of Vitamin D Supplementation 138
6.4.4 Cardiovascular Pathophysiology 139
6.4.4.1 Inflammatory Factors 139
6.4.4.2 Cardiovascular Function 141
6.4.5 Summary 141
References 142
Chapter 7: Induction of Differentiation in Cancer Cellsby Vitamin D: Recognition and Mechanisms* 153
7.1 Introduction 155
7.2 Solid Tumors 156
7.2.1 Colon Cancer 156
7.2.2 Breast Cancer 159
7.2.3 Prostate Cancer 160
7.2.4 Keratinocytes and Squamous Cell Carcinoma Cells 162
7.2.5 Osteosarcoma and Osteoblasts 164
7.3 Leukemias 165
7.3.1 Signaling of Monocytic Differentiation by MAPKand Parallel Pathways 167
7.3.2 p35/Cdk5, a Protein Kinase System That May Interface Differentiation Processes with Cell Cycle Arrest 170
7.3.2.1 Control of p35 Expression by the EGR-1 Transcription Factor 171
7.3.2.2 The Cdk5/p35 Complex Phosphorylates MEK 171
7.3.2.3 C/EBP B Transcription Factor as an Effector of Monocytic Differentiation 172
7.4 Conclusion 173
References 173
Chapter 8: Vitamin D and Cancer Chemoprevention 185
8.1 Introduction 186
8.2 Pre-clinical Studies 187
8.2.1 Colorectal Cancer 187
8.2.2 Prostate Cancer 189
8.2.3 Breast Cancer 190
8.2.4 Lung Cancer 192
8.2.5 All Other Cancers 193
8.2.6 Summary 194
8.3 Clinical Prevention Trials 194
8.3.1 Results from the Women’s Health Initiative 195
8.3.2 Colon Cancer Prevention 196
8.3.3 On-going Clinical Trials 197
References 197
Chapter 9: Molecular Biology of Vitamin D Metabolism and Skin Cancer 200
9.1 Introduction 202
9.2 The Induction of Skin Cancer by UV Radiation 204
9.3 The Vitamin D3 Metabolic Pathway and Its Actions 204
9.3.1 UV Radiation Induced Vitamin D3 Synthesis in the Skin 204
9.3.2 Genomic Actions of 1,25-Dihydroxyvitamin D3 205
9.3.3 Non-genomic Actions of 1,25-Dihydroxyvitamin D3 207
9.3.4 Classical Roles of 1,25-Dihydroxyvitamin D3 208
9.4 Epidemiological Evidence on the Relationship of Sun exposure and Cancer 210
9.4.1 Epidemiologic Evidence on the Roleof 1,25-Dihydroxyvitamin D3 in Skin Cancer 210
9.4.2 Polymorphisms of the Vitamin D Receptor 212
9.5 Vitamin D and Skin Cancer 213
9.5.1 The Role and Expression of 1,25-Dihydroxyvitamin D3 in Extra Renal Sites 213
9.5.2 The Role of 1,25-Dihydroxyvitamin D3 in Normal Skin 214
9.5.3 The Role of Vitamin D in Regulating Proliferationand Differentiation in Skin Cancer 215
9.5.4 The Role of Vitamin D in Photoprotection 216
9.5.5 Vitamin D Analogs as Potential Agent for Skin Cancer Prevention 218
9.6 Future Perspectives: Current Controversies on Sun Exposure and Vitamin D Recommendations 218
References 221
Chapter 10: Vitamin D and Prostate Cancer 229
10.1 Introduction 230
10.2 Vitamin D Physiology 230
10.3 The Biologic Activity of Vitamin D in Prostate Cancer 231
10.4 Mechanisms of Anti-neoplastic Activity 232
10.5 Epidemiology 234
10.5.1 UV Exposure and Prostate Cancer Risk 234
10.5.2 Dietary Vitamin D and Calcium Intake and Prostate Cancer Risk 235
10.5.3 Vitamin D Blood Levels and the Risk of Prostate Cancer 237
10.6 Therapeutic Applications of Vitamin D 239
10.6.1 Vitamin D in Combination with Other Antineoplastic Agents in Preclinical Models 239
10.6.1.1 Steroids 240
10.6.1.2 Cytotoxic Chemotherapy 240
10.6.1.3 Retinoid Receptor Ligands 240
10.6.1.4 Tamoxifen 240
10.6.1.5 Non-steroidal Anti-inflammatory Agents (NSAIDS) 241
10.6.1.6 Radiation 241
10.6.2 Clinical Trials of Calcitriol in Prostate Cancer 241
10.6.2.1 Phase I Studies of Single Agent Calcitriol 241
Daily Administration 241
Every Other Day Subcutaneous Administration 242
Weekly Oral Dosing 242
10.6.2.2 Early Stage Studies of Calcitriol in Combination with Other Agents 242
Daily Administration 242
Dosing 3 of Every 7 Days 243
Intravenous Calcitriol 243
10.6.2.3 Phase II Studies 243
Weekly Dosing 243
Less Frequent Dosing 245
10.6.2.4 Phase III Studies 247
10.6.3 Clinical Trials of Calcitriol Analogs in Prostate Cancer 248
References 249
Chapter 11: Vitamin D and Hematologic Malignancies 258
11.1 Overview of Hematopoiesis 258
11.2 Vitamin D Receptors in Blood Cells 260
11.2.1 Vitamin D Receptors in Myeloid Cells 260
11.2.2 Vitamin D Receptors in Lymphoid Cells 261
11.2.3 Hematopoiesis in VDR Knockout Mice 262
11.3 Effects of Vitamin D Compounds on Normal Hematopoiesis 262
11.4 Effects of Vitamin D Compounds on Leukemic Cells 263
11.4.1 Cellular Effects of Vitamin D Compounds on Leukemic Cells 263
11.4.2 Molecular Mechanisms of Action of Vitamin D Compounds Against Leukemic Cells 265
11.4.2.1 Molecular Mechanisms of Genomic Action of 1,25(OH)2D3 in Leukemic Cells 265
11.4.2.2 Molecular Mechanisms of Kinase Activities of 1,25(OH)2D3 in Leukemic Cells 268
11.4.3 Vitamin D Compounds in Combination with Other Agents 269
11.5 Vitamin D Analogs Effective against Leukemic Cells 271
11.6 Summary and Conclusions 275
References 276
Chapter 12: The Vitamin D Signaling Pathway in Mammary Gland and Breast Cancer 286
12.1 Introduction to Vitamin D and Breast Cancer 287
12.2 Vitamin D and Breast Cancer Links in Populations 288
12.2.1 Diet, Sunlight Exposure and Breast Cancer Risk 288
12.2.2 Serum 25-Hydroxyvitamin D and Breast Cancer Risk 288
12.2.3 Prevalence of Vitamin D Insufficiency 289
12.3 Mechanistic Links Between Vitamin D and Breast Cancer 290
12.3.1 General Effects of VDR Agonists in Breast Cancer Cells 290
12.3.2 Cellular and Molecular Targets of VDR in Breast Cancer Cells 290
12.3.3 Emerging Role of Vitamin D in Cellular Stress Responses 291
12.3.4 Preclinical Studies of VDR Agonists in Animal Models of Breast Cancer 291
12.4 Evidence for Breast Cancer Prevention by Vitamin D 292
12.4.1 VDR Expression in Normal Mammary Cells 292
12.4.2 Vitamin D Metabolites Mediate Growth Inhibition in Normal Mammary Cells 292
12.4.3 Prevention of Mammary Carcinogenesis by VDR Agonists in Animal Models 293
12.5 Mammary Gland Development and Carcinogenesis in VDR Null Mice 294
12.6 Vitamin D Resistance Pathways 295
12.7 Conclusions and Directions for Future Research 296
References 297
Chapter 13: Vitamin D and Colorectal Cancer 301
13.1 Epidemiology of Vitamin D and Colorectal Cancer 301
13.1.1 Sunlight and Colorectal Cancer 301
13.1.2 Vitamin D Status and Risk of Colorectal Neoplasia 302
13.1.2.1 Vitamin D Metabolism 302
13.1.2.2 Assessment of Vitamin D3 Status 303
13.1.2.3 Vitamin D Status and Adenomatous Polyps 306
13.1.2.4 Vitamin D Status and Colorectal Cancer 307
13.1.2.5 Vitamin D Intake and the Risk of Colorectal Cancer 309
13.1.2.6 Vitamin D Receptor Polymorphism and Colorectal Cancer 310
13.2 Colorectal Cancer Prevention with Vitamin D Supplementation 311
13.2.1 Pathological Basis for Vitamin D Supplementation 311
13.2.2 Clinical Studies with Vitamin D Supplementation 312
13.3 Vitamin D Status in Advanced Colorectal Cancer 313
13.4 Vitamin D Status and Colorectal Cancer Outcome 314
13.5 Vitamin D Replacement Strategies and Recommended Dosing in Colorectal Cancer 314
References 315
Chapter 14: Unique Features of the Enzyme Kinetics for the Vitamin D System, and the Implications for Cancer Prevention and Therapeutics 320
14.1 Introduction 320
14.1.1 Relationship Between Vitamin D and Prostate Cancer 321
14.2 Vitamin D Hydroxylase Enzyme Kinetics 322
14.2.1 Vitamin D Metabolism and Points of Regulation 323
14.2.2 Vitamin D Cellular Adaptation 325
14.2.3 Vitamin D Modulation of Hydroxylases 325
14.3 Vitamin D and Cancer Risk: Sun Exposure and Levels of 25(OH)D 325
14.3.1 Adaptation of Vitamin D Hydroxylases and Cancer Risk 327
14.4 Vitamin D Hypothesis for Cancer Prevention 327
14.4.1 Implications of the Model 327
References 328
Chapter 15: Assessment of Vitamin D Status in the 21st Century 332
15.1 Introduction 333
15.2 Vitamin D Structure and Chemistry 333
15.3 Methods of 25(OH)D Quantitation 334
15.3.1 Competitive Protein-Binding Assay 334
15.3.2 Radioimmunoassay 335
15.3.3 Random-Access Automated Instrumentation 336
15.3.4 Direct Physical Detection Methods 337
15.4 Clinical Reporting of Circulating 25(OH)D Concentrations 337
15.5 Methods of 1,25(OH)2D Quantitation 339
15.5.1 Radioreceptor Assay 339
15.5.2 Radioimmunoassay 340
References 340
Index 344

Produkt-Details

• Erscheint lt. Verlag: 9.12.2010
• Zusatzinfo: XI, 342 p.
• Verlagsort: New York
• Sprache: englisch
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Onkologie
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Pharmakologie / Pharmakotherapie
• Themenwelt: Studium ► 1. Studienabschnitt (Vorklinik) ► Biochemie / Molekularbiologie
• Themenwelt: Naturwissenschaften ► Biologie
• Themenwelt: Technik
• Schlagworte: Cancer • Cancer Research • Candace Johnson • D • Donald Trump • Vitamin D
• ISBN-10: 1-4419-7188-2 / 1441971882
• ISBN-13: 978-1-4419-7188-3 / 9781441971883