Chemoprevention of cancer and DNA damage by dietary factors:
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| Format: | Buch |
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2009
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| Beschreibung: | Literaturangaben |
| Beschreibung: | XLVIII, 787 S. Ill., graph. Darst. 25 cm |
| ISBN: | 9783527320585 352732058X |
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| 245 | 1 | 0 | |a Chemoprevention of cancer and DNA damage by dietary factors |c ed. by Siegfried Knasmüller ... |
| 264 | 1 | |a Weinheim |b Wiley-VCH |c 2009 | |
| 300 | |a XLVIII, 787 S. |b Ill., graph. Darst. |c 25 cm | ||
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| 500 | |a Literaturangaben | ||
| 650 | 4 | |a Anticarcinogenic Agents | |
| 650 | 4 | |a Cancer |x Chemoprevention | |
| 650 | 4 | |a Cancer |x Diet therapy | |
| 650 | 4 | |a Chemoprevention |x methods | |
| 650 | 4 | |a DNA Damage | |
| 650 | 4 | |a Diet Therapy | |
| 650 | 4 | |a Micronutrients |x therapeutic use | |
| 650 | 4 | |a Neoplasms |x drug therapy | |
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Datensatz im Suchindex
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Titel: Chemoprevention of cancer and DNA damage by dietary factors
Autor: Knasmüller, Siegfried
Jahr: 2009
V
Contents
Preface XXVII
Foreword: Prevention of Cancer, and the Other Degenerative
Diseases of Aging, Through Nutrition XXXI
Bruce N. Ames and Joyce C. McCann
List of Contributors XXXIX
Part One General Principles 1
1 Molecular Mechanisms of Cancer Induction and Chemoprevention 3
Helmut Bartsch and Clarissa Cerhauser
1.1 Cancer Chemoprevention 3
1.2 Molecular Mechanisms and Targets of Chemopreventive Agents 4
1.2.1 Carcinogen-Blocking Activities 5
1.2.2 Antimutagenic Effects and DNA Repair 5
1.2.3 Targeting Epigenetic Mechanisms 6
1.2.4 Radical-Scavenging and Antioxidant Effects 7
1.2.5 Anti-Inflammatory Mechanisms 8
1.2.6 Antitumor Promoting Activities 9
1.2.7 Antiproliferative Mechanisms 11
1.2.8 Induction of Apoptosis and Terminal Cell Differentiation 12
1.2.9 Inhibition of Angiogenesis (Angioprevention) 13
1.3 Perspectives 15
1.4 Conclusion 16
References 17
2 Types and Consequences of DNA Damage 21
Daniel T. Shaughnessy and David M. DeMarini
2.1 Introduction 21
Chemoprevention of Cancer and DNA Damage by Dietary Factors.
Edited by Siegfried Knasmiiller, David M. DeMarini, Ian Johnson, and Clarissa Gerhauser
Copyright © 2009 WILEY-VCH Verlag GmbH Co. KGaA, Weinheim
ISBN: 978-3-527-32058-5
VI Contents
2.2 Types of DNA Damage 22
2.3 How to Detect DNA Damage Experimentally 24
2.4 DNA Damage Response 26
2.5 Types of DNA Repair 27
2.5.1 Direct DNA Repair 27
2.5.2 Base Excision Repair 27
2.5.3 Nucleotide Excision Repair 28
2.5.4 Mismatch Repair 29
2.5.5 Homologous and Nonhomologous Recombination
for Repair of Double-Strand Breaks 29
2.5.6 DNA Damage Tolerance: SOS Repair and Trans-Lesion Synthesis 30
2.6 Types of Mutations 31
2.7 Assays to Detect Mutagens 31
2.8 Implications for Chemoprevenrion 32
References 32
3 Induction of DNA Damage and Cancer by Dietary Factors 35
Wolfram Parzefall, Nina Kager, and Siegfried Knasmuller
3.1 Introduction 35
3.2 Nitrosamines 35
3.3 Heterocyclic Aromatic Amines 37
3.4 Polycyclic Aromatic Hydrocarbons 40
3.5 Other Thermal Degradation Products 42
3.6 Mycotoxins 46
3.7 Carcinogens in Plant Foods 49
3.8 Food Additives and Pesticides/Herbicide Residues 49
3.9 Human Cancer Risks of Food Specific Carcinogens 50
References 52
4 Mechanisms of Chemoprevention, Antimutagenesis, and
Anticarcinogenesis: An Overview 57
Silvio De Flora, Carlo Bennicelli, Alessandra Battistella, and
Maria Bagnasco
4.1 Antimutagenesis and Anticarcinogenesis 57
4.2 Strategies for Preventing Cancer and Other Mutation-Related
Diseases 57
4.3 Classification of Mechanisms of Chemopreventive Agents 59
4.4 Overview of Mechanisms of Inhibitors of Mutagenesis and
Carcinogenesis 60
4.4.1 Extracellular Mechanisms 60
4.4.1.1 Inhibition of Uptake 60
4.4.1.2 Inhibition of Endogenous Formation 60
4.4.1.3 Complexation, Dilution, and Deactivation 61
4.4.2 Inhibition of Genotoxic Damage and Cancer Initiation 61
4.4.2.1 Modulation of Metabolism 61
Contents VII
4.4.2.2 Nucleophilicity 62
4.4.2.3 Antioxidant Mechanisms 62
4.4.2 A Inhibition of Cell Replication 62
4.4.2.5 Maintenance of DNA Structure and Modulation
of its Metabolism and Repair 63
4.4.2.6 Control of Gene Expression 63
4.4.3 Inhibition of Tumor Promotion 64
4.4.3.1 Anti-Inflammatory Activity 64
4.4.3.2 Signal Transduction Modulation 64
4.4.3.3 Protection of Gap Junctional Intercellular Communications (GJIC) 64
4.4.3.4 Induction of Cell Differentiation 65
4.4.3.5 Modulation of Apoptosis 65
4.4.4 Inhibition of Tumor Progression 65
4.4.4.1 Inhibition of Angiogenesis 65
4.4.4.2 Modulation of the Hormonal Status 66
4.4.4.3 Effects on the Immune System 66
4.4.5 Inhibition of Invasion and Metastasis 66
4.5 Concluding Remarks 67
References 68
5 Antioxidants and Cancer: Fact and Fiction 73
Andrew R. Collins and Alain Favier
5.1 Introduction 73
5.2 Fruits and Vegetables: the Evidence 73
5.3 Oxidative Damage and Antioxidants 74
5.4 Large-Scale Intervention Studies with Antioxidants 75
5.4.1 The Iinxian Study 75
5.4.2 The Alpha-Tocopherol Beta-Carotene Trial in Finland 77
5.4.3 The Beta-Carotene and Retinol Efficiency Trial in the United States 77
5.4.4 The US Physicians Health Study 77
5.4.5 The MRC/BHF Heart Protection Study, United Kingdom 78
5.4.6 The SU.VI.MAX Study 78
5.4.7 Two Meta-Analyses 78
5.5 Using Surrogate Biomarkers for Disease Risk 79
5.5.1 Oxidation of Bases in DNA 79
5.5.2 Intervention Trials with Antioxidants, Using the Comet Assay
to Assess DNA Damage 84
5.6 Nonantioxidant Effects of Antioxidants 87
5.7 Conclusions 87
References 88
6 Xenobiotic Metabolism: A Target for Nutritional Chemoprevention
ofCancer? 93
Hansruedi Clatt
6.1 Xenobiotics and Their Disposition - Basal Aspects 93
VIII Contents
6.2 Classification of Biotransformation Reactions and Enzymes 95
6.2.1 Conventional Phase I/Phase 2 Concept 95
6.2.2 Toxicological Classification of Biotransformation Reactions 98
6.2.3 Chaos and Selection 99
6.2A Modified Phase I/Phase 2 Terms Used in the Chemoprevention
Area 100
6.2.5 Good and Bad Enzymes 101
6.3 Toxicokinetic Interactions Leading to Enhanced or Reduced
Effects of Carcinogens 102
6.3.1 Individual Known Carcinogens 102
6.3.2 Wide Sets of Identified and Unidentified Carcinogens 103
6.4 Conclusions 106
References 107
7 Dietary Factors Regulate Metabolism of Carcinogens through
Transcriptional Signaling Pathways 109
Soona Shin and Thomas W. Kensler
7.1 Introduction 109
7.2 Nrf2 110
7.2.1 Keapl-Mediated Regulation of Nrf2 112
7.2.2 Phosphorylation 113
7.2.2.1 Mitogen-Activated Protein Kinases 113
7.2.2.2 Protein Kinase C 114
7.2.2.3 CK2 114
7.3 Aryl Hydrocarbon Receptor 114
7.3.1 Regulation 115
7.4 Nuclear Receptors 116
7 A.I Regulation of the CAR Pathway 117
7.4.2 Regulation of the PXR Pathway 117
7.5 Conclusions 118
References 118
8 Endocrine-Related Cancers and Phytochemicals 121
Johannes C. Huber and Johannes Ott
8.1 Introduction 121
8.2 Phytoestrogens and Endocrine-Related Cancers - Epidemiological
Studies 122
8.2.1 Isoflavones and Breast Cancer 122
8.2.1.1 Isoflavones and the "Window of Opportunity" 122
8.2.1.2 Serum Isoflavones and Breast Cancer 122
8.2.2 Iignans and Breast Cancer 124
8.2.3 Phytoestrogens and Prostate Cancer 125
8.3 Mechanisms of Cancer Chemoprevention by Phytoestrogens 125
8.4 Estrogen Carcinogenesis 126
8.4.1 Estrogen Metabolites and Carcinogenesis 126
j
Contents IX
8.4.2 CYP1A1 129
8.4.2.1 Polymorphisms 129
8.4.2.2 Clinical Aspects of CYP1A1 Genotypes 130
8.4.2.3 Breast and CYP1A1 131
8.4.2.4 Pharmacogenomics and Phytochemicals 132
8.4.3 CYP1B1 133
8.4.3.1 Gene and Protein Structure of CYP1B1 133
8.4.3.2 Gene Regulation 133
8.4.3.3 Epigenetic Regulation 134
8.4.3.4 Polymorphisms 134
8.4.3.5 Breast Cancer 135
8.4.3.6 Endometrial Cancer 136
8.4.3.7 Pharmacogenomics and Phytochemicals 136
8.5 Conclusion 137
References 137
9 Inflammation-Induced Carcinogenesis and Chemoprevention 145
Hiroshi Ohshima, Susumu Tomono, Ying-Ling Lai, and
Noriyuki Miyoshi
9.1 Introduction 145
9.2 Prevention of Inflammation-Associated Cancer by Avoidance of
Causes of Tissue Damage 146
9.3 Chemoprevention by Modulating Inflammatory Processes 147
9.3.1 NF-kB 147
9.3.2 iNOS 148
9.3.3 COX-2 149
9.3.4 ROS-Generating Enzymes and Antioxidant Defense
Mechanisms 149
9.4 Conclusion 150
References 351
10 DNA Methylation 153
Ian T. Johnson, NigelJ. Belshaw, and Giles O. Elliott
10.1 Introduction 153
10.2 Effects of Diet on DNA Methylation 355
10.3 Impact of Environment and Nutrition on the Human
Epigenome 156
10.4 Modification of DNA Methylation by Nutrients and
Phytochemicals 157
10.4.1 Folates 157
10.4.2 Selenium 158
10.4.3 Polyphenols 159
10.4.4 Isothiocyanates 160
10.5 Conclusions 160
References 161
X Contents
11 Prevention of Angiogenesis and Metastasis 163
Tariq A. Bhat, Anil Mittal, and Rana P. Singh
11.1 Introduction 163
11.2 Angiogenesis 164
11.2.1 Angiogenesis Process 165
11.2.2 Tumor Angiogenesis 166
11.2.3 Angiopreventive Agents 166
11.2.4 Lymphangiogenesis 170
11.3 Metastasis 171
11.3.1 Basic Steps in Cancer Metastasis 172
11.3.2 Epithelial-Mesenchymal Transition in Metastasis 173
11.3.3 Invasion and Migration 174
11.3.4 Homing Mechanisms 175
11.3.5 Preventive Agents for Metastasis 177
11.4 Summary 177
References 178
12 Impact of Dietary Factors on the Immune System 183
Alexa L. Meyer
12.1 A Short Presentation of the Immune System 183
12.1.1 The First line of Defense 183
12.1.2 Adaptive Immunity 185
12.1.3 The Immune System in Cancerogenesis 185
12.1.4 Cancer - A Serious Opponent 186
12.2 The Role of Nutrition in Immunity 186
12.2.1 Fat and Fatty Acids: Their Role in Inflammation
and Beyond 186
12.2.2 Trace Elements 188
12.2.3 Vitamins 189
12.2.4 Nonnutritive Food Components 190
References 194
r
13 Epidemiological Studies 199
Anthony B. Miller
13.1 Introduction 199
13.2 Observational Epidemiology Studies: What Can We Learn
From Them? 200
13.3 What Are We Trying To Do with Chemoprevention? 201
13.4 How Will We Know If We Are Successful? 201
13.5 The Example of Beta-Carotene 202
13.6 Folk Acid 204
13.7 Other Micronutrients 205
13.8 Green Tea and Other Agents 206 '
13.9 Conclusions 207 :
References 207
r
i
I
I
i
Contents XI
Part Two Experimental Models and Methods Used in Chemoprevention
Studies 209
14 Methods Used for the Detection of Antimutagens: An Overview 211
Armen Nersesycm, Miroslav Misik, and Siegfried Knasmiiller
14.1 Introduction 211
14.2 Mechanisms of DNA Protection 212
14.3 Methodological Aspects 212
14.3.1 End Points Used in Antigenotoxicity Studies 212
14.3.2 In Vitro Approaches 224
14.3.3 In Vitro Systems 215
14.3.4 Human Biomonitoring Studies 218
14 A Limitations of the Predictive Value of Different Endpoints and
Test Systems 219
14.5 Specificity of Protection 220
14.6 Dose-Effect Relationships 221
14.7 Future Trends 222
References 222
15 Methods to Determine Total Antioxidative Capacity and Oxidative
DNA Damage 229
Karl-Heinz Wagner, Miroslav Misik, Armen Nersesyan, and
Siegfried Knasmuller
15.1 Introduction 229
15.2 Methods 229
15.2.1 Trapping of Reactive Species 229
15.2.2 Approaches to Determine the Total Antioxidant Capacity 230
15.2.3 Free Radical Quenching Methods 231
15.2.4 Single-Electron Transfer Methods 234
15.3 Oxidation of Macromolecules 235
15.3.1 Biomarkers of lipid Oxidation 235
15.3.2 Biomarkers of Protein Oxidation 238
15.4 Methods Used to Monitor Oxidative DNA Damage 239
15.4.1 In Vitro and In Vivo Approaches 240
15.5 Conclusions and Outlook 241
References 241
16 Measurement of Enzymes of Xenobiotic Metabolism in
Chemoprevention Research 245
Wolfgang W. Huber and Michael Grusch
16.1 Introduction 245
16.2 Important Enzymes of Xenobiotic Metabolism in Cancer
Chemoprevention Research 246
16.3 Measurement of Xenobiotic Metabolism: General
Aspects 247
XII Contents
16.3.1 Determination of Enzyme Encoding genes (Investigation at
DNA Level) 249
16.3.2 Determination of Enzyme Transcription (Investigation at
RNA Level) 249
16.3.3 Determination of Enzyme Protein 250
16.3.3.1 Measurement of Enzyme Activity: General Aspects 252
16.3.3.2 Activity Measurements in Humans 255
16.4 Summary 255
References 256
17 Methods for the Analysis of DNA Methylation 263
Keith N. Rand and Peter L Molloy
17.1 Introduction 263
17.2 Measurement of Global and Repeat Sequence Methylation 264
17.3 Measurement of Methylation of Individual Genes or
Regions 267
17.3.1 Methylation Sensitive PCR 269
17.3.2 Non-Bisulfite-Based Assay 270
17A Scanning Genome-Wide for Changes in DNA Methylation 270
References 273
18 Methods Used to Study Alterations of Cell Signaling and
Proliferation 277
Clarissa Cerhauser
18.1 Introduction 277
18.2 Methods to Detect Alterations in Cell Signaling 278
18.2.1 Initializing Events 278
18.2.2 Signal Transduction to Inrracellular Targets 280
18.2.2.1 Detection Using Phosphospecific Antibodies 280
18.2.2.2 Kinase Assay After Immunoprecipitation 281
18.2.3 Transcription Factor Activation 281
18.2.3.1 Transcription Factor-DNA Binding 281
18.2.3.2 Promoter Assays After Transfection with Reporter Gene
Constructs 281
18.2.4 Gene Transcription and Translation 282
18.3 Methods to Measure Cell Proliferation 282
18.3.1 Microplate Screening Assays for Cytotoxicity 282
18.3.2 Cell Cycle Analysis [20] 282
18.3.3 Cell Death: Induction of Apoptosis 286
18.3.3.1 Methods to Detect Induction of Apoptosis 286
References 287
19 Methods for the Assessment of Antiangiogenic Activity 291
Clarissa Cerhauser
19.1 Introduction 291
i
Contents XIII
19.2 Methods for Assaying Angiogenesis 291
19.2.1 In vitro Test Systems 292
19.2.1.1 Cell-Based Systems 292
19.2.1.2 Organ Culture Systems 295
19.2.2 In vivo Models 296
19.3 Conclusions 299
References 300
20 Nutrigenomics 303
Jan Frank and Gerald Rimbach
20.1 Defining the "-omics" 303
20.2 Post-Transcriptional Gene Regulation by Small RNAs 305
20.3 Methods and Techniques Used in Nutrigenomic Research 306
20.3.1 Northern Blotting 306
20.3.2 Reverse Transcription Polymerase Chain Reaction 306
20.3.3 Microarrays 307
20.3.4 Microarray Data Normalization 310
20.3.4.1 Per Array Normalization 310
20.3.4.2 Per Gene Normalization 310
20.3.5 Microarray Data Analysis 311
20.3.5.1 Fold Change 311
20.3.5.2 Class Comparison, Class Discovery, and Class Prediction 313
201.4 Applications of Nutrigenomics 314
20.5 Proteomics 319
20.6 Metabolomics 320
20.7 Promoting Nutrigenomic Research 322
20.8 Summary 322
References 323
21 Preneoplastic Models and Carcinogenicity Studies with Rodents 335
Veronika A. Ehrlich and Siegfried Knasmuller
21.1 Introduction 335
21.2 Animal Models Based on the Use of Carcinogens 335
21.2.1 Use of Preneoplastic Lesions in Experimental Oncology 335
21.2.1.1 Altered Hepatic Foci (AHF) - Morphology and Phenorypes 337
21.2.1.1.1 Methodical Aspects 338
21.2.1.1.2 Initiators and Promoters of AHF 339
21.2.1.1.3 Mechanistic Aspects to the Action of Promoters 339
21.2.1.1.4 Inhibition of Foci Formation in the liver 339
21.2.1.1.5 New Developments 340
21.2.1.2 Aberrant Crypts in the Colon 340
21.2.1.2.1 Morphology 340
21.2.1.2.2 Biochemical and Immunohistochemical Alterations of ACF 341
21.2.1.2.3 Genetic and Epigenetic Alterations 341
21.2.1.2.4 Methodological Aspects 341
XIV Contents
21.2.1.2.5 Use of the ACF Model for the Detection of Chemoprotective
Compounds 343
21.2.1.2.6 New Developments 346
21.3 Genetically Engineered Rodent Models Used in Cancer
Prevention Studies 346
21.3.1 Intestinal Cancers in Transgenic ApcMin/+Mouse Model 347
21.3.2 Germline p53-Defkient and p53 Mutated Animals 347
21.3.3 Rodent Models of Prostate Cancer 347
21.3.4 Other Transgenic Models 349
21.4 Xenograft Models 349
21.5 Conclusions 350
References 351
22 The Role of Nutrition in the Etiology of Human Cancer
Methodological Considerations Concerning Epidemiological
Studies 357
Heiner Boeing
22.1 Introduction 357
22.2 Principles for Evaluating the link between Nutrition and Cancer 358
22.2.1 Intervention Studies 358
22.2.2 Prospective Cohort Studies 359
22.2.3 Case-Control and Other Studies 359
22.3 Methodological Statistical Challenges Regarding Dietary
Assessment 360
22 A Complexity of Dietary Data and Their Analyses 361
22.5 Current Status of the Evidence 362
22.5.1 Fruit and Vegetables 362
22.5.2 Meat and Meat Products 363 '
22.5.3 Grains 364
22.5.4 Iipids (Fat) 364
22.5.5 Use of Alcoholic Beverages 364
22.6 Summary and Conclusion 365 '
References 365
Part Three Selected Chemoprotective Dietary Factors and Components 369
23 Carotenoids and vitamin A 371
M. Cristina Polidori and Wilhelm Stahl
23.1 Introduction 371
23.2 Carotenoids - Biochemical Properties 374
23.3 P-Carotene - Cancer Prevention 376
23.4 Lycopene - Cancer Prevention 377 '
23.5 Other Carotenoids - Cancer Prevention 378
23.6 Retinoids - Biological Properties 378
i
Contents XV
23.7 Retinoids - Cancer Prevention 380
References 382
24 Selected Vitamins 385
24.1 Vitamin C 385
Pavel Kramata and Nanjoo Suh
24.1.1 Introduction 385
24.1.2 Physicochemical Properties 386
24.1.3 Bioavailability and Metabolism 387
24.1.4 Mechanism of Protection: In Vitro and In Vivo Studies 388
24.1.4.1 Vitamin C and Oxidative DNA Damage 389
24.1.4.2 Vitamin C, Cell Proliferation, Signal Transduction, and Apoptosis 389
24.1.5 Human Studies 390
24.1.5.1 Epidemiological Studies 390
24.1.5.2 Clinical Studies 391
24.1.6 Impact of Cooking and Food Processing on Protective
Properties 392
24.2 Vitamin D 393
Heide S. Cross and Thomas Nittke
24.2.1 Introduction 393
24.2.1.1 How Much Vitamin D is Enough? 393
24.2.2 Vitamin D Synthesis 394
24.2.3 Bioavailability and Metabolism of 1,25-(OH)2-D3 394
24.2.4 Mechanisms of Protection 395
24.2.4.1 Vitamin D Signaling Pathways in Cancer 395
24.2.5 In Vivo Studies with 1,25-D3 for Tumor Prevention
or Treatment 397
24.2.5.1 Treatment 397
24.2.5.2 Tumor Prevention 399
24.2.6 Impact of Processing on Vitamin D in Human Nutrition
and Conclusion 402
24.3 Vitamin E 402
Hongjin Lee and Nanjoo Suh
24.3.1 Introduction 402
24.3.2 Physicochemical Properties of Vitamin E, Chemical Structures,
and Chemical Reactions 403
24.3.2.1 Structure of Vitamin E Components 403
24.3.2.2 Vitamin E in Human Diet 403
24.3.3 Bioavailability and Metabolism of Vitamin E 404
24.3.3.1 Bioavailability and Biopotency of Vitamin E 404
24.3.3.2 Metabolism of Vitamin E 404
24.3.4 In Vitro and Animal Studies of Vitamin E 406
24.3.4.1 Mechanism of Antioxidant Protection 406
24.3.4.2 Nonantioxidant Functions of Vitamin E 407
24.3.4.3 Anticancer Mechanisms of Vitamin E Action 407
XVI Contents
24.3.4.4 Vitamin E and Predinical Studies 407
24.3.5 Vitamin E and Human Intervention Trials 408
24.3.6 Impact of Cooking, Processing, and Other Factors on Protective
Properties of Vitamin E 409
References 409
25 Folate and Vitamins B2, B6, and B12 417
Philip Thomas and Michael Fenech
25.1 Introduction 417
25.2 Physicochemical and Transport Properties 418
25.3 Bioavailability and Metabolism of Active Compounds 420
25.3.1 Bioavailability 420
25.3.2 Metabolism 422
25 A Mechanisms of Protection - In Vitro Studies 423
25.5 Results from Human Studies 424
25.6 Impact of Cooking, Processing, and Other Factors on Protective
Properties 429
257 Conclusions 430
References 430
26 Micronutrients and Susceptibility to Cancer: Focus on Selenium
and Zinc 435
Dianne Ford and John Hesketh
26.1 Introduction 435
26.2 Selenium and Zinc in Food 435
26.3 Mechanisms of Chemoprevention by Selenium: Results of In Vitro
and Animal Studies 436
26 A Results from Human Studies of the Influence of Selenium j
Status on Cancer Risk 438 \
26.4.1 Genetic Influences on Selenium Metabolism and Disease •
Risk 440 i
26.5 Mechanisms of Chemoprevention by Zinc: Results of In Vitro '
and Animal Studies 441
26.5.1 Zinc as an Antioxidant 442
26.5.2 Effects of Zinc on Cell Proliferation and Apoptosis 443
26.5.3 Effects of Zinc on Cell Motility and Invasion 444
26.5.4 Effects of Zinc on Intermediary Metabolism 444
26.5.5 Intracellular Zinc Signaling in Cancer 444
26.5.6 Zinc Transporters and Cancer 445
26.5.7 Effects of Dietary Zinc Manipulation on Cancer Incidence
and Progression in Animal Models 445
26.6 Human Studies of links between Zinc, Carcinogenesis, and
Tumor Progression 446
26.6.1 Associations Between Zinc Status and Cancer Incidence and
Progression 446
Contents XVII
26.6.2 Effects of Dietary Zinc Manipulation on Cancer Incidence and
Progression In Vivo 447
26.7 Conclusions 448
References 449
27 DNA Damage and Cancer Chemoprevention by Polyphenols 455
Ajaikumar B. Kunnumakkara, Preetha Anand, Kuzhuvelil B. Harikumar,
and Bharat B. Aggaiwal
27.1 Introduction 455
27.2 Physical-Chemical Properties of Polyphenols and Their
Occurrence 455
27.3 Mechanisms of Chemoprevention by Phenolic Compounds:
Results of In Vitro Studies 460
27.3.1 Polyphenols Protect Against Chemical-Induced DNA Damage 460
27.3.2 Polyphenols Protect Against Radiation-Induced DNA Damage 464
27.4 Mechanisms of Chemoprevention by Phenolic Compounds: Results
of In Vivo Studies 465
27.4.1 Polyphenols Prevent Colon, Esophagus, and Gastric Cancer 465
27.4.2 Polyphenols Prevent Ascites Tumor 468
27.4.3 Polyphenols Inhibit Breast Cancer 468
27.4.4 Polyphenols Inhibit liver Cancer 469
27.4.5 Polyphenols Inhibit Neuroblastoma and Glioma 470
27.4.6 Polyphenols Inhibit Leukemia 470
27.4.7 Polyphenols Inhibit Prostate Cancer 471
27.4.8 Polyphenols Inhibit Skin Cancer 472
27.4.9 Polyphenols Inhibit Lung Cancer 473
27.4.10 Polyphenols Inhibit Bladder Cancer 474
27.4.11 Polyphenols Inhibit Oral Cancer 474
27.5 Mechanisms of Chemoprevention by Phenolic Compounds:
Results of Human Studies 475
27.6 Effects of Food Processing on Chemoprotective Properties of
Polyphenols 476
27.7 Conclusion 476
References 477
28 Antioxidant, Anti-inflammatory, and Anticarcinogenic Effects
of Ginger and Its Ingredients 483
Hye-Kyung Na, Joydeb Kumar Kundu, and Young-Joon Surh
28.1 Introduction 483
28.2 Antioxidant Effects 483
28.3 Anti-Inflammatory Effects 485
28.4 Anticarcinogenic Effects 488
28.4.1 Inhibition of Mouse Skin Carcinogenesis 488
28.4.2 Inhibition of Gastric Lesions and Tumorigenesis 489
28.4.3 Inhibition of Bladder Carcinogenesis 490
XVIII Contents
28.4.4 Inhibition of Tumor Cell Growth and Proliferation 490
28.4.5 Antimetastasis and Antiangiogenesis 492
28.4.6 Effects on Mulridrug Resistance 492
28.5 Chemoprotective Effects 493
28.6 Conclusion 493
References 494
29 Tannins: Bioavailability and Mechanisms of Action 499
Fulgencio Saura-Calixto andjara P6rez-Jim6nez
29.1 Introduction 499
29.2 Physicochemical Properties 500
29.3 Bioavailability and Metabolism 501
29.3.1 Proanthocyanidins 501
29.3.2 Hydrolyzable Tannins 502
29.4 Mechanisms of Protection 503
29.5 Results of Human Studies 505
29.6 Impact of Cooking and Processing 506
References 506
30 Selected Flavonoids 509
30.1 Quercetin and other Flavonols 509
Loi'c Le Marchand and Adrian A. Franke
30.1.1 Introduction 509
30.1.2 Physicochemical Properties of Active Compounds and their
Occurrence 509
30.1.3 Biovailability and Metabolisms of Active Compounds 512
30.1.4 Mechanisms of Protection 514
30.1.5 Results of Human Studies 514
30.1.5.1 Cohort Studies 515
30.1.5.2 Case-Control Studies 515
30.1.6 Impact of Storage, Processing, and Cooking on Protective
Properties 515
30.1.7 Research Needs 516
30.2 Anthocyanidins 516
Li-Shu Wang and Gary D. Stoner
30.2.1 Introduction 516
30.2.2 Physiochemical Properties of Anthocyanidins 517
30.2.3 Bioavailability and Metabolism of Anthocyanins 518
30.2.4 Mechanisms of Chemoprotection by Anthocyanidins and
Anthocyanins 518
30.2.4.1 In Vitro Studies 518
30.2.4.2 Animal Studies 522
30.2.5 Human Studies 523
30.2.6 Impact of Processing on the Stability of Anthocyanins 524
30.2.7 Conclusions 524
Contents XIX
30.3 Proanthocyanidins 525
Clarissa Cerhauser
30.3.1 Introduction 525
30.3.2 Physicochemical Properties and Occurrence 525
30.3.2.1 Physicochemical Properties 525
30.3.2.1.1 Interaction with Proteins 525
30.3.2.1.2 Antioxidant and Radical Scavenging Capacity 527
30.3.2.1.3 Complexation of Metal Ions 527
30.3.2.2 Occurrence 527
30.3.3 Bioavailability and Metabolisms [97-99,104-107] 528
30.3.4 Mechanisms of Protection: Results of In Vitro and Animal Studies 529
30.3.4.1 In vitro Antioxidant Activity 529
30.3.4.2 Potential Cancer Chemopreventive Activity in Cell Culture 529
30.3.4.3 Cancer Chemopreventive Activity in Animal Models 534
30.3.5 Results of Human Studies 534
30.3.5.1 Short-Term Intervention Studies 534
30.3.5.2 Epidemiological Studies 537
30.3.6 Impact of Cooking, Processing, and other Factors on Protective
Properties 537
30.3.7 Conclusions 538
References 538
31 Phytoestrogens 547
31.1 Isoflavones: Sources, Intake, Fate in the Human Body, and
Effects on Cancer 547
Alicja Mortensen, Sabine Kulling Heidi Schwartz, and Gerhard Sontag
31.1.1 Introduction 547
31.1.2 Dietary Isoflavone Sources 547
31.1.3 Dietary Intake of Isoflavones 548
31.1.4 Absorption, Distribution, Metabolism, and Excretion of
Isoflavones 549
31.1.4.1 Absorption 549
31.1.4.2 Metabolism 550
31.1.4.3 Distribution 551
31.1.4.4 Excretion 552
31.1.4.5 Pharmacokinetics 552
31.1.4.6 Factors Affecting the Pharmacokinetics of Isoflavones 552
31.1.5 Effects of Isoflavones on Breast, Prostate, and Intestinal Cancer 553
31.1.5.1 Breast Cancer 553
31.1.5.2 Prostate Cancer 554
31.1.5.3 Intestinal Cancer 554
31.2 Lignans 555
Eric Laini, Christophe Hano, and Frederic Lamblin
31.2.1 Introduction 555
31.2.2 Occurrence and Physicochemical Properties 556
XX Contents
31.2.2.1 Phytoestrogenic Nature 558
31.2.2.2 Antioxidant Properties 560
31.2.3 Bioavailability 561
31.2.4 Mechanisms of Protection: Results of In Vitro and Animal Studies 562
31.2.4.1 Inhibition of Tumorigenesis 562
31.2.4.2 Inhibition of Metastasis 562
31.2.4.3 Other Less Documented Mechanisms 562
31.2.5 Results of Human Studies 565
31.2.5.1 Breast Cancer 566
31.2.5.2 Prostate Cancer 567
31.2.5.3 Colon Cancer 567
31.2.6 Impact of Cooking, Processing, and Other Factors on Protective
Properties 567
31.2.7 Conclusions 568
References 568
32 Chemopreventive Properties of Coffee and Its Constituents 579
Gernot Faustmann, Christophe Cav'm, Armen Nersesyan, and
Siegfried Knasmiiller
32.1 Introduction 579
32.2 Bioactive Components in Coffee 580
32.3 Mechanisms of Chemoprevention 580
32.3.1 Protective Properties of Coffee 581
32.3.1.1 Antioxidant Effects 581
32.3.1.2 Induction of Detoxifying Enzymes 583
32.3.2 Protective Properties of Coffee Components 583
32.3.2.1 Antioxidant Effects 583
32.3.2.2 Induction of Detoxifying Enzymes 585
32.3.2.3 Protective Effects of Coffee Constituents Toward Genotoxic
Carcinogens 585
32.3.2.4 Interaction of Coffee and Coffee Diterpenes with Cell
Signaling Pathways 587
32.4 Coffee Consumption and Human Cancer Risks 588
32.5 Concluding Remarks 590
References 590
33 Tea and Its Constituents 595
33.1 Green Tea and Its Constituents: Protection Against DNA Damage
and Carcinogenesis 595
Joshua D. Lambert and Chung S. Yang
33.1.1 Introduction 595
33.1.2 Bioavailability and Biotransformation of Tea Polyphenols 596
33.1.2.1 Biotransformation of Tea Polyphenols 596
33.1.2.2 Pharmacokinetics of Tea Polyphenols 598
33.1.3 In Vitro and Animal Studies of Cancer Prevention by Tea 599
Contents XXI
33.1.3.1 Antioxidative/Pro-Oxidative Activities 599
33.1.3.2 Effects on Carcinogen Metabolism 600
33.1.3.3 Prevention and Repair of DNA Damage 601
33.1.3.4 Prevention of Carcinogenesis and Potential Postinitiation
Mechanisms 602
33.1.4 Studies on the Cancer-Preventive Activity of Tea in Humans 604
33.1.4.1 Antioxidative Activity 604
33.1.4.2 Effects on Carcinogen Metabolism 604
33.1.4.3 Prevention and Repair of DNA Damage 604
33.1.4.4 Epidemiological and Intervention Studies on Cancer
Prevention by Tea 605
33.1.5 Impact of Cooking, Processing, and Other Factors on
Protective Effects 607
33.1.6 Concluding Remarks 60S
33.2 Black and Other Teas 609
Wentzel C.A. Gelderblom, Kareemah Camieldien, and Elizabeth Joubert
33.2.1 Introduction 609
33.2.2 Physicochemical Properties of Active Compounds and their
Occurrence 610
33.2.2.1 Black Tea 610
33.2.2.2 Rooibos Tea 610
33.2.2.3 Honeybush Tea 613
33.2.3 Bioavailability and Metabolism of Active Compounds 615
33.2.4 Mechanisms of Protection: Results of In Vitro and Animal Studies 616
33.2.4.1 Antimutagenic Properties 616
33.2.4.2 Antioxidant Properties 617
33.2.4.3 Studies in Animals 619
33.2.4.4 Cell Survival Parameters 620
33.2.5 Results of Human Studies 621
33.2.6 Impact of Heat and Processing on Protective
Properties 622
33.2.6.1 Black Tea 622
33.2.6.2 Rooibos and Honeybush 622
33.2.7 Concluding Remarks 623
References 623
34 Protective Effects of Alcoholic Beverages and their Constituent 635
34.1 Wine 635
Philipp Saiko, Akos Szakmary, and Thomas Szekeres
34.1.1 Introduction 635
34.1.1.1 General Information and Historical Background 635
34.1.1.2 The Health Effects of Wine 636
34.1.1.3 Ingredients of Wine 636
34.1.2 Physicochemical Properties of Active Compounds, Occurrences,
and Chemical Structures 637
XXII Contents
34.1.2.1 Resveratrol 637
34.1.2.1.1 History and Sources 637
34.1.2.1.2 French Paradox 638
34.1.2.1.3 Effects of Resveratrol 638
34.1.2.2 Piceatannol: A Naturally Occurring Resveratrol
Metabolite 640
34.1.2.3 Gallic Acid 640
34.1.3 Bioavailability and Metabolism of Active Compounds 642
34.1.3.1 Bioavailability of Resveratrol 642
34.1.3.2 Metabolites of Resveratrol: Glucuronide
and Sulfate Conjugates 642
34.1.3.3 Bioavailability of Resveratrol in Grape Juice Compared to Its
Pure Aglycone 642
34.1.4 Mechanisms of Protection 643
34.1.4.1 Results of In Vitro Studies 643
34.1.4.2 Results of In Vivo Studies 643
34.1.5 Results of Human Studies 643
34.1.6 Conclusions 643
34.2 Beer 648
Metka Filipic, Janja Plazar, and Sakae Arimoto-Kobayashi 648
34.2.1 Introduction 648
34.2.2 Physicochemical Properties of Bioactive Compounds 649
34.2.2.1 Prenylated Flavonoids 649
34.2.2.2 Bitter Acids 650
34.2.2.3 Nitrogenous Compounds 651
34.2.3 Mechanisms of Chemoprevention: Results In Vitro
and In Vivo 652
34.2.3.1 Prenylated Flavonoids 652
34.2.3.2 Bitter Acids 653
34.2.3.3 Nitrogenous Compounds and other Unidentified Components 653
34.2.4 Results of Human Studies 655
34.2.5 Effect of Beer Processing on Chemoprotective
Properties 656
References 656
35 Sulfides in Allium Vegetables 663
Claus Jacob and Awais Anwar
35.1 Introduction 663
35.2 Physicochemical Properties 665
35.3 Bioavailability and Metabolisms of Active Compounds 667
35.3.1 Enzymatic Generation of Reactive Sulfur Species as Part
of Binary Plant Defense Systems 667
35.3.2 Follow-On Products Formed by Degradation of Reactions
with Biomolecules 669
35.3.3 Chemical Recycling of Allicin 670
Contents XXIII
35.4 Mechanisms of Protection 671
35.4.1 Sulfur-based Scavengers of Free Radicals and Other
Oxidative Stressors 671
35.4.2 Prevention of Carcinogen Activation by Inhibition
of Metabolic (Phase I) Enzymes 673
35.4.3 Induction of Phase II Enzymes 673
35.4.4 Sulfur Agents as HDAC Inhibitors 674
35.4.5 Interference with Cancer Promoting, Cell Signaling Pathways 674
35.4.6 Cell Cycle Arrest and Induction of Apoptosis 675
35.4.7 Sulfur Agents and Angiogenesis 676
35.4.8 Counteracting Multidrug Resistance 677
35.5 Results of Human Studies 677
35.6 Impact of Cooking, Processing, and Other Factors on
Protective Properties 678
35.7 Outlook 680
35.8 Conclusion 681
References 681
36 Clucosinolates and Cruciferous Vegetables 685
L Adele Boyd, Cris Gill, Tomas Borkowski, and Ian Rowland
36.1 Introduction 685
36.1.1 Cruciferous Vegetables and Their Components 685
36.1.2 Physicochemical Properties of Phytochemicals in Cruciferous
Vegetables 685
36.2 Bioavailability and Metabolisms of Active
Compounds 686
36.2.1 Gastric and Small-Intestinal Breakdown 689
36.2.2 Colonic Metabolism 689
36.2.3 Absorption from the Gut 689
36.2.4 Metabolism and Excretion of Hydrolysis Products 689
36.3 Mechanisms of Protection: Results of In Vitro and
Animal Studies 690
36.3.1 Animal Studies 690
36.3.2 Effects of Vegetable Extracts and Components at the Cellular
and Molecular Level 691
36.4 Human Studies 692
36.4.1 Epidemiology 692
36.4.2 Dietary Intervention Studies 692
36.4.2.1 Effects on Phase I and Phase II Enzyme Activities
and Carcinogen Excretion in Humans 693
36.4.2.2 Antigenotoxic Effects of Cruciferous Vegetables 694
36.5 Impact of Cooking and Processing 695
36.5.1 Storage and Processing 695
36.5.2 Cooking 695
36.5.3 Consequences for Bioavailability 695
XXIV Contents
36.6 Conclusions 696
References 696
37 Chlorophyll 699
Hikoya Hayatsu, Tomoe Negishi, and Sakae Arimoto-Kobayashi
37.1 Introduction 699
37.2 Chemical Nature of Chlorophylls 699
37.3 Historical Background 701
37.4 Basic Studies on Antigenotoxic Activities of Chlorophylls
and the Mechanism of the Actions 702
37.5 Chlorophyll-Carcinogen Complex Formation 702
37.6 Studies with Higher Organisms 704
37.7 Studies with Human Subjects 705
References 706
38 Dietary Fibers 709
Philip J. Harris and Lynnette R. Ferguson
38.1 Introduction 709
38.2 Physicochemical Properties of Active Compounds and Their
Occurrence 711
38.3 Bioavailability and Metabolism of Active
Compounds 712
38.4 Mechanisms of Chemoprevention: Results of In Vitro
and Animal Studies 712
38.4.1 Iignified or Suberized Cell Walls 713
38.4.2 Cell Walls Containing Hydroxycinnamic Acids 714
38.5 Results of Human Studies 715
38.6 Impact of Cooking, Processing, and Other Factors on Protective
Properties 716
38.7 Conclusions 716
References 717
39 Dietary Fiber Carbohydrates and their Fermentation Products 721
Lynnette R. Ferguson and Philip J. Harris
39.1 Introduction 721
39.2 Physicochemical Properties of Active Compounds and their
Occurrence 721
39.3 Bioavailability and Metabolism of Active Compounds 724
39.4 Mechanisms of Chemoprevention: Results of In Vitro and
Animal Studies 724
39.4.1 Hypotheses Suggesting that SCFAs are Protective 724
39.4.2 The Butyrate Hypothesis 724
39.4.3 Prebiotic Effects 725
39.4.4 Evidence from Animal Models 725
39.5 Results of Human Studies 726
Contents XXV
39.6 Impact of Cooking, Processing, and other Factors on Protective
Properties 726
39.7 Conclusions 727
References 727
40 Lactobacilli and Fermented Foods 731
Sabine Fuchs, Reinhard Stidl, Verena Koller, Gerhard Sontag, Armen
Nersesyan, and Siegfried Knasmuller
40.1 Introduction 731
40.2 Occurrence of Lactic Acid Bacteria 733
40.3 Detoxification of Genotoxic Carcinogens by Lactic Acid Bacteria 733
40.4 Antioxidant Effects of Lactic Acid Bacteria 737
40.5 Effect of Lactic Acid Bacteria on the Immune Status 739
40.6 Results of Carcinogenicity Studies with Laboratory Rodents 740
40.7 Impact of Lactic Acid Bacteria on Cell Proliferation and Apoptosis 742
40.8 Results of Human Epidemiological Studies 742
40.9 Conclusions and Future Research 743
References 743
41 Fatty Acids and Cancer Prevention 749
Elizabeth K. Lund 749
41.1 Introduction 749
41.2 Fatty Acid Structure 750
41.3 Bioavailability 751
41.4 Epidemiology 752
41.5 Animal Models 753
41.6 In Vitro Studies 754
41.7 Mechanisms of Action 754
41.8 Conclusion 757
References 757
42 Protease Inhibitors 761
Ann R. Kennedy
42.\ Introduction 763
42.2 Physicochemical Properties of Active Compounds and Their
Occurrence 761
42.3 Bioavailability and Metabolism of Active Compounds 762
42.4 Mechanisms of Protection and Results of In Vitro and Animal
Studies 762
42.5 Results of Human Studies 764
42.6 Impact of Cooking Processing 766
References 766
Index 769 |
| any_adam_object | 1 |
| author_GND | (DE-588)11483993X |
| building | Verbundindex |
| bvnumber | BV035601150 |
| callnumber-first | R - Medicine |
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| ctrlnum | (OCoLC)288986436 (DE-599)DNB991677633 |
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| dewey-hundreds | 600 - Technology (Applied sciences) |
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| dewey-search | 614.5999 616.9940654 |
| dewey-sort | 3614.5999 |
| dewey-tens | 610 - Medicine and health |
| discipline | Medizin |
| format | Book |
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| id | DE-604.BV035601150 |
| illustrated | Illustrated |
| indexdate | 2024-07-20T10:14:11Z |
| institution | BVB |
| isbn | 9783527320585 352732058X |
| language | English |
| oai_aleph_id | oai:aleph.bib-bvb.de:BVB01-017656194 |
| oclc_num | 288986436 |
| open_access_boolean | |
| owner | DE-355 DE-BY-UBR DE-1029 |
| owner_facet | DE-355 DE-BY-UBR DE-1029 |
| physical | XLVIII, 787 S. Ill., graph. Darst. 25 cm |
| publishDate | 2009 |
| publishDateSearch | 2009 |
| publishDateSort | 2009 |
| publisher | Wiley-VCH |
| record_format | marc |
| spelling | Chemoprevention of cancer and DNA damage by dietary factors ed. by Siegfried Knasmüller ... Weinheim Wiley-VCH 2009 XLVIII, 787 S. Ill., graph. Darst. 25 cm txt rdacontent n rdamedia nc rdacarrier Literaturangaben Anticarcinogenic Agents Cancer Chemoprevention Cancer Diet therapy Chemoprevention methods DNA Damage Diet Therapy Micronutrients therapeutic use Neoplasms drug therapy Prävention (DE-588)4076308-0 gnd rswk-swf DNS-Strangbruch (DE-588)4267604-6 gnd rswk-swf Physiologische Chemie (DE-588)4076124-1 gnd rswk-swf Ernährung (DE-588)4015332-0 gnd rswk-swf Krebs Medizin (DE-588)4073781-0 gnd rswk-swf Krebs Medizin (DE-588)4073781-0 s Prävention (DE-588)4076308-0 s Ernährung (DE-588)4015332-0 s Physiologische Chemie (DE-588)4076124-1 s DE-604 DNS-Strangbruch (DE-588)4267604-6 s Knasmüller, Siegfried 1956- Sonstige (DE-588)11483993X oth text/html http://deposit.dnb.de/cgi-bin/dokserv?id=3192030&prov=M&dok_var=1&dok_ext=htm Inhaltstext HBZ Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=017656194&sequence=000004&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Chemoprevention of cancer and DNA damage by dietary factors Anticarcinogenic Agents Cancer Chemoprevention Cancer Diet therapy Chemoprevention methods DNA Damage Diet Therapy Micronutrients therapeutic use Neoplasms drug therapy Prävention (DE-588)4076308-0 gnd DNS-Strangbruch (DE-588)4267604-6 gnd Physiologische Chemie (DE-588)4076124-1 gnd Ernährung (DE-588)4015332-0 gnd Krebs Medizin (DE-588)4073781-0 gnd |
| subject_GND | (DE-588)4076308-0 (DE-588)4267604-6 (DE-588)4076124-1 (DE-588)4015332-0 (DE-588)4073781-0 |
| title | Chemoprevention of cancer and DNA damage by dietary factors |
| title_auth | Chemoprevention of cancer and DNA damage by dietary factors |
| title_exact_search | Chemoprevention of cancer and DNA damage by dietary factors |
| title_full | Chemoprevention of cancer and DNA damage by dietary factors ed. by Siegfried Knasmüller ... |
| title_fullStr | Chemoprevention of cancer and DNA damage by dietary factors ed. by Siegfried Knasmüller ... |
| title_full_unstemmed | Chemoprevention of cancer and DNA damage by dietary factors ed. by Siegfried Knasmüller ... |
| title_short | Chemoprevention of cancer and DNA damage by dietary factors |
| title_sort | chemoprevention of cancer and dna damage by dietary factors |
| topic | Anticarcinogenic Agents Cancer Chemoprevention Cancer Diet therapy Chemoprevention methods DNA Damage Diet Therapy Micronutrients therapeutic use Neoplasms drug therapy Prävention (DE-588)4076308-0 gnd DNS-Strangbruch (DE-588)4267604-6 gnd Physiologische Chemie (DE-588)4076124-1 gnd Ernährung (DE-588)4015332-0 gnd Krebs Medizin (DE-588)4073781-0 gnd |
| topic_facet | Anticarcinogenic Agents Cancer Chemoprevention Cancer Diet therapy Chemoprevention methods DNA Damage Diet Therapy Micronutrients therapeutic use Neoplasms drug therapy Prävention DNS-Strangbruch Physiologische Chemie Ernährung Krebs Medizin |
| url | http://deposit.dnb.de/cgi-bin/dokserv?id=3192030&prov=M&dok_var=1&dok_ext=htm http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=017656194&sequence=000004&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
| work_keys_str_mv | AT knasmullersiegfried chemopreventionofcanceranddnadamagebydietaryfactors |