CHEMICAL INDUCTION OF CANCER: CANCER STRUCTURAL BASES AND BIOLOGICAL MECHANISMS
CONTENTS CHAPTER 1 THE ROLE OF DNA DAMAGE IN CANCERS CAUSED BY CHEMICALS 1 INTRODUCTION 2 STUDIES IN EXPERIMENTAL MODELS 3 DNA DAMAGE IN HUMANS: METHODOLOGIES 4 DNA DAMAGE IN HUMANS: DOSIMETRY 5 DNA DAMAGE IN HUMANS: RELATIONSHIP TO CANCER RISK ABBREVIATIONS REFERENCES GLOSSARY CHAPTER 2 THE ROLE OF CYTOCHROME P450 ENZYMES IN CARCINOGEN METABOLISM: LESSONS LEARNED FROM STUDIES WITH BENZO[A]PYRENE AND ARISTOLOCHIC ACID 2 CYTOCHROMES P450 — NOMENCLATURE, LOCALIZATION, AND CATALYSIS 3 CYTOCHROMES P450 — THE MAJOR ENZYMES METABOLIZING XENOBIOTICS 4 CYTOCHROMES P450 INVOLVED IN METABOLISM OF CARCINOGENS: ACTIVATION 5 CYTOCHROMES P450 INVOLVED IN METABOLISM OF CARCINOGENS: DETOXIFICATION 6 P450 ENZYMES CONTRIBUTING TO THE OXIDATION OF BP AND AAI 6 1 BENZO[A]PYRENE 6 2 ARISTOLOCHIC ACID I 7 MECHANISM OF A MONOOXYGENATION REACTION CATALYZED BY P450S 8 CONCLUDING REMARKS ACKNOWLEDGMENTS CHAPTER 3 DNA DAMAGE BY TOBACCO CARCINOGENS 2 CANCER-CAUSING AGENTS (CARCINOGENS) ARE PRESENT IN TOBACCO PRODUCTS 3 DNA ADDUCTS ARE CENTRAL IN CARCINOGENESIS BY TOBACCO PRODUCTS 4 DNA ADDUCTS ARE FORMED BY REACTION OF CARCINOGENIC METABOLITES WITH DNA 5 SPECIFIC ADDUCTS ARE FOUND IN SMOKERS’ DNA 6 DNA ADDUCTS CAUSE MUTATIONS 7 THE PREDICTED MUTATIONS ARE FOUND AT SPECIFIC SITES IN CRITICAL GENES 8 THOUSANDS OF MUTATIONS ARE PRESENT IN SMOKERS’ LUNG TUMORS 9 SUMMARY CHAPTER 4 MEASUREMENT OF POLYCYCLIC AROMATIC HYDROCARBON-DNA ADDUCTS AND STUDIES OF HUMAN CANCER RISK USING ANTIBODY-BASED METHODS 2 ANTIBODIES AND METHODOLOGIES FOR MEASURING PAH-DNA ADDUCTS 3 APPLICATION OF ANTIBODIES TO DETECTION OF PAH-DNA ADDUCTS IN HUMAN POPULATIONS 3 1 ENZYME-LINKED IMMUNOSORBENT ASSAYS 3 2 IMMUNOHISTOCHEMICAL LOCALIZATION OF PAH-DNA ADDUCTS 3 3 IMMUNOAFFINITY CHROMATOGRAPHY 4 SUMMARY CHAPTER 5 CHEMICAL EXPOSURES, DNA DAMAGE, AND HUMAN LUNG CANCER RISK 2 RELEVANCE OF INITIATION AND PROMOTION IN HUMAN LUNG CANCER RISK 3 GENE–ENVIRONMENT INTERACTION IN HUMAN LUNG CARCINOGENESIS 4 CLASSES OF CHEMICAL CARCINOGEN KNOWN TO DAMAGE HUMAN LUNG DNA 4 1 POLYCYCLIC AROMATIC HYDROCARBONS 4 2 AROMATIC AMINES 4 3 DIESEL ENGINE EXHAUST FUMES 4 4 NITROSAMINES 4 5 ALKYLATING AGENTS 5 ADDITIONAL DNA-ALTERING MECHANISMS: EPIGENETICS AND REACTIVE OXYGEN SPECIES 6 HUMAN DNA ADDUCT FORMATION IN LUNG, BRONCHUS, AND SURROGATE WHITE BLOOD CELLS 6 1 RISK OF LUNG CANCER ASSOCIATED WITH HIGH LEVELS OF CARCINOGEN-DNA ADDUCTS 6 2 MUTATIONS FOUND IN DIFFERENT TYPES OF LUNG TUMORS 6 3 LUNG ADENOCARCINOMA 6 4 LUNG SQUAMOUS CELL CARCINOMA 6 5 SMALL CELL AND LARGE CELL LUNG CARCINOMA 6 6 EARLY DETECTION OF LUNG CANCER 7 CONCLUSIONS ACKNOWLEDGMENT CHAPTER 6 AFLATOXIN EXPOSURE, HUMAN LIVER CANCER RISK, AND CHEMOPREVENTION 1 HUMAN EXPOSURE TO AFLATOXINS 1 1 AFLATOXIN-INDUCED HEPATOCARCINOGENESIS 1 1 1 HUMAN EPIDEMIOLOGY 1 1 2 ANIMAL MODELS: CARCINOGENICITY AND CHEMOPREVENTION 1 2 AFLATOXIN METABOLISM: APPLICATION TO BIOMARKERS 1 3 AFLATOXIN BIOMARKERS IN HUMAN STUDIES 1 4 INTERVENTION TRIALS USING AFLATOXIN BIOMARKERS 1 4 1 PRIMARY PREVENTION 1 4 2 SECONDARY PREVENTION: HUMAN CHEMOPREVENTION TRIALS 2 SUMMARY CHAPTER 7 METAL CARCINOGENESIS AND DNA DAMAGE: A CASE STUDY USING HEXAVALENT CHROMIUM 1 OVERVIEW OF METAL CARCINOGENESIS 2 METAL ION UPTAKE AND METABOLISM 3 METALS AND DNA DAMAGE 4 METALS AND DNA REPAIR 5 HOW METALS IMPACT CELL DIVISION AND MITOSIS 6 EPIGENETIC CHANGES 7 SUMMARY: METALS AND CARCINOGENESIS PARADIGMS CHAPTER 8 MONITORING DNA DAMAGE INDUCED BY CHEMOTHERAPEUTIC AGENTS AS A PREDICTOR OF CLINICAL OUTCOME 2 DNA ADDUCT FORMATION BY CANCER CHEMOTHERAPEUTIC DRUGS 2 1 DNA ADDUCT FORMATION BY CANCER CHEMOTHERAPEUTIC DRUGS: PLATINUM-BASED AGENTS 2 1 1 METHODS FOR MEASURING DNA ADDUCTS OF PLATINUM-BASED DRUGS 2 1 2 MEASUREMENT OF DNA DAMAGE INDUCED BY PLATINUM-BASED CHEMOTHERAPY AND DISEASE RESPONSE IN OVARIAN AND TESTICULAR CANCER PATIENTS 2 1 3 MEASUREMENT OF DNA DAMAGE INDUCED BY PLATINUM-BASED CHEMOTHERAPY AND DISEASE RESPONSE IN MISCELLANEOUS TUMOR TYPES 2 1 4 HOW CAN PLATINUM DRUG DOSING BE OPTIMIZED? 2 1 5 IN VITRO DNA ADDUCTS OF PLATINUM- BASED DRUGS, AND THEIR REPAIR, AS PREDICTIVE MARKERS OF THERAPEUTIC RESPONSE 2 1 6 CONCLUSIONS REGARDING THE RELATIONSHIP BETWEEN DNA DAMAGE AND THERAPEUTIC RESPONSE TO PLATINUM-BASED DRUGS 2 2 DNA ADDUCT FORMATION BY CANCER CHEMOTHERAPEUTIC DRUGS: NITROGEN MUSTARDS 2 2 1 METHODOLOGIES FOR MEASURING NITROGEN MUSTARD-INDUCED DNA DAMAGE 2 2 2 CLINICAL STUDIES: MULTIPLE MYELOMA 2 2 3 CLINICAL STUDIES: SARCOMA 2 2 4 IN VITRO DNA ADDUCTS OF NITROGEN MUSTARDS, AND THEIR REPAIR, AS PREDICTIVE MARKERS OF THERAPEUTIC RESPONSE 2 2 5 CONCLUSIONS REGARDING THE RELATIONSHIP BETWEEN DNA DAMAGE AND THERAPEUTIC RESPONSE TO NITROGEN MUSTARDS 2 3 DNA ADDUCT FORMATION BY CANCER CHEMOTHERAPEUTIC DRUGS: CHLOROETHYL NITROSOUREAS, METHYLATING AGENTS, AND RELATED DRUGS 2 3 1 METHODS FOR MEASURING ALKYLATED DNA ADDUCTS 2 3 2 CLINICAL STUDIES: HODGKIN’S AND NON-HODGKIN LYMPHOMA 2 3 3 CLINICAL STUDIES: MALIGNANT MELANOMA 2 3 4 CONCLUSIONS REGARDING THE RELATIONSHIP BETWEEN DNA DAMAGE AND THERAPEUTIC RESPONSE TO CHLOROETHYL NITROSOUREAS, METHYLATING AGENTS, AND RELATED DRUGS 3 USE OF DNA DAMAGE RESPONSE AS A BIOMARKER OF CHEMOTHERAPEUTIC EFFICACY 4 CONCLUDING REMARKS CHAPTER 9 ANTIRETROVIRAL DRUGS, GENOTOXICITY, AND CARCINOGENESIS THERAPY 3 NRTIS BECOME INCORPORATED INTO NUCLEAR, MITOCHONDRIAL, AND TELOMERIC DNA 3 1 GENOTOXIC CONSEQUENCES OF AZT EXPOSURE: NDNA 3 2 GENOTOXIC CONSEQUENCES OF AZT EXPOSURE: MTDNA 3 3 TUMORIGENIC CONSEQUENCES OF AZT EXPOSURE IN MICE 3 4 GENOTOXIC AND TUMORIGENIC CONSEQUENCES OF AZT EXPOSURE IN PRIMATES 3 5 AZT INCORPORATES INTO DNA OF HUMAN PLACENTA AND INFANT BLOOD DNA 4 CONCLUSIONS CHAPTER 10 CANCER CHEMOPREVENTION VIA REDUCTION OF DNA DAMAGE 2 DESIGN OF CHEMOPREVENTION STUDIES: DNA ADDUCT ENDPOINT 3 DESIGN OF CHEMOPREVENTION STUDIES: TUMOR ENDPOINT 4 MECHANISMS FOR INHIBITION OF DNA DAMAGE 4 1 INHIBITORS OF PHASE I CYTOCHROME P450 ENZYMES 4 2 INDUCERS OF CYTOCHROME P450 ENZYMES 4 3 INDUCERS OF PHASE II ENZYMES 4 4 SCAVENGERS OF ELECTROPHILES AND OXIDATIVE FREE RADICALS 5 SUMMARY CHAPTER 11 CHEMICAL CARCINOGEN EXPOSURE, DNA DAMAGE, AND EPIGENETIC ALTERATIONS KOSTIANTYN DREVAL AND IGOR P POGRIBNY 1 INTRODUCTION 2 BRIEF OVERVIEW OF EPIGENETICS 3 GENOTOXIC CARCINOGENS 3 1 BENZO[A]PYRENE (BP): GENOTOXICITY AND EPIGENETICS 3 2 1,3-BUTADIENE 3 3 BENZENE 3 4 2-ACETYLAMINOFLUORENE 3 5 TAMOXIFEN 4 NONGENOTOXIC CARCINOGENS 4 1 METHAPYRILENE 4 2 FURAN 5 MECHANISMS OF EPIGENETIC ALTERATIONS INDUCED BY GENOTOXIC AND NONGENOTOXIC CARCINOGENS 6 CONCLUSIONS CHAPTER 12 ADDUCTOMICS 1 THE EXPOSOME 2 DNA ADDUCTOMICS 3 PROTEIN ADDUCTOMICS 3 1 HEMOGLOBIN 3 2 ALBUMIN 4 PROSPECTS FOR THE FUTURE