Bioreduction in the Activation of Drugs (eBook)

Front Cover 1
Bioreduction in the activation of Drugs 6
Copyright Page 7
Table of Contents 8
Session A: Enzymology Chairman 10
CHAPTER 1. OVERVIEW OF ENZYME SYSTEMS INVOLVED IN BIOREDUCTION OF DRUGS AND IN REDOX CYCLING 10
QUINONES 11
ANTHRACYCLINES 11
PARAQUAT 13
BLEOMYCIN 13
NITRO COMPOUNDS 13
CONCLUSION 13
REFERENCES 14
CHAPTER 2. REGULATION OF REDUCTIVE PROCESSES BY GLUTATHIONE 16
NADPH GENERATION 16
GLUTATHIONE REDUCTASE AND GLUTATHIONE PEROXIDASE 16
GLUTATHIONE REDOX CYCLE 17
DIAMIDE 18
BCNU INACTIVATION OF GLUTATHIONE REDUCTASE 19
BIO-REDUCTION REACTIONS 19
ADRIAMYCIN 20
CONCLUSIONS 21
REFERENCES 21
CHAPTER 3. THE CRUCIAL ROLE OF LOW STEADY STATE OXYGEN PARTIAL PRESSURES IN HALOALKANE FREE-RADICAL-MEDIATED LIPID PEROXIDATION 24
DUAL ROLE OF MOLECULAR OXYGEN IN HALOALKANE FREE-RADICAL-MEDIATED LIPID PEROXIDATION 24
THE OXYSTAT SYSTEM 25
EFFECT OF Po2 ON HALOALKANE FREE-RADICAL-MEDIATEDLIPID PEROXIDATION IN LIVER MICROSOMES AND ISOLATED HEPATOCYTES 26
POSSIBLE IMPLICATIONS IN HALOALKANE LIVER INJURY 27
REFERENCES 28
CHAPTER 4. REDUCTION BY THE GUT MICROFLORA OF ANIMALS AND MAN 36
INTER-INDIVIDUAL VARIATION 37
DIFFERENCES BETWEEN THE GUT FLORAS OF ANIMALS AND MAN 37
SOME TOXICOLOGICAL IMPLICATIONS OF REDUCTION BY THE GUT FLORA 39
CONCLUSIONS AND SUGGESTIONS FOR ALTERNATIVE METHODOLOGY 39
REFERENCES 40
CHAPTER 5. Generation of photoemissive species during quinone redox cycling 31
REFERENCES 32
Chairman's Summary of Session A 34
Session B: Bacterial and Parasite Infections Chairman 36
CHAPTER 6. REDUCTION BY THE GUT MICROFLORA OF ANIMALS AND MAN 36
INTER-INDIVIDUAL VARIATION 37
DIFFERENCES BETWEEN THE GUT FLORAS OF ANIMALS AND MAN 37
SOME TOXICOLOGICAL IMPLICATIONS OF REDUCTION BY THE GUT FLORA 39
CONCLUSIONS AND SUGGESTIONS FOR ALTERNATIVE METHODOLOGY 39
REFERENCES 40
CHAPTER 7. THE METABOLIC ACTIVATION OF RONIDAZOLE [(1-METHYL-5-NITROIMIDAZOLE-2-YL)-METHYL CARBAMATE] TO REACTIVE METABOLITES BY MAMMALIAN, CECAL BACTERIAL AND T. FOETUS ENZYMES 42
METHODS 42
RESULTS AND DISCUSSION 43
REFERENCES 45
CHAPTER 8. REDUCTIVE ACTIVATION OF NITROIMIDAZOLES IN ANAEROBIC MICROORGANISMS 46
REDUCTIVE ACTIVATION OF 5-NITROIMIDAZOLES 46
REDUCTION OF DIFFERENT NITROIMIDAZOLES 48
FERREDOXIN AND METRONIDAZOLE REDUCTION 48
NITROIMIDAZOLE RESISTANCE 49
REFERENCES 50
CHAPTER 9. COMPARING THE REDUCTION OF NITROIMIDAZOLES IN BACTERIA AND MAMMALIAN TISSUES AND RELATING IT TO BIOLOGICAL ACTIVITY 52
BACTERIAL REDUCTION OF THE NITROIMIDAZOLES 53
ASSOCIATING BACTERIAL REDUCTION OF METRONID-AZOLE WITH BACTERICIDAL ACTIVITY 54
IS THE BACTERIAL MODEL APPLICABLE TO MAMMALIAN TISSUES 57
ONE ELECTRON REDUCTION POTENTIAL OF NITRO-HETEROCYCLIC COMPOUNDS AND THEIR REDUCTION BY MAMMALIAN TISSUES 59
REFERENCES 59
CHAPTER 10. REDUCTION OF NITROIMIDAZOLES IN VITRO AND DNA DAMAGE 62
REDUCTION AND ENTRY INTO THE CELL 63
NITROIMIDAZOLES DAMAGE DNA 63
WHAT IS THE REDUCTION INTERMEDIATE RESPONSIBLE FOR DNA DAMAGE? 64
REDUCTION OF NITROIMIDAZOLES IN HYPOXIA 65
REFERENCES 66
CHAPTER 11. In vitro reductive activation of nitroimidazoles 68
REFERENCES 70
CHAPTER 12. Inhibition of hydrogen production in drug-resistant and susceptible Trichomonas vaginalis strains by a range of nitroimidazole derivatives 70
REFERENCES 72
CHAPTER 13. The role of the gut flora in the reduction of sulphoxide containing drugs 73
REFERENCES 73
Chairman's Summary of Session B 74
Session C: Role in Treatment of Cancer—Part I Chairman 76
CHAPTER 14. THE ROLE OF MITOMYCIN ANTIBIOTICS IN THE CHEMOTHERAPY OF SOLID TUMORS 76
REFERENCES 78
CHAPTER 15. HYPOXIA-MEDIATED NITRO-HETEROCYCLIC DRUGS IN THE RADIO- AND CHEMOTHERAPY OF CANCER 80
MISONIDAZOLE AND ITS ANALOGUES 80
BIOREDUCIBILITY OF NITROHETEROCYLICS 81
CHEMOSENSITIZATION 82
THE PRE-INCUBATION EFFECT 83
MECHANISMS OF CHEMOSENSITIZATION IN VITRO AND IN VIVO 83
REFERENCES 84
CHAPTER 16. BIOCHEMISTRY OF REDUCTION OF NITRO HETEROCYCLES 86
GENERAL SCHEME FOR REDUCTION AND METABOLISM OF NITROCOMPOUNDS 86
ROLE OF GLUCOSE IN REDUCTION OF NITROCOMPOUNDS 87
FACTORS INFLUENCING PEROXIDE PRODUCTION WITH VARIOUS NITRO COMPOUNDS 89
EFFECTS OF L-BSO AND MISONIDAZOLE ON CELLULAR GSH LEVELS 89
EFFECTS OF L-BSO AND MISONIDAZOLE ON CELL GROWTH AND SURVIVAL 90
EFFECT OF CATALASE ON MISONIDAZOLE-LINKED TOXICITY 90
ASSAY OF ENDOGENOUS PEROXIDASE ACTIVITY FOR L-BSO+MISONIDAZOLE TREATED CELLS 90
SCHEMATIC SHOWING THE POTENTIAL ROLE FOR GSH IN THE REDUCTION OF NITRO DRUG PRODUCED HYDROPEROXIDES AND RADICALS 91
SCHEMATIC SHOWING THE MITOCHONDRIAL ROLE IN PRODUCTION OF RADICALS 93
PENTOSE CYCLE AND HYPOXIC METABOLISM OF MISONIDAZOLE 93
HYPOXIC REDUCTION OF MISONIDAZOLE 93
THE PREINCUBATION EFFECT: THIOL DEPLETION AND ITS CAUSAL RELATIONSHIP TO CELLULAR TOXICITY AND CHEMOSENSITIZATION 93
INHIBITION OF AEROBIC AND ANAEROBIC GLYCOLYSIS AS A CONSEQUENCE OF METABOLIC ACTIVATION TOREACTIVE INTERMEDIATES 93
POTENTIATION OF TOXICITY OF CHEMOTHERAPEUTIC AGENT BY PRETREATMENT WITH MISONIDAZOLE 95
POTENTIATION OF MISONIDAZOLE EFFECTS WITH THIOL DEPLETION 97
SUMMARY AND CONCLUSIONS 97
REFERENCES 98
CHAPTER 17. Toxicity of oxygen at amospheric concentration for newly explanted cancer cells 100
REFERENCES 101
CHAPTER 18. The effect of bioreduction on the oncogenicity of nitroimidazoles 102
REFEREBCES 103
Chairman's Summary of Session C 104
Session D: Role in Treatment of Cancer—Part II Chairman 106
CHAPTER 19. THE BIOLOGICAL PROPERTIES OF REDUCED NITROHETEROCYCLICS AND POSSIBLE UNDERLYING BIOCHEMICAL MECHANISMS 106
BIOLOGICAL EFFECTS OF NITROHETEROCYCLICS 106
NITRO REDUCTION AND BIOLOGICAL EFFECTS 107
REDUCTION CHEMISTRY OF NITROHETEROCYCLIC COMPOUNDS 108
REACTIONS OF 2-HYDROXYLAMINOIMIDAZOLES 108
REACTIONS OF HYDROXYLAMINES IN BIOLOGICAL SYSTEMS 110
CONCLUSIONS 111
REFERENCES 112
CHAPTER 20. RSU 1069, A NITROIMIDAZOLE CONTAINING AN AZIRIDINE GROUP 114
THE DIFFERENTIAL TOXICITY OF NITRO COMPOUNDS TOWARDS HYPOXIC MAMMALIAN CELLS 114
MOLECULAR STUDIES 115
CELL SURVIVAL IN VITRO 116
BIOFUNCTIONAL CHARACTER OF RSU 1069 117
TUMOUR CELL SURVIVAL IN VIVO 117
CONCLUSIONS 118
REFERENCES 118
CHAPTER 21. SENSITIZATION OF CANCER CHEMOTHERAPEUTIC AGENTS BY NITROHETEROCYCLICS 120
REFERENCES 123
CHAPTER 22. Benznidazole: nitroreduction and inhibition of cytochrome P-450 in chemosensitization of tumour response to cytotoxic drugs 126
REFERENCES 128
Chairman's Summary of Session D 130
REFERENCES 130