The role of glutathione in radiation and drug induced cytotoxicity.

The cellular response to radiation and various chemotherapy drugs, whose mechanism in part includes production of free radicals or DNA damage, may be altered by modification of cellular thiols. The recent introduction of agents which either inhibit glutathione (GSH) biosynthesis (buthionine sulfoximine, BSO) or stimulate GSH synthesis (oxothiazolidine-4-carboxylate, OTZ) has enabled detailed studies assessing the role of GSH in the radiation and chemotherapy response. GSH depletion by BSO has resulted in radiosensitization of both aerobic and hypoxic cells, with some discrepancy among laboratories as to the extent of sensitization of hypoxic cells. GSH elevation (by approximately 200% of control) has resulted in modest protection of aerobic and hypoxic cells. GSH has been shown to play an important role in the radiosensitization of hypoxic cells using nitroimidazoles. The extent of nitroimidazole hypoxic radiosensitization has recently been shown to depend on intracellular GSH levels. Recent findings that some human tumour cell lines, as opposed to rodent cell lines, are high in cellular GSH have prompted a need to evaluate in vivo, GSH levels in human tumours. Possible roles of GSH in the chemotherapy response include: (1) detoxification of H2O2 and/or organoperoxides through GSH peroxidase, (2) non-catalyzed nucleophilic reaction of GSH and drug, (3) binding of the drug with GSH catalyzed by GSH transferase, and (4) activation of certain drugs to toxic species by GSH. The role of GSH as it relates to the various topics mentioned above is discussed with emphasis on direction for future studies.