title: Glutathione depletion, radiosensitization, and misonidazole potentiation in hypoxic Chinese hamster ovary cells by buthionine sulfoximine.
abstract: Buthionine sulfoximine (BSO) inhibits the synthesis of glutathione (GSH), the major nonprotein sulfhydryl (NPSH) present in most mammalian cells. BSO concentrations from 1 microM to 0.1 mM reduced intracellular GSH at different rates, while BSO greater than or equal to 0.1 mM (i.e., 0.1 to 2.0 mM), resulting in inhibitor-enzyme saturation, depleted GSH to less than 10% of control within 10 hr at about equal rates. BSO exposures used in these experiments were not cytotoxic with the one exception that 2.0 mM BSO/24 hr reduced cell viability to approximately 50%. However, alterations in either the cell doubling time(s) or the cell age density distribution(s) were not observed with the BSO exposures used to determine its radiosensitizing effect. BSO significantly radiosensitized (ER = 1.41 with 0.1 mM BSO/24 hr) hypoxic, but not aerobic, CHO cells when the GSH and NPSH concentrations were reduced to less than 10 and 20% of control, respectively, and maximum radiosensitivity was even achieved with microM concentrations of BSO (ER = 1.38 with 10 microM BSO/24 hr). Furthermore, BSO exposure (0.1 mM BSO/24 hr) also enhanced the radiosensitizing effect of various concentrations of misonidazole on hypoxic CHO cells.
mesh_terms: D000818:Animals; D019328:Buthionine Sulfoximine; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects*; D006224:Cricetinae; D003412:Cricetulus; D004307:Dose-Response Relationship, Radiation; D004357:Drug Synergism; D005260:Female; D005978:Glutathione / Q000502:physiology*; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008920:Misonidazole / Q000494:pharmacology*; D009593:Nitroimidazoles / Q000494:pharmacology*; D010053:Ovary; D010100:Oxygen; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D008920:Misonidazole; D005978:Glutathione; D010100:Oxygen