There is considerable evidence that the existence of hypoxic cells in human tumors may pose a problem for clinical radiotherapy. The purpose of this project is to study the effects of ionizing radiation delivered at different exposure rates with respect to cell killing, cell cycle status, and cellular redox potential of mammalian cells grown either under aerated or hypoxic conditions. A major portion of this study will be concerned with various means of modulating the cellular redox potential by using drugs that either deplete or elevate cellular glutathione (GSH). Depletion of GSH by buthionine sulfoximine (BSO) enhanced nitroimidazole (2508) sensitization while GSH elevation by oxothiazoidine (OTZ) provided protection of 2508 hypoxic sensitization. Human tumor cell lines were found to be high in cellular GSH and thus less responsive to 2508 sensitization than hamster cell lines. These data may provide explanations for the failure of nitroimidazoles in the clinic. These human tumor cell lines found to be high in GSH can be markedly sensitized to nitroimidazoles by GSH depletion. Preliminary studies have begun using GSH esters to rapidly increase GSH levels and ascertain radiation effects. These esters may be useful in restoring GSH levels of BSO treated cells in an attempt to get back to baseline GSH levels after BSO sensitization.
