Selective Enhancement of Hypoxic Cell Killing by Melphalan Via Thiol Depletion: In Vitro Studies With Hypoxic Cell Sensitizers and Buthionine Sulfoximine2

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Abstract
The relationship between thiol depletion and its enhancement of melphalan (L-PAM) cytotoxicity was studied with the use of V-79-379A Chinese hamster cells in vitro. Selective killing of hypoxic cells by use of a specific and nonspecific reducer of endogenous cellular thiols was the approach used in combining drugs with disparate mechanisms of action. Noncytotoxic concentrations of agents were employed in those experiments designed to mimic a practical scheme for their implementation in vivo. Cells made hypoxic by gassing in suspension with 95% nitrogen and 5% CO2 were treated with buthionine S-R-sulfoximine (BSO), a specific inhibitor of glutathione synthesis and a hypoxic cell sensitizer (i.e., either misonidazole or SR-2508) before their exposure to the alkylating agent. Cellular loss of nonprotein thiols by treatment with BSO correlated with enhanced L-PAM toxicity; however, a far greater effect was achieved when this enzymatic inhibitor was used in combination with a hypoxic cell sensitizer. This chemopotentiation of hypoxic cell killing by L-PAM, along with little potentiation of toxic cell killing, indicated the practical and potential benefit of this sort of drug therapy in vivo.