POTENTIATION OF TREOSULFAN TOXICITY BY THE GLUTATHIONE-DEPLETING AGENT BUTHIONINE SULFOXIMINE IN HUMAN-MALIGNANT GLIOMA-CELLS - THE ROLE OFBCL-2

Median survival of human malignant glioma patients is less than one ye ar even with cytoreductive surgery and postoperative radiotherapy. Adj uvant chemotherapy has been rather ineffective. Here, we studied the p otentiation by L-buthionine-[S,R]-sulfoximine (BSO), a glutathione-dep leting agent, of anticancer drug actions on two human malignant glioma cell lines, LN-229 and T98G. LN-229 has wild-type p53 status, T98G is mutant for p53. Glutathione levels were depleted by BSO with similar kinetics in both cell lines. Only LN-229 cells were growth-inhibited b y BSO. BSO had minor effects on the toxicity of doxorubicin, ACNU yrim idinyl)methyl]-3-(2-chlorethyl)-3-nitrosourea, nimustine) and vincrist ine. BSO failed to alter teniposide or cytarabine toxicity. BSO induce d prominent sensitization to the alkylating agent, treosulfan, in both cell lines, as assessed by viability assays, in situ DNA end labeling and quantitative DNA fragmentation. Treosulfan is thought to mediate toxicity via formation of reactive epoxides. In the absence of BSO, tr eosulfan had little acute cytotoxic and moderate antiproliferative eff ects. Synergistic glioma cell cytotoxicity induced by treosulfan and B SO was not associated with reactive oxygen species formation. Ectopic expression of bcl-2 did not alter basal glutathione levels but attenua ted glutathione depletion induced by BSO. Bcl-2 provided only moderate protection from synergistic induction of glioma cell death by treosul fan and BSO. Glutathione depletion may play a role in BSO-mediated che mosensitization, but other mechanisms are probably involved as well. B SO may be a useful agent for glioma cell sensitization to specific che motherapeutic drugs such as treosulfan. (C) 1998 Elsevier Science Inc.