Enhanced melphalan cytotoxicity following buthionine suffoximine-mediated glutathione depletion in a human medulloblastoma xenograft in athymic mice

The effect and therapeutic consequences of buthionine-(SR)-sulfoxi- (BS0)-mediated depletion of glutathione in the human medullo-blastoma-derived cell line, TE-671, growing as s.c. xenografts in athymic nude mice were examined. The glutathione content of the s.c. xenografts was 1.11 ±0.15 μmol/g (7.79 ± 1.61 nmol/mg of protein). Administration Lp. to tumor-bearing mice of D,L-BSO(two doses at 12-h intervals; 5 mmol/kg) depleted the glutathione content of the xenografts to 25.7% of control Administration of a 30 mM solution of L-BSO in drinking water for 96 h depleted the glutathione content to 17.4% of control Depletion of glutathione with these regimens resulted in a significant increase in the s.c. tumor growth delay over that produced by melphalan alone: 17.2 days versus 12.6 days for D,L-BSO (i.p.) plus melphalan versus melphalan and 22.9 days versus 16.6 days for L-BSO (p.o.) plus melphalan versus melphalan. These studies demonstrate the increased cytotoxicity of melphalan resulting from BSO-mediated depletion of glutathione in human medulloblastoma and support further efforts to modulate the chemosensitivity and radiosensitivity of this tumor by modulation of glutathione.