Medulloblastoma Xenograft in Athymic Mice Sulfoximine-mediated Glutathione Depletion in a Human Enhanced Melphalan Cytotoxicity following Buthionine

The effect and therapeutic consequences of buthionim--(.S'A)-sulfoximine (BSO)-inediated depletion of glutathione in the human medulloblastoma-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(imol/g(7.79± 1.61 nmol/mgof protein). Administration i.p. to tumor-bearing mice of n.i.-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 RIMsolution 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 mel phalan resulting from BSD-mediated depletion of glutathione in human medulloblastoma and support further efforts to modulate the chemosensitivity and radiosensitivity of this tumor by modulation of glutathione.