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Enhanced Melphalan Cytotoxicity following Buthionine Sulfoximine-mediated Glutathione Depletion in a Human Medulloblastoma Xenograft in Athymic Mice¹

Departments of Pediatrics [S. X. S., H. S. F.], Pathology [D. D. B., H. S. F.], and Medicine [G. B. E.], and the Preuss Laboratory for Brain Tumor Research [D. D. B.], Duke University Medical Center, Durham, North Carolina 27710; the Johns Hopkins Oncology Center [O. M. C.], Baltimore, Maryland 21205; and the Department of Biochemistry [O. W. G.], Cornell University Medical College, New York, New York 10021

The effect and therapeutic consequences of buthionine-(SR)-sulfoximine (BSO)-mediated 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 µmol/g (7.79 ± 1.61 nmol/mg of protein). Administration i.p. 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.

¹ This work was supported by NIH Grants CA11898, 1 NINCDS NS 20023, 1 KO7 NS 00958, AM26912, and CA44640.

² To whom requests for reprints should be addressed, at P.O. Box 2916, Department of Pediatrics, Division of Hematology/Oncology, Duke University Medical Center, Durham, NC 27710.

Received 11/ 4/87. Revised 2/12/88. Accepted 2/18/88.

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