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

S. X. Skapek, O. M. Colvin, O. W. Griffith, G. B. Elion, D. D. Bigner, H. S. Friedman

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Abstract

The effect and therapeutic consequences of buthionine-(SR)-sulfoximine (BSO)-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 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.

Original languageEnglish (US)
Pages (from-to)2764-2767
Number of pages4
JournalCancer Research
Volume48
Issue number10
StatePublished - 1988

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Buthionine Sulfoximine
Medulloblastoma
Melphalan
Heterografts
Nude Mice
Glutathione
Neoplasms
Radiation Tolerance
Therapeutic Uses
Drinking Water
Cell Line
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Enhanced melphalan cytotoxicity following buthionine sulfoximine-mediated glutathione depletion in a human medulloblastoma xenograft in athymic mice. / Skapek, S. X.; Colvin, O. M.; Griffith, O. W.; Elion, G. B.; Bigner, D. D.; Friedman, H. S.

In: Cancer Research, Vol. 48, No. 10, 1988, p. 2764-2767.

Research output: Contribution to journalArticle

Skapek, S. X. ; Colvin, O. M. ; Griffith, O. W. ; Elion, G. B. ; Bigner, D. D. ; Friedman, H. S. / Enhanced melphalan cytotoxicity following buthionine sulfoximine-mediated glutathione depletion in a human medulloblastoma xenograft in athymic mice. In: Cancer Research. 1988 ; Vol. 48, No. 10. pp. 2764-2767.
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AU - Colvin, O. M.

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AU - Bigner, D. D.

AU - Friedman, H. S.

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N2 - The effect and therapeutic consequences of buthionine-(SR)-sulfoximine (BSO)-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 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.

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