Buthionine sulfoximine-mediated depletion of glutathione in intracranial human glioma-derived xenografts

Stephen X. Skapek, O. Michael Colvin, Owen W. Griffith, Dennis R. Groothuis, Edward V. Colapinto, Yisheng Lee, John Hilton, Gertrude B. Elion, Darell D. Bigner, Henry S. Friedman

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

D-54 MG, a human glioma-derived continuous cell line growing as subcutaneous or intracranial xenografts in athymic mice, was found to be sensitive to the effects of d,l-buthionine-(SR)-sulfoximine, a selective inhibitor of γ-glutamylcysteine synthetase. Intraperitoneal administration of one dose of buthionine sulfoximine (BSO, 5 mmol/kg) resulted in depletion of total intracellular glutathione to 57 and 47% of control 12 hr, and 73 and 23% of control 24 hr, after BSO in subcutaneous and intracranial xenografts respectively. Concurrent measurement of total glutathione in the contralateral (non-tumor-containing) cerebral hemisphere in mice bearing intracranial D-54 xenografts demonstrated insignificant depletion of glutathione. Multiple doses of BSO, at 12-hr intervals, resulted in further depletion to 27% (s.c.) and 16.5% (i.c.) of control 12 hr following the final dose of BSO. Quantitative analysis of BSO delivery to xenograft and contralteral brain tissue revealed transfer constants, K1, of 15.8-24.1 × 10-3 and 2.4 × 10-3 ml · g-1 · min-1 for xenograft and "normal" brain respectively. This highly selective depletion of glutathione in neoplastic tissue versus surrounding non-neoplastic host tissue may have therapeutic implications for the rational use of chemotherapeutic and radiotherapeutic intervention.

Original languageEnglish (US)
Pages (from-to)4313-4317
Number of pages5
JournalBiochemical Pharmacology
Volume37
Issue number22
DOIs
StatePublished - Nov 15 1988

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

Fingerprint Dive into the research topics of 'Buthionine sulfoximine-mediated depletion of glutathione in intracranial human glioma-derived xenografts'. Together they form a unique fingerprint.

  • Cite this

    Skapek, S. X., Colvin, O. M., Griffith, O. W., Groothuis, D. R., Colapinto, E. V., Lee, Y., Hilton, J., Elion, G. B., Bigner, D. D., & Friedman, H. S. (1988). Buthionine sulfoximine-mediated depletion of glutathione in intracranial human glioma-derived xenografts. Biochemical Pharmacology, 37(22), 4313-4317. https://doi.org/10.1016/0006-2952(88)90612-0