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

Published

Journal Article

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 gamma-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 contralateral brain tissue revealed transfer constants, K1, of 15.8-24.1 x 10(-3) and 2.4 x 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.

Full Text

Duke Authors

Cited Authors

  • Skapek, SX; Colvin, OM; Griffith, OW; Groothuis, DR; Colapinto, EV; Lee, Y; Hilton, J; Elion, GB; Bigner, DD; Friedman, HS

Published Date

  • November 1988

Published In

Volume / Issue

  • 37 / 22

Start / End Page

  • 4313 - 4317

PubMed ID

  • 3196356

Pubmed Central ID

  • 3196356

Electronic International Standard Serial Number (EISSN)

  • 1873-2968

International Standard Serial Number (ISSN)

  • 0006-2952

Digital Object Identifier (DOI)

  • 10.1016/0006-2952(88)90612-0

Language

  • eng