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

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...

Full description

Saved in:
Bibliographic Details
Published inBiochemical pharmacology Vol. 37; no. 22; p. 4313
Main Authors 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
Format Journal Article
LanguageEnglish
Published England 15.11.1988
Subjects
Animals
Buthionine Sulfoximine
Cell Line
Female
Glioma - metabolism
Glutathione - metabolism
Humans
Male
Methionine Sulfoximine - analogs & derivatives
Methionine Sulfoximine - pharmacology
Mice
Mice, Inbred BALB C
Transplantation, Heterologous
Online AccessGet more information

Cover

More Information
Summary: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.
ISSN:0006-2952
DOI:10.1016/0006-2952(88)90612-0