TY - JOUR
T1 - Buthionine sulfoximine-mediated depletion of glutathione in intracranial human glioma-derived xenografts
AU - Skapek, Stephen X.
AU - Colvin, O. Michael
AU - Griffith, Owen W.
AU - Groothuis, Dennis R.
AU - Colapinto, Edward V.
AU - Lee, Yisheng
AU - Hilton, John
AU - Elion, Gertrude B.
AU - Bigner, Darell D.
AU - Friedman, Henry S.
N1 - Funding Information:
* Supported by: NIH Grants CA44640, CA11898, NS 20023, K07 NS 00958, AM 26912, NS12745, NS 00814 and SlO-RR03321. t Address correspondence to: Henry S. Friedman, M.D., P.O. Box 2916, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710.
PY - 1988/11/15
Y1 - 1988/11/15
N2 - 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.
AB - 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.
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U2 - 10.1016/0006-2952(88)90612-0
DO - 10.1016/0006-2952(88)90612-0
M3 - Article
C2 - 3196356
AN - SCOPUS:0023727621
VL - 37
SP - 4313
EP - 4317
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
SN - 0006-2952
IS - 22
ER -