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 language | English (US) |
|---|---|
| Pages (from-to) | 4313-4317 |
| Number of pages | 5 |
| Journal | Biochemical Pharmacology |
| Volume | 37 |
| Issue number | 22 |
| DOIs | |
| State | Published - Nov 15 1988 |
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ASJC Scopus subject areas
- Pharmacology
Cite this
Buthionine sulfoximine-mediated depletion of glutathione in intracranial human glioma-derived xenografts. / Skapek, Stephen X.; Colvin, O. Michael; Griffith, Owen W.; Groothuis, Dennis R.; Colapinto, Edward V.; Lee, Yisheng; Hilton, John; Elion, Gertrude B.; Bigner, Darell D.; Friedman, Henry S.
In: Biochemical Pharmacology, Vol. 37, No. 22, 15.11.1988, p. 4313-4317.Research output: Contribution to journal › Article
}
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.
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.
UR - http://www.scopus.com/inward/record.url?scp=0023727621&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0023727621&partnerID=8YFLogxK
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 -