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 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.
Skapek
S X
SX
Department of Pediatrics, Duke University Medical Center, Durham, NC 27710.
Colvin
O M
OM
Griffith
O W
OW
Groothuis
D R
DR
Colapinto
E V
EV
Lee
Y
Y
Hilton
J
J
Elion
G B
GB
Bigner
D D
DD
Friedman
H S
HS
D000818:Animals; D019328:Buthionine Sulfoximine; D002460:Cell Line; D005260:Female; D005910:Glioma / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D014183:Transplantation, Heterologous
D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D005978:Glutathione