O6-alkylguanine DNA-alkyltransferase is not a major determinant of sensitivity to 1,3-bis(2-chloroethyl)-1-nitrosourea in four medulloblastoma cell lines.
The protein O6-alkylguanine-DNA alkyltransferase (O6-AGT) has been implicated as a major determinant of resistance of diverse tumors to chloroethylnitrosoureas. To evaluate the contribution of O6-AGT to resistance of medulloblastomas to chloroethylnitrosoureas, we assessed the role of O6-AGT in determining (BCNU). Sensitivity to BCNU cytotoxicity, measured as dose dependent survival of soft agar colony forming ability, varied among the lines. Two lines (UW443 and UW228-3) displayed linear survival curves and comparable BCNU sensitivity (D37 ca. 140 microM). The other lines (UW228-2 and UW228-1) had biphasic survival curves indicating that each line was composed of two sub-populations that differed in BCNU sensitivity. The D37 for these sub-populations ranged from 51 microM to 253 microM. The O6-AGT activities of the cell lines, however, did not reflect their varied susceptibilities to BCNU as evidenced by a 9-fold difference in O6-AGT activity between UW443 and UW228-3. Moreover, elimination of O6-AGT activity by the inhibitor O6-benzylguanine did not appreciably increase sensitivity to BCNU compared with the response of other human tumor cells [Dolan et al. Cancer Res. 51:3367-3372, 1991]. Our results demonstrate that O6-AGT is not a major determinant of BCNU sensitivity in the four medulloblastoma lines.
Silber
J R
JR
Department of Neurological Surgery, University of Washington, Seattle 98195.
Bobola
M S
MS
Ewers
T G
TG
Muramoto
M
M
Berger
M S
MS
D002330:Carmustine / Q000378:metabolism / Q000494:pharmacology*; D002470:Cell Survival; D002528:Cerebellar Neoplasms / Q000378:metabolism*; D004351:Drug Resistance; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008527:Medulloblastoma / Q000378:metabolism*; D008780:Methyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019853:O(6)-Methylguanine-DNA Methyltransferase; D014407:Tumor Cells, Cultured
C064976:O(6)-benzylguanine; D006147:Guanine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002330:Carmustine