Increased repair of O6-alkylguanine DNA adducts in glioma-derived human cells resistant to the cytotoxic and cytogenetic effects of 1,3-bis(2-chloroethyl)-1-nitrosourea.
We investigated the cytotoxic and cytogenetic effects of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) treatment on two cell lines derived from human glioma biopsy specimens. SF-188 cells are 3-fold more resistant to the cytotoxic effects of BCNU and 14-fold more resistant to sister chromatid exchange (SCE) induction caused by BCNU treatment than are SF-126 cells. After treatment with BCNU, 60% fewer DNA interstrand crosslinks were found in SF-188 than in SF-126 cells. The O6-methylguanine alkylation product was removed rapidly from DNA in SF-188 cells treated with [3H]methylnitrosourea, but very little repair of alkylation product occurred in SF-126 cells. These results suggest that one of the mechanisms responsible for cellular resistance to BCNU treatment is increased repair of O6-alkylguanine products in DNA, which reduces the number of crosslinks formed and thereby increases survival and reduces the number of SCEs induced in resistant cells.
W J
WJ
Bodell
T
T
Aida
M S
MS
Berger
M L
ML
Rosenblum
D000478:Alkylation; D002330:Carmustine / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism*; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005910:Glioma / Q000378:metabolism; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D008770:Methylnitrosourea / Q000378:metabolism; D008780:Methyltransferases / Q000032:analysis; D009603:Nitroso Compounds / Q000494:pharmacology; D019853:O(6)-Methylguanine-DNA Methyltransferase; D012854:Sister Chromatid Exchange / Q000187:drug effects*; D014316:Tritium
D009603:Nitroso Compounds; D014316:Tritium; D006147:Guanine; C041148:N-(2-chloroethyl)-N-nitrosoacetamide; D008770:Methylnitrosourea; D004247:DNA; C008449:O-(6)-methylguanine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002330:Carmustine