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

Abstract

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.