[Mechanisms of cellular resistance to chloroethylnitrosourea in cell lines derived from human brain tumors].
The cytotoxic and cytogenetic effects 1-(4-amino-2-methyl 1-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) and 1, 3-bis (2-chloroethyl)-1-nitrosourea (BCNU) treatments on five cell lines derived from human malignant glioma were studied. Compared to sensitive cell line SF-126, SF-188 cells were 3- to 6.9 fold more resistant to the cytotoxic effect and 8 to 14 fold more resistant to the induction of sister chromatid exchanges (SCEs). Cytotoxic effects and induction of SCEs were intermediate for SF-268, SF-210 and SF-295 cell lines compared with SF-126 and SF-188. There was a good correlation between susceptibility to the cytotoxic effects and formation of DNA interstrand crosslinks for cells treated with ACNU and BCNU. The effects of cis-diamminedichloroplatinum (II) (cis-Pt) and nitrogen mustard (HN2) in these cells were also studied. Cis-Pt was equally cytotoxic and induced the same number of SCEs and DNA interstrand cross-links in all five cel lines. In contrast to the results obtained by treatment with chloroethylnitrosoureas (CENUs), SF-126 cells treated with HN2 were more resistant to the cytotoxic effects, the induction of SCEs, and the induction of DNA interstrand cross-links than were SF-188 cells. The repair of O6-methylguanine after treatment of these cell lines with (3H) methylnitrosourea were quantitated. SF-126 cells showed no detectable repair of O6-methylguanine, SF-268, SF-210 and SF-295 cells had intermediate levels of repair, and SF-188 had very high level of repair. These results suggest that cellular resistance to CENUs dose not result in cross-resistance to HN2 or cis-Pt, and that one of mechanisms of cellular resistance to CENUs is increased repair of O6-alkylguanine derivatives in DNA, which prevents DNA interstrand cross-links and then reduces both cytotoxic effects and the induction of SCEs in cell resistant to CENUs.
Aida
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Department of Neurosurgery, Hokkaido University, School of Medicine, Sapporo, Japan.
D001932:Brain Neoplasms / Q000473:pathology*; D002330:Carmustine / Q000494:pharmacology*; D002460:Cell Line; D004249:DNA Damage; D004351:Drug Resistance; D005910:Glioma / Q000473:pathology*; D006801:Humans; D015376:Nimustine; D009607:Nitrosourea Compounds / Q000494:pharmacology*; D012854:Sister Chromatid Exchange; D014407:Tumor Cells, Cultured / Q000187:drug effects
D009607:Nitrosourea Compounds; D015376:Nimustine; D002330:Carmustine