X-ray induction of O6-alkylguanine-DNA alkyltransferase protects against some of the biological effects of N-methyl-N'-nitro-N-nitrosoguanidine in C3H 10T1/2 cells.
We have shown previously that the repair of O6-methylguanine can be induced in murine fibroblasts (C3H 10T1/2 cells) by exposure to X rays. The magnitude of the response is less, however, than is observed in the well-characterized adaptive response of various prokaryotes to methylating agents. To determine whether the induction of O6-alkylguanine-DNA alkyltransferase in C3H 10T1/2 cells is sufficient for protection against the genotoxic effects of the methylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), cells were challenged with MNNG after alkyltransferase induction by 1.5 Gy X rays and assayed for cytotoxicity, mutagenicity, and neoplastic transformation. Preirradiated cells were significantly more resistant to the mutagenic effects of MNNG as scored by formation of ouabain-resistant colonies. The protective effect was greatest in cells challenged with a low dose (0.2 or 0.4 micrograms/ml) of MNNG. Protection against neoplastic transformation by MNNG was also observed, although the protective effect in this case was significant only in cells treated with a high dose (1.0 micrograms/ml) of MNNG. In cells that were preirradiated, there was no reduction in the cytotoxicity caused by MNNG or the chloroethylating agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). These data indicate that alkyltransferase induction in C3H 10T1/2 cells is sufficient to protect cells against some of the genotoxic effects of the alkylating agent MNNG. The data also suggest that formation of O6-alkylguanine may not be the only means by which alkylating agents can transform C3H 10T1/2 cells.
von Hofe
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Department of Pharmacology, University of Massachusetts Medical Center, Worcester 01655.
Kennedy
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D000818:Animals; D002330:Carmustine / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D004249:DNA Damage; D004790:Enzyme Induction / Q000528:radiation effects; D008769:Methylnitronitrosoguanidine / Q000633:toxicity*; D008780:Methyltransferases / Q000096:biosynthesis*; D051379:Mice; D008809:Mice, Inbred C3H; D009154:Mutation; D019853:O(6)-Methylguanine-DNA Methyltransferase; D014965:X-Rays
D008769:Methylnitronitrosoguanidine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002330:Carmustine