Increased O6-methylguanine-DNA methyltransferase activity and reduced mutability in 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2- chloroethyl)-3-nitrosourea-resistant HeLa S3 cells.
To clarify the involvement of O6-methylguanine (O6-MeG) in mutagenesis, we have been trying to isolate Mer+ cells from a HeLa S3 Mer- cell line, and to compare the mutation frequencies between the cell lines. We previously isolated the N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-resistant cells, MR10-1, from HeLa S3 Mer- cells. However, the MR10-1 cells still had only a little O6-MeG-DNA methyltransferase (MT) activity. In the present study, we have isolated two 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU)-resistant cells, ACr41 and ACr42, from the MR10-1 cells. The two ACr cells had increased MT activities. The ACr cells were also significantly more resistant to 1-(2-chloroethyl)-1-nitrosourea and slightly more resistant to MNNG than the MR10-1 cells. When the mutation frequencies were tested at the hypoxanthine-guanine phosphoribosyl transferase and ouabain loci in these cell lines, the two ACr cells were more resistant to the mutagenic effect of MNNG than the MR10-1 cells. These results show the linkage between the resistance to the cytotoxic effect of nitrosourea compounds and MT activity, and strongly support the hypothesis that O6-MeG is the main pre-mutagenic lesion induced by MNNG.
Ishida
R
R
Laboratory of Biochemistry, Aichi Cancer Center Research Institute, Nagoya, Japan.
Takahashi
T
T
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000494:pharmacology; D004351:Drug Resistance; D006367:HeLa Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007700:Kinetics; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D008780:Methyltransferases / Q000378:metabolism*; D015376:Nimustine; D009607:Nitrosourea Compounds / Q000494:pharmacology*; D019853:O(6)-Methylguanine-DNA Methyltransferase
D000970:Antineoplastic Agents; D009607:Nitrosourea Compounds; D015376:Nimustine; D008769:Methylnitronitrosoguanidine; D004247:DNA; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase