Properties of N-methyl-N-nitrosourea-resistant, Mex- derivatives of an SV40-immortalized human fibroblast cell line.
We have selected two N-methyl-N-nitrosourea (MNU)-resistant derivatives of the SV40-transformed, alkyltransferase-deficient (Mex-) human fibroblast cell line MRC5V1. Both derivatives remain Mex-. They are cross-resistant to methylmethanesulphonate (MMS) and 6-thioguanine (6TG) but not 2,6-diaminopurine. They show increased sensitivity to the bifunctional chloroethylating agent mitozolomide (MTZ). We have transfected MRC5V1 and one of our MNU-resistant lines with the bacterial O6-methylguanine (O6-MeG)-DNA methyltransferase (ada) gene. Transfectants of MRC5V1 are significantly more resistant to MNU but exhibit only a small increase in resistance to MMS and MTZ. Transfectants of the MNU-resistant derivative exhibit only a small additional increase in resistance to MNU, no further increase in resistance to MMS and a large increase in resistance to MTZ. The pattern of resistance to cytotoxic agents of these transfectants suggests that a second mechanism of resistance to MNU, independent of alkyltransferase expression, is operating in our resistant lines. This mechanism apparently enables the cells to tolerate O6-MeG and 6TG, but not chloroethyl adducts in their DNA.
Green
M H
MH
MRC Cell Mutation Unit, Sussex University, Brighton, UK.
Lowe
J E
JE
Petit-Frère
C
C
Karran
P
P
Hall
J
J
Kataoka
H
H
D002273:Carcinogens / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D004351:Drug Resistance; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D008770:Methylnitrosourea / Q000494:pharmacology*; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D019853:O(6)-Methylguanine-DNA Methyltransferase; D010957:Plasmids; D013539:Simian virus 40 / Q000235:genetics*; D014162:Transfection
D002273:Carcinogens; D008770:Methylnitrosourea; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase