A human cell line proficient in O6-methylguanine-DNA-methyltransferase and hypersensitive to alkylating agents.
The involvement of O6-methylguanine (O6-meGua) in mutagenesis is well established, while the toxic effect of these residues is still controversial. In this study, we compare the cytotoxicity of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and N-methyl-N-nitrosourea (MNU) on three cell lines of different origin, which have different abilities to repair O6-meGua residues (Mer phenotype): a human hepatoma cell line (LICH cells, Mer+), a rat hepatoma cell line (H4 cells, Mer+) and a Chinese hamster cell line (CHO cells, Mer- phenotype). LICH and CHO cells show the same sensitivity to the killing effect of MNNG and MNU and are approximately 5-fold more sensitive than H4 cells. However, LICH and H4 cells share similar sensitivities to the toxic effect of 1,3-bis(2-chloroethyl)-1-nitrosourea. O6-meGua residues are removed at the same rate from the DNA of [3H]MNU-treated LICH and H4 cells, which also do not differ in the rate of removal of N3-methyladenine residues nor in overall DNA repair synthesis. The results suggest that MNNG and MNU produce a lethal lesion that is repaired by a process that does not involve the alkyltransferase.
Lefebvre
P
P
Groupe Radiochimie de l'ADN, U247 INSERM, Institut Gustave Roussy, Villejuif, France.
Laval
F
F
D000477:Alkylating Agents / Q000633:toxicity*; D000818:Animals; D016466:CHO Cells / Q000201:enzymology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D006224:Cricetinae; D004249:DNA Damage / Q000502:physiology; D004260:DNA Repair / Q000502:physiology*; D004342:Drug Hypersensitivity / Q000201:enzymology* / Q000209:etiology; D004351:Drug Resistance; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D008769:Methylnitronitrosoguanidine / Q000633:toxicity; D008770:Methylnitrosourea / Q000633:toxicity; D008780:Methyltransferases / Q000378:metabolism*; D019853:O(6)-Methylguanine-DNA Methyltransferase; D010641:Phenotype; D051381:Rats; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000477:Alkylating Agents; D008769:Methylnitronitrosoguanidine; D006147:Guanine; D008770:Methylnitrosourea; C008449:O-(6)-methylguanine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase