A human cell line proficient in O6-methylguanine-DNA-methyltransferase and hypersensitive to alkylating agents

• Published in: Carcinogenesis (New York) Vol. 14; no. 8; p. 1671
• Main Authors: Lefebvre, P, Laval, F
• Format: Journal Article
• Language: English
• Published: England 01-08-1993
• Subjects: Alkylating Agents - toxicity; Animals; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - enzymology; Carcinoma, Hepatocellular - pathology; Cell Death - drug effects; Cell Division - drug effects; CHO Cells - enzymology; Cricetinae; DNA Damage - physiology; DNA Repair - physiology; Drug Hypersensitivity - enzymology; Drug Hypersensitivity - etiology; Drug Resistance; Guanine - analogs & derivatives; Guanine - metabolism; Guanine - physiology; Humans; Liver Neoplasms - drug therapy; Liver Neoplasms - enzymology; Liver Neoplasms - pathology; Liver Neoplasms, Experimental - drug therapy; Liver Neoplasms, Experimental - enzymology; Liver Neoplasms, Experimental - pathology; Methylnitronitrosoguanidine - toxicity; Methylnitrosourea - toxicity; Methyltransferases - metabolism; O-Methylguanine-DNA Methyltransferase; Phenotype; Rats; Tumor Cells, Cultured - drug effects
• ISSN: 0143-3334
• DOI: 10.1093/carcin/14.8.1671

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.