methylnitronitrosoguanidine has been researched along with Drug-Hypersensitivity* in 2 studies
2 other study(ies) available for methylnitronitrosoguanidine and Drug-Hypersensitivity
| Article | Year |
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Human monocytes, but not dendritic cells derived from them, are defective in base excision repair and hypersensitive to methylating agents.
Monocytes and dendritic cells are key players in the immune response. Because dendritic cells drive the tumor host defense, it is important that monocytes and dendritic cells survive cytotoxic tumor therapy. Although most of the anticancer drugs target DNA, the DNA repair capacity of monocytes and dendritic cells has not yet been investigated. We studied the sensitivity of monocytes and monocyte-derived dendritic cells against various genotoxic agents and found monocytes to be more sensitive to overall cell kill and apoptosis upon exposure to methylating agents (e.g., N-methyl-N'-nitro-N-nitrosoguanidine, methyl methanesulfonate, and the anticancer drug temozolomide). On the other hand, upon treatment with the cross-linking chemotherapeutics fotemustine, mafosfamide, and cisplatin, monocytes and dendritic cells responded in the same way. Monocytes were also more sensitive than lymphocytes. The data indicate a defect in the repair of DNA methylation damage in monocytes. Because the expression of the repair protein O(6)-methylguanine-DNA methyltransferase was higher in monocytes than in dendritic cells, and because its inhibition by O(6)-benzylguanine had no effect on the sensitivity of monocytes, we investigated the base excision repair (BER) pathway. In contrast to dendritic cells, monocytes are unable to perform BER following exposure to methylating agents. Expression studies revealed that monocytes lack XRCC1 and ligase IIIalpha, whereas dendritic cells, similar to human lymphocytes, express these repair proteins at a high level. The data revealed a DNA repair defect in a specific human cell population. The BER defect in monocytes may cause them to be selectively killed during tumor therapy with alkylating agents, provoking hematotoxicity and sustained immunosuppression. Topics: Alkylating Agents; Cell Survival; Cells, Cultured; Dacarbazine; Dendritic Cells; DNA Methylation; DNA Repair; Drug Hypersensitivity; Humans; Methyl Methanesulfonate; Methylnitronitrosoguanidine; Monocytes; Mutagens; Temozolomide | 2007 |
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. Topics: Alkylating Agents; Animals; Carcinoma, Hepatocellular; Cell Death; Cell Division; CHO Cells; Cricetinae; DNA Damage; DNA Repair; Drug Hypersensitivity; Drug Resistance; Guanine; Humans; Liver Neoplasms; Liver Neoplasms, Experimental; Methylnitronitrosoguanidine; Methylnitrosourea; Methyltransferases; O(6)-Methylguanine-DNA Methyltransferase; Phenotype; Rats; Tumor Cells, Cultured | 1993 |