title: The effects of pretreatment of human tumour cells with MNNG on the DNA crosslinking and cytotoxicity of mitozolomide.
abstract: Mitozolomide and its decomposition product MCTIC were found to be more cytotoxic to BE colon carcinoma cells in vitro than to HT-29 cells, another colon carcinoma cell line. In addition mitozolomide and MCTIC induced DNA interstrand crosslinks in the BE but not the HT-29 cell line. BE cells are deficient in the repair of O6-methylguanine lesions and are designated Mer-, whereas, HT-29 cells are proficient in this repair process and are designated Mer+. Thus DNA interstrand crosslinking produced by mitozolomide and MCTIC appears to correlate with the Mer phenotype. Pretreatment of HT-29 cells (Mer+) with the DNA methylating agent MNNG allows mitozolomide or MCTIC to produce DNA interstrand crosslinks. HT-29 cells also become more sensitive to the cell killing of mitozolomide and MCTIC with MNNG pretreatment. Pretreatment of Mer- cells (BE) had little effect on either cell killing or DNA crosslinking levels induced by mitozolomide or MCTIC. DNA interstrand crosslinking induced by mitozolomide and MCTIC is probably a consequence of an initial alkylation at the O6-position of guanine followed by a delayed reaction with the opposite DNA strand.
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism*; D003432:Cross-Linking Reagents; D004247:DNA / Q000378:metabolism*; D004357:Drug Synergism; D006801:Humans; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology*; D009588:Nitrogen Mustard Compounds / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay
chemical_list: D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D009588:Nitrogen Mustard Compounds; D008769:Methylnitronitrosoguanidine; D004247:DNA; C040369:mitozolomide