The effects of pretreatment of human tumour cells with MNNG on the DNA crosslinking and cytotoxicity of mitozolomide.

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.