Circumvention of deficient activation in mitomycin C-resistant human colonic carcinoma cells by the mitomycin C analogue BMY25282.

BMY25282, a newly designed analogue of mitomycin C (MMC) with the substitution of an amidine group at position 7 of MMC, can circumvent MMC resistance in a series of human colonic carcinoma cells that were selected for resistance to MMC (J.K.V. Willson et al., Cancer Res., 45:5281-5286, 1985). In this study MMC resistance was found to be associated with an inability of the resistant cells to activate MMC. However, both the MMC-sensitive and -resistant cells were observed to metabolize BMY25282 extensively in vitro to a reactive species capable of alkylating 4-(p-nitrobenzyl)pyridine (a trapping agent for activated drug). The results of these studies suggested that the deficient cellular reductive activating mechanism was associated with MMC resistance and that analogue BMY25282 was able to overcome this deficiency in MMC-resistant cells by virtue of its enhanced activation.