Mitomycin C (MC) is a cytotoxic chemotherapeutic agent that causes DNA damage in the form of
DNA cross-links as well as a variety of
DNA monoadducts and is known to induce p53. The various
DNA adducts formed upon treatment of mouse mammary
tumor cells with MC as well as 10-decarbamoyl MC (DMC) and
2,7-diaminomitosene (2,7-DAM), the major MC metabolite, have been elucidated. The cytotoxicity of DMC parallels closely that of MC in a number of rodent cell lines tested, whereas 2,7-DAM is relatively noncytotoxic. In this study, we investigate the ability of MC, DMC, and 2,7-DAM to activate p53 at equidose concentrations by treating tissue culture cell lines with the three
mitomycins. Whereas MC and DMC induced p53
protein levels and increased the levels of p21 and Gadd45
mRNA, 2,7-DAM did not. Furthermore, MC and DMC, but not 2,7-DAM, were able to induce apoptosis efficiently in ML-1 cells. Therefore the 2,7-DAM monoadducts were unable to activate the p53 pathway. Interestingly, DMC was able to initiate apoptosis via a p53-independent pathway whereas MC was not. This is the first finding that adducts of a multiadduct type
DNA-damaging agent are differentially recognized by DNA damage sensor pathways.