Mitomycin resistance in mammalian cells expressing the bacterial mitomycinC resistance protein MCRA

The mitomycin C-resistance gene, mcrA, of Streptomyces lavendulae produces MCRA, a protein that protects this microorganism from its own antibiotic, t he antitumor drug mitomycin C. Expression of the bacterial mcrA gene in mam malian Chinese hamster ovary cells causes profound resistance to mitomycin C and to its structurally related analog porfiromycin under aerobic conditi ons but produces little change in drug sensitivity under hypoxia. The mitom ycins are prodrugs that are enzymatically reduced and activated intracellul arly, producing cytotoxic semiquinone anion radical and hydroquinone reduct ion intermediates. Irt vitro, MCRA protects DNA from crosslinking by the hy droquinone reduction intermediate of these mitomycins by oxidizing the hydr oquinone back to the parent molecule; thus, MCRA acts as a hydroquinone oxi dase. These findings suggest potential therapeutic applications for MCRA in the treatment of cancer with the mitomycins and imply that intrinsic or se lected mitomycin C resistance in mammalian cells may not be due solely to d ecreased bioactivation, as has been hypothesized previously, but instead co uld involve an MCRA-like mechanism.