MITOMYCIN-C - A PROTOTYPE BIOREDUCTIVE AGENT

Hypoxic cells of solid tumors represent a therapeutically resistant po pulation that limits the curability of many solid tumors by x-irradiat ion and by most chemotherapeutic agents. The oxygen deficit, however, creates an environment conducive to reductive processes that results i n a major exploitable difference between normal and neoplastic tissues . Mitomycin C (MC) can be reductively activated by a number of oxidore ductases, in a process required for the production of its therapeutic effects. This enzymatic reduction results in preferential activation o f MC under hypoxia and, in most instances, the production of greater t oxicity to oxygen-deficient cells than to their oxygenated counterpart s. DNA appears to be the most important target of the reactive species generated from MC, with both mono- and bis-adducts of DNA being forme d in drug-treated cells. The demonstration that MC, used to kill the h ypoxic fraction, in combination with x-irradiation, to eradicate the o xygenated portion of the tumor, produced enhanced cytodestructive effe cts on solid tumors of animals has led to the clinical evaluation of t he mitomycin antibiotics in combination with x-rays in patients with c ancers of the head and neck. The findings from these clinical trials h ave demonstrated the utility of directing a concerted therapeutic atta ck on the hypoxic fraction of solid tumors as an approach toward enhan cing the curability of localized neoplasms by x-irradiation.