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.