Some derivatives of
phenazine 5,10-dioxide are selectively toxic to hypoxic cells commonly found in solid
tumors. Previous studies of the
phenazine 5,10-dioxide mechanism of action indicated that a bioreduction process could be involved in its selective toxicities, maybe as result of its potential H(*)-releasing capability in
hypoxia. The major unresolved aspect of the mechanism of
phenazine 5,10-dioxides is the identity of the
reductase(s) in the cell responsible for activating the
drug to its toxic form and metabolites. We have studied the metabolism in both
hypoxia and oxia of some selected 2-amino and
2-hydroxyphenazine 5,10-dioxides, 1- 5, using rat liver microsomal and cytosol fractions. Differential hypoxic/oxic metabolism was found to be correlated to a compound's cytotoxic selectivity but, in general, without metabolic differences between liver microsomal or cytosolic
enzymes.
Dicoumarol and
ketoconazole were found to inhibit the hypoxic metabolism of the most selective
phenazine 5,10-dioxide, 1, inferring a role for
DT-diaphorase and
cytochrome P450. The least hypoxic selective agents, 4 and 5, possess different
hypoxia-metabolic profiles as compared to derivative 1, explaining the differential cytotoxic
biological behavior. The nonselective derivative, 2, suffered bioreduction in both conditions and, according to the inhibition studies with
dicoumarol and
ketoconazole, involves both
DT-diaphorase and
cytochrome P450. The nontoxic derivative, 3, showed poor bioreductive behavior.