Modulation of the antineoplastic efficacy of mitomycin C by dicoumarol in vivo

Dicoumarol (DIC) modulates the intracellular metabolism of mitomycin C (MC) in vitro, increasing the toxicity of MC to hypoxic EMT6 cells and decreasing its toxicity to aerobic cells. The present experiments assessed whether DIC could be used to increase the therapeutic ratio attainable in vivo when MC was used as an adjunct to radiotherapy. Experiments with transplanted EMT6 tumors in mice showed that DIC increased the toxicity of MC to hypoxic tumor cells and increased the antineoplastic efficacy of regimens combining MC with radiation. DIC did not increase the hematologic toxicity of MC, and pretreatment with DIC plus MC did not augment radiation-induced skin reactions. The increase in antineoplastic effect was therefore obtained without a concomitant increase in normal tissue toxicities, and therapeutic gain was obtained.