PHASE-I STUDY OF MITOMYCIN-C AND MENADIONE IN ADVANCED SOLID TUMORS

A phase I study of mitomycin C with menadione (2-methyl-1,4-naphthoqui none, a vitamin K analogue which lowers intracellular pools of reduced glutathione) was designed as an approach to overcoming tumor cell res istance to alkylating agent chemotherapy. Patients with refractory sol id tumors (it = 51) were treated with a 48-h continuous intravenous in fusion of menadione followed by a bolus intravenous dose of mitomycin C at the completion of the menadione infusion. Initial menadione doses of 8.0 and 4.0 g/m(2) over 48 h were associated with hemolysis, so su bsequent dose levels of menadione ranged from 1.0 to 3.0 g/m(2) with m itomycin C from 5 to 20 mg/m(2). All three patients treated with menad ione at 8.0 g/m(2) and the single patient treated at 4.0 g/m(2) with m itomycin C at 5 mg/m(2) developed clinically significant hemolysis des pite the presence of red blood cell glucose-6-phosphate dehydrogenase. Subsequently, a revised escalation scheme for menadione was used, and all patients tolerated menadione doses of 1-2.5 g/m(2) over 48 h with mitomycin C doses up to 20 mg/m(2). Since the 3.0 g/m(2) dose of mena dione was associated with mild hemolysis in three of four patients, th e maximum tolerated dose of menadione was established at 2.5 g/m(2). A ll of the mitomycin dose levels were tolerated without unexpected toxi cities attributable to the combination. Prolonged infusions of menadio ne at doses which have been associated with lowering of intracellular glutathione pools in short-term exposure are limited by dose-dependent hemolysis, probably due to depletion of erythrocyte glutathione by me nadione-related redox cycling. There was no detectable deleterious eff ect of pre-exposure to menadione on mitomycin C tolerance. We recommen d a combination of menadione at 2.5 g/m(2) as a continuous intravenous infusion and mitomycin C at 15 mg/m(2) for further study in solid tum ors for which treatment with single-agent mitomycin C is appropriate.