MITOMYCIN-C AND MENADIONE FOR THE TREATMENT OF ADVANCED GASTROINTESTINAL CANCERS - A PHASE-II TRIAL

A phase II trial of menadione (2.5 g/m(2) as a continuous intravenous infusion over 48 h) followed by mitomycin C (10-20 mg/m(2) i.v. bolus) administered every 4-6 weeks was performed in 43 patients with advanc ed gastrointestinal cancer. Menadione, a vitamin K analog that lowers intracellular pools of reduced glutathione, was combined with mitomyci n C in an attempt to overcome thiol-mediated resistance to alkylating- agent chemotherapy, The median age of patients entered on this trial w as 58 years; performance status ranged from 60%-100%. None of the 43 e valuable patients obtained an objective response to this combination r egimen. Median survival was 6.6 months. Treatment with menadione and m itomycin C was reasonably well tolerated except for hematological toxi city. A total of 27% of treatment courses were complicated by grade 3 or 4 hematological toxicity including one episode of hemolytic anemia and one episode of hemolytic uremic syndrome, One patient developed ir reversible interstitial pneumonitis, and 1 patient had an asymptomatic decrease in the left-ventricular ejection fraction. Despite preclinic al evidence indicating that menadione pretreatment enhances the cytoto xicity of mitomycin C, our study documents the resistance of advanced gastrointestinal cancers, particularly colorectal cancer, to mitomycin C modulated by menadione.