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 advanced gastrointestinal cancer. Menadione, a vitamin K analog that lowers intracellular pools of reduced glutathione, was combined with mitomycin C in an attempt to overcome thiol-mediated resistance to alkylating-agent chemotherapy, The median age of patients entered on this trial was 58 years; performance status ranged from 60%-100%. None of the 43 evaluable patients obtained an objective response to this combination regimen. Median survival was 6.6 months. Treatment with menadione and mitomycin C was reasonably well tolerated except for hematological toxicity. 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 irreversible interstitial pneumonitis, and 1 patient had an asymptomatic decrease in the left-ventricular ejection fraction. Despite preclinical evidence indicating that menadione pretreatment enhances the cytotoxicity of mitomycin C, our study documents the resistance of advanced gastrointestinal cancers, particularly colorectal cancer, to mitomycin C modulated by menadione.