Mechanism of DNA strand breaks by mitonafide, an imide derivative of 3-nitro-1,8-naphthalic acid

The metabolism and the mechanism of action of 5-nitro-2-(2-dimethylaminoethyl)-benzo(de) isoquinoline-1,3-dione (mitonafide), a nitro-containing antitumor drug, have been studied. Incubation of mitonafide under anaerobic conditions with rat liver microsomes and NADPH formed the fully reduced amine metabolite, 5-aminomitonafide. The formation of the amine metabolite was not inhibited by SKF-525A, metyrapone or piperonyl butoxide, indicating that the cytochrome P-450 was not involved in this reduction. Incubation of mitonafide with rat liver microsomes and NADPH under aerobic conditions stimulated oxygen consumption; piperonyl butoxide, SKF-525A, superoxide dismutase and catalase had no effect on this stimulation. Both mitonafide and 5-aminomitonafide were found to bind to DNA in a similar manner. However, in inducing single-stand breaks in the DNA of L1210 cells mitonafide was 10-fold more potent than 5-aminomitonafide. These results suggest that metabolic activation of mitonafide to species Other than that of the amine metabolite may play a significant role in the induction of DNA damage and the biological activity of the drug.