OXIDATIVE-METABOLISM OF MITOXANTRONE BY THE HUMAN NEUTROPHIL ENZYME MYELOPEROXIDASE

The anti-cancer drug mitoxantrone is readily oxidized by the human heme enzyme myeloperoxidase (MPG) and H2O2. Direct oxidation yielded up to three products, which depended on the ratio of H2O2 to mitoxantrone. At an H2O2:mitoxantrone ratio of 1.0, one major product was obtained, with a spectrum and HPLC retention time identical to that resulting from oxidation by horseradish peroxidase. This metabolite is a substituted hexahydronaphtho[2,3-f]quinoxaline-7,12-dione and has been discovered in the urine of patients treated with mitoxantrone, hence implicating MPO in the in vivo metabolism of mitoxantrone. At higher concentrations of H2O2, the oxidation of mitoxantrone was more complex, with two further metabolites being identified. When mitoxantrone was incubated with neutrophils that had been stimulated with phorbol myristate acetate, it was oxidized by an MPO-dependent mechanism. Therefore, it appears that MPO may play a significant role in the clinical activity displayed by mitoxantrone against acute myelogenous leukemias, as neutrophils, monocytes and their bone marrow precursors contain high levels of the enzyme.