Mitoxantrone (1,4dihydroxy5,8bis{2[(2hydroxyethyl) amino]ethyl} amino 9,10- anthracenedione; MXH2) is a novel anthracenedionebased anticancer agent which is useful in the treatment of leukemia and breast cancer. MXH2 is administered intravenously and therefore it can interact directly with blood components and blood component products. Earlier studies have established that oxidative activation may be important for the drug biological activity and, possibly, its cytotoxicity. Our goal is to elucidate the role of reactive nitrogen species (RNS) in the oxidative non-enzymatic activation of mitoxantrone to active quinonoid metabolites. We have already shown that mitoxantrone can function as a trap of nitrous acid, HNO2. This species is formed from nitrite at acid pH and is highly mutagenic (carcinogenic) and cytotoxic. The reaction of HNO2 with MXH2 leads to oxidation of the drug through free radical intermediates, and its transformation to products that are identical to those produced by enzymatic oxidation (by horseradish peroxidase or myeloperoxidase). The primary objective of the present study was to investigate the interaction between MXH2 and the nitrogen dioxide radical (?NO2). This radical is an important air pollutant but it can also be produced in vivo from nitrite ((NO2-) by its enzymatic oxidation, or along the nitric oxide (?NO) pathway. To generate ?NO2 radicals we have employed the lactoperoxidase (LPO)/H2O2/NO2- system. We have found that while mitoxantrone monomers undergo readily oxidation by LPO/H2O2 alone, oxidation of mitoxantrone dimers by LPO/H2O2 requires a mediator such as nitrite. This study shows that mitoxantrone is an effective scavenger of ?NO2 radicals which, at the same time, oxidize the drug to its active form. We have also found that mitoxantrone is an effective scavenger of ?NO2 radicals which, at the same time, oxidize the drug to its active form. We intend to extend these investigations to include other reactive nitrogen species such as peroxynitrite as well as mitoxantrone analogs.This project has been completed
