ACID-CATALYZED OXIDATION OF THE ANTICANCER AGENT MITOXANTRONE BY NITRITE IONS

Mitoxantrone roxyethyl)amino-]ethyl}amino-9,10-anthracenedione; MXH(2) ) is a novel anticancer agent that is useful in the treatment of leuke mia and breast cancer. In contrast to other anthracenedione-based agen ts, this drug causes fewer side effects, mainly because it is resistan t to metabolic reduction. We investigated the interaction between MXH( 2) and inorganic nitrite (NO2-) in aqueous solutions and found that th is drug undergoes acid-catalyzed oxidation by nitrite. The rate of thi s reaction measured Versus [NaNO2] at constant pH or versus pH at cons tant [NaNO2] was found to be directly proportional to the actual HNO2 concentration, indicating HNO2 to be the major oxidizing species. Invo lvement of (NO)-N-. and/or NO2. radicals as minor oxidants is suggeste d based on the dependence of the rate of oxidation on the presence of air. Spectrophotometric and electron paramagnetic resonance analyses i ndicate that early products of the reaction are identical to those gen erated by oxidation of MXH(2) by a horseradish peroxidase/hydrogen per oxide system. The major product is hexahydronaphtho[2,3-f]quinoxaline- 7,12-dione, which is formed by intramolecular cyclization of one alkyl amino side chain in the oxidized, diiminoquinone MX(N) form of the dru g. This study shows that MXH(2) effectively scavenges HNO2 and possibl y other nitrogen oxides. Because these reactive forms of nitrogen may be present in vivo, this property of the drug may be relevant to its b iological or perhaps anticancer activities.