Mitoxantrone (1,4-dihydroxy-5,8-bis{2-[(2-hydroxyethyl) amino]-ethyl} amino -9,10- anthracenedione; MXH2) is a novel anthracenedione-based 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. The primary objective of this research project was to investigate the interaction between MXH2 and nitrous acid, HNO2. Nitrous acid is present in vivo, being produced from nitric oxide and from inorganic nitrite (NO2-) at low pH (pKa (HNO2/NO2-) =3.35). The intracellular pH of cancer cells is acidic, reaching pH values as low as 3-4 in some solid tumors, thereby providing conditions suitable for the formation of the acid. HNO2 is highly mutagenic (carcinogenic) and cytotoxic so it can be harmful both to cancer and host tissues. We found that the addition of nitrite to an acidic solution of MXH2 caused rapid oxidation of drug. The rate of this reaction measured versus [NaNO2] at constant pH, or versus pH at constant [NaNO2], was directly proportional to the actual HNO2 concentration, pointing to HNO2 as a major oxidizing species. Spectrophotometric and EPR analyses indicate that early products of the reaction are identical to those generated by oxidation of MXH2 by the HRP/H2O2 system. This study shows that mitoxantrone effectively scavenges nitrous acid. Because HNO2 may be present in cancer cells in vivo, this property of the drug may be relevant to its biological or, perhaps, even anticancer activities. We intend to extend these investigations to include other reactive nitrogen species as well as mitoxantrone analogs.
