Description_x000D_ Biochem/physiol Actions_x000D_ Pixantrone (BBR 2778) is an aza-anthracenedione with enhanced antitumor activity due to its DNA-intercalating and topoisomerase II-poisoning activity. Pixantrone shows no signs of acute or delayed cardiotoxicity seen with anthracyclines mitoxantrone and doxorubicin (DOX), while exhibiting comparable in vivo efficacy against solid tumors in mice. Tests conducted on human myocardial strips ex vivo shows that not only pixantrone does not form superoxide anion and hydrogen peroxide (O2•− and H2O2) seen with DOX due to redox activation, pixantrone and its metabolites, especially N-dealkylated, show competitive inhibition against DOX reduction. While mitoxantrone does not form O2•− and H2O2 on its own, it synergizes with DOX to form more O2•− and H2O2, whose formation and subsequent production of the long-lived metabolite doxorubicinol contribute to DOX cardiotoxicity.