TY - JOUR T1 - The novel anthracenedione, pixantrone, lacks redox activity and inhibits doxorubicinol formation in human myocardium: Insight to explain the cardiac safety of pixantrone in doxorubicin treated patients JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.112.200568 SP - jpet.112.200568 AU - Emanuela Salvatorelli AU - Pierantonio Menna AU - Odalys Gonzalez Paz AU - Massimo Chello AU - Elvio Covino AU - Jack W Singer AU - Giorgio Minotti Y1 - 2012/01/01 UR - http://jpet.aspetjournals.org/content/early/2012/12/03/jpet.112.200568.abstract N2 - Cardiotoxicity from the antitumor anthracycline, doxorubicin, correlates with doxorubicin cardiac levels, redox activation to superoxide anion (O2._) and hydrogen peroxide (H2O2), formation of the long-lived secondary alcohol metabolite, doxorubicinol. Cardiotoxicity may first manifest during salvage therapy with other drugs, such as the anthracenedione mitoxantrone. Minimal evidence for cardiotoxicity in anthracycline-pretreated patients with refractory-relapsed non Hodgkin’s lymphoma was observed with the novel anthracenedione, pixantrone. We characterized whether pixantrone and mitoxantrone caused different effects on doxorubicin levels, redox activation, doxorubicinol formation. Pixantrone and mitoxantrone were probed in a validated ex vivo human myocardial strip model that was either doxorubicin-naïve or preliminarily subjected to doxorubicin loading and washouts to mimic doxorubicin treatment and elimination in the clinical setting. In doxorubicin-naive strips, pixantrone showed higher uptake than mitoxantrone; however, neither drug formed O2._ or H2O2. In doxorubicin-pretreated strips, pixantrone or mitoxantrone did not alter the distribution and clearance of residual doxorubicin. Mitoxantrone showed an unchanged uptake, lacked effects on doxorubicin levels, but synergized with doxorubicin to form more O2._ and H2O2, as evidenced by O2._ -dependent inactivation of mitochondrial aconitase or mitoxantrone oxidation by H2O2 -activated peroxidases. In contrast, pixantrone uptake was reduced by prior doxorubicin exposure; moreover, pixantrone lacked redox synergism with doxorubicin, and formed an N-dealkylated product that inhibited metabolism of residual doxorubicin to doxorubicinol. Redox inactivity and inhibition of doxorubicinol formation correlate with the cardiac safety of pixantrone in doxorubicin-pretreated patients. Redox inactivity in the face of high cardiac uptake suggests that pixantrone might be safe also in doxorubicin-naive patients. ER -