Abstract 3428: Effect of a non cardiotoxic Doxorubicin analog, 13-deoxy, 5-imino doxorubicin on decatenation of DNA by Topoisomerase II.

Abstract

Abstract Anthracyclines such as doxorubicin are widely used to treat solid and hematological cancers. However, within the course of treatment they have the potential to cause life threatening chronic cardiotoxicity which limits their potential use. The cause of cardiotoxicity is not thoroughly understood, with previous research indicating the generation of reactive oxygen species and free iron accumulation as possible causes for cardiomyocyte death. Recent publications have shown the interaction between doxorubicin and Topoisomerase IIβ plays a key role in anthracycline induced cardiotoxicity. Topoisomerase enzymes are utilized during the coiling and uncoiling of DNA within the cell and are active targets of anthracyclines not only in tumoricidal action (Topoisomerase IIα) but also in the pathogenesis of cardiotoxicity (Topoisomerase IIβ). In this research we seek to further evaluate the interaction between doxorubicin, doxorubicin analogues and Topoisomerase IIβ. The analogues were selected due to previous chronic in vivo experiments in rabbits where classical manifestations of cardiotoxicity (including reduced left ventricular shortening fraction and pathological changes in cardiac tissue) were not observed. Furthermore, one analogue (13-deoxy, 5-imino doxorubicin) has shown promising clinical data suggesting a strong antineoplastic effect without the cardiotoxic effects. Doxorubicin and this analogue were placed in the presence of catenated DNA for 6 hours at 37°C prior to exposure to Topoisomerase IIα and β enzymes. The reaction was allowed to proceed for 30 minutes at 37°C and analyzed for decatenation of the DNA by the enzyme. This experiment was then repeated in cardiac H9c2 cells to assay possible differential inhibition at the cellular level. Citation Format: Nicole Frank, Richard Olson, Gerald M. Walsh, Todd Talley, Barry Cusack. Effect of a non cardiotoxic Doxorubicin analog, 13-deoxy, 5-imino doxorubicin on decatenation of DNA by Topoisomerase II. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3428. doi:10.1158/1538-7445.AM2013-3428