Abstract 5384: Amonafide demonstrates a clearly differentiated chemoresistance and chemosensitivity profile when compared to classical TopoII inhibitors

Abstract

Abstract Background: Amonafide is a novel DNA intercalator that induces apoptosis by mechanisms involving Topo II. Previous pharmacogenomic studies have shown differences between amonafide and classical TopoII inhibitors. Here data from publicly available gene expression studies have been analyzed to determine the chemoresistance and chemosensitivity profiles of amonafide compared to other agents. Methods: Data were mined from the Stanford, MIT-Broad and NCI databases. A subset of genes associated with drug efflux, chemo-sensitivity & -resistance was selected from the array data. Effects on gene expression were assessed by determining Pearson correlation coefficients (PCC) for gene-drug pairs. Results: For drug efflux genes & 15 genes associated with cell regulation, amonafide, and 5-azacytidine (azaC) had a positive correlation between expression & cytotoxicity; doxorubicin (Dox), and daunorubicin (Dnr) showed a negative correlation; cytarabine (araC) was unaffected. The chemo-sensitivity and -resistance profiles were determined by identifying the 15 genes with the highest correlation for each of the 5 drugs vs the other 4. Amonafide & aza-C differed clearly from araC, Dnr & Dox. Genes conferring chemosensitivity to amonafide had a negative correlation for araC, Dnr, and Dox. Genes with a positive correlation for araC, Dnr, and Dox, had a negative correlation with amonafide & azaC. A similar pattern of differences was seen for chemoresistance. Conclusions: Amonafide is a unique chemical entity whose cytotoxicity is not affected by multi-drug resistance expression. Amonafide may evade many of the pharmacogenomic drivers confering resistance to ara-C and anthracyclines. It should therefore retain greater efficacy in combination with araC and as an alternative to anthracyclines, especially in the treatment of myeloid leukemias. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5384. doi:10.1158/1538-7445.AM2011-5384