Modulation Of Cellular Uptake And Increased Therapeutic Efficacy Of The Azacytidine-Elaidic Acid Ester Cp-4200 In Vitro And In Vivo

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Azacytidine is an established nucleoside drug that is well known for its ability to modulate epigenetic gene regulation by inhibition of DNA methylation. Despite recent advances in the clinical development of azacytidine, the use of the drug is limited by its low bioavailability and dependency on variably expressed nucleoside transporters for cellular uptake. To investigate the function of CP-4200, an elaidic acid ester of azacytidine, we performed DNA methyltransferase depletion assays, DNA methylation analysis using capillary electrophoresis and Infinium methylation arrays, transport studies and mouse experiments. We show here that CP-4200 has strong epigenetic modulatory potency in human cancer cell lines, as evidenced by efficient depletion of DNA methyltransferase protein, genome-wide DNA demethylation and robust reactivation of epigenetically silenced tumor suppressor genes. Importantly, new results show that the uptake mechanisms of colon and leukemic cancer cell lines for CP-4200 and its parent drug azacytidine are fundamentally different, with CP-4200 being substantially less dependent on nucleoside transporters. Correspondingly, CP-4200 showed a significantly higher antitumoral activity than azacytidine in an orthotopic mouse tumor model for acute lymphocytic leukemia. These results establish a fundamentally novel approach for the delivery of azacytidine to human cancer cells which might have important therapeutic implications. Reference: Brueckner, B., et al. (2010). Mol. Cancer Ther. 9: 1256-1264. 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 2013. doi:10.1158/1538-7445.AM2011-2013