Abstract LB-201: New derivatives of etoposide show promise as more potent inhibitors of cancer cell growth

Abstract

Abstract The DNA repair enzyme Topoisomerase II (TopoII) has been recognized in the oncology field as a clinically important therapeutic target for a variety of cancers. The class of agents known as etoposides were specifically designed with this target in mind. Etoposides lacked the major problem of cardiac toxicity associated with the anthracyclines class of drugs (e.g. doxorubicin). Sunshine Biopharma has recognized that the reduced efficacy and high toxicity of etoposide are due to instability of the molecule leading to a conversion of the drug which then functions as a tubulin inhibitor rather than a TopoII inhibitor (unpublished observations). Accordingly, the company set out to develop a true TopoII inhibitor and these efforts have yielded two compounds called Adva-27a and Adva-32a. These drugs and their derivatives have been described in US Patent Application Number: 20090318675. Using cell lines derived from a variety of human cancers, Adva-27a is almost always a more potent inhibitor of cell growth compared to etoposide, and cells expressing the MDR-drug resistance protein are very sensitive to this drug. Furthermore, consistent with the literature, amplification of the TOP2α gene is associated with increased sensitivity to growth inhibition. The preliminary data show that in all but the brain tumor cell line, increased TOP2α copy number is associated with even greater percent inhibition by Adva-27a versus etoposide regardless of the tissue of origin of the tumor cell lines. This data and plans for further analysis of these drugs will be presented. 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 LB-201. doi:10.1158/1538-7445.AM2011-LB-201