Abstract LB-59: Amrubicin, a third-generation synthetic anthracycline, is active in anthracycline-resistant tumors

Abstract

Abstract Amrubicin, a third generation synthetic anthracycline and a potent topoisomerase (topo) II inhibitor, is approved in Japan for the treatment of lung cancer (both small-cell and non-small cell) and is being evaluated in a phase III trial in the North America and Europe for the second line treatment of SCLC. The aim of these studies was to evaluate the cross-resistance of amrubicin with other anthracyclines (doxorubicin, epirubicin) and the topo-II inhibitor etoposide, and to identify potential mechanisms of resistance to amrubicin. The doxorubicin-resistant cell lines H69-AR, MES-SA-DX5 & NCI-ADR/RES were confirmed to be resistant to doxorubicin (∼25-fold relative resistance), however, their resistance to amrubicin was low or absent (∼2-fold relative resistance). Additionally, a number of primary human ovarian and breast tumor explants that were resistant to doxorubicin and/or etoposide retained sensitivity to amrubicin. Unlike doxorubicin, amrubicin induced DNA damage, G2M cell cycle arrest and apoptosis in both doxorubicin-sensitive and -resistant lines at or below clinically relevant plasma concentrations (∼10 uM). Furthermore, in contrast to doxorubicin, fluorescence time-lapse imaging demonstrated relatively small differences in amrubicin uptake and accumulation kinetics in doxorubicin-sensitive and resistant cell lines. Using gene expression profiling studies, we showed that a greater number of genes were regulated by amrubicin than by doxorubicin in both OVCAR8 and NCI-ADR/RES lines. Amrubicin is a moderate P-glycoprotein (Pgp) substrate; however, we demonstrated that the inhibitory effect and accumulation of amrubicin is not solely modulated by Pgp in cell lines over-expressing efflux pumps including Pgp. We postulate that the high intracellular accumulation and retention of amrubicin is a result of rapid influx due to the high intrinsic permeability and lipophilic properties of amrubicin. This may explain why amrubicin overcomes pleiotropic drug resistance. In summary, we demonstrated that amrubicin has a distinct mode of action compared with other anthracyclines, is less susceptible to typical anthracycline resistance mechanisms and therefore, may be useful in the treatment of anthracycline-resistant tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-59.