Abstract 4438: A membrane modulating strategy improves doxorubicin therapy in spontaneous mouse breast carcinoma

Abstract

Abstract BACKGROUND: Frequently, clinical anti-cancer therapy is suboptimal because of the inability to deliver high levels of cytostatics into tumor cells. We identified a class of short-chain sphingolipids that facilitate the translocation of amphiphilic drugs over the plasma membrane, including various cytostatics. RESULTS: The sphingolipid analogue N-octanoyl-GlucosylCeramide (GC) elevates intracellular doxorubicin levels four- to eight-fold, both in vitro and in xenografted B16 melanoma tumor tissue. In order to examine enhanced anti-tumor efficacy by GC preclinically, we used a spontaneous mouse breast cancer model that closely mimics human Invasive Lobular Carcinoma (ILC), and we applied a two-step experimental set-up with mouse cohorts of increasing tumor heterogeneity. In both populations, GC co-administration significantly increased tumor growth delay by doxorubicin, when compared to the conventional free or liposomal doxorubicin formulations. In contrast, the GC co-administration did not add upon bone marrow suppression, the main doxorubicin toxicity as revealed by pathological examination. Overall, mice treated with the GC-doxorubicin co-formulation better endured therapy and showed extended overall survival. CONCLUSION: Concomitant in vivo membrane modulation by short-chain sphingolipids widens the therapeutic window of the anti-cancer agent doxorubicin in a preclinical model for human ILC. 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 4438. doi:10.1158/1538-7445.AM2011-4438