Abstract 4184: Development of ixabepilone-induced CIPN is related to pre-treatment with paclitaxel in a mouse model

Abstract

Abstract The mechanisms and underlying factors that predispose individuals to development of chemotherapy-induced peripheral neuropathy (CIPN) are not clearly understood. CIPN results in the dose attenuation, delay, or discontinuation of drug in patients otherwise responding to chemotherapy. Moderate to severe CIPN can interfere with function and activities of daily living. Microtubule-stabilizing agents, including taxanes and epothilones are strongly associated with development of CIPN. Ixabepilone, the first FDA-approved epothilone, is specifically used in taxane-resistant metastatic breast cancer. Any ixabepilone-induced CIPN may be as high as 71% depending on administration regimen. Specific risk factors for development of this side effect are unknown. Here we present data using a murine model of sensory hyperalgesia that suggests pretreatment with paclitaxel, currently a labeling indication for use of ixabepilone in metastatic breast cancer, is itself a predisposing factor for development of ixabepilone-induced peripheral neuropathy. Wild type DB/A2 adult mice were treated with intraperitoneal 25 mg/kg paclitaxel, 2.5 mg/kg ixabepilone, or diluent (cremophor: ethanol) every other day for 4 doses. Mice were analyzed by rota-rod to test sensory-motor function and by hot and cold plate to test for temperature hyperalgesia. There was no difference in performance of either of the three treatment groups following the initial treatment cycle. Mice were then treated with a further cycle of chemotherapy, either the same as they received initially, except that half of the paclitaxel-treated group was crossed-over to ixabepilone. Rota-rod and hot plate testing again failed to show a difference between groups. However, cold-plate testing showed a statistically significant increase in cold hyperalgesia in mice treated first with paclitaxel followed by ixabepilone in comparison to all other treatment groups. EM and immunofluorescence analyses of dorsal root ganglia and sciatic nerve sections from mice in all four treatment groups are ongoing. Although preliminary, these results suggest that prior chemotherapy regimens have a significant effect on development of CIPN in this model. The exact mechanisms of injury are under evaluation. A complementary clinical study is underway in women with breast cancer to understand the effect of ixabepilone on an ultrastructural level and its potential role in the development of peripheral neuropathy. 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 4184.