Abstract 2053: F-XA7, a novel derivative of vinca alkaloid with potent antitumor activity, efficiently overrides P-glycoprotein-mediated drug resistance both in vitro and in vivo.

Abstract

Abstract Vinorelbine, a semi-synthetic vinca alkaloid, is widely used for the treatment of non-small cell lung cancer, metastatic breast cancer and ovarian cancer by inhibiting microtubule assembly. However, drug resistance mediated by P-glycoprotein (P-gp) and neurotoxic side effect possibly caused by microtubule paracrystal are major obstacles to vinorelbine application in clinic. Here, we describe a vinorelbine derivative F-XA7 as a novel microtubule-disrupting agent. F-XA7 inhibits microtubule assembly by binding to tubulin at the same site as vinorelbine and thus inhibiting the proliferation of cultured tumor cells. In vivo, F-XA7 exhibits potent antitumor activity against human tumor xenografts in nude mice. More importantly, F-XA7 is active against vinorelbine-resistant tumor cells mediated by P-gp-overexpression and significantly suppresses the growth of P-gp-overexpressing tumor xenograft in vivo, indicating that F-XA7 efficiently overrides P-gp-mediated drug resistance. In addition, the activity of F-XA7 to induce microtubule paracrystal is much weaker than that of vinorelbine in cultured cells, suggesting it may have less neurotoxic side effect. Collectively, these results indicate that F-XA7 is a novel and promising microtubule-disrupting agent for cancer therapy. Citation Format: Haitian Quan, Yongping Xu, Lihong Hu, Liguang Lou. F-XA7, a novel derivative of vinca alkaloid with potent antitumor activity, efficiently overrides P-glycoprotein-mediated drug resistance both in vitro and in vivo. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2053. doi:10.1158/1538-7445.AM2013-2053