Vascular disruptive agent OXi4503 and anti-angiogenic agent Sunitinib combination treatment prolong survival of mice with CRC liver metastasis

BMC Cancer

Research Article

Linh Nguyen¹  Christopher Christophi¹  Theodora Fifis¹ 

[1] Department of Surgery, University of Melbourne, Austin Health, Lance Townsend Building Level 8, Studley Rd, 3084, Heidelberg, VIC, Australia;

关键词: Combination therapy;    Vascular disruptive agent;    OXi4503;    Hypoxia;    Sunitinib;    Tumor resistance;   

DOI  :  10.1186/s12885-016-2568-7

 received in 2015-10-19, accepted in 2016-07-14,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundPreclinical research indicate that vascular disrupting agent (VDA) treatment induces extensive tumor death but also a systemic mobilization of bone marrow derived cells including endothelial progenitor cells (EPC) leading to revascularization and renewed growth within the residual tumor. This study investigates if combination of VDA with the anti-angiogenic agent Sunitinib increases the treatment efficacy in a colorectal liver metastases mouse model.MethodsCBA mice with established liver metastases were given a single dose of OXi4503 at day 16 post tumor induction, a daily dose of Sunitinib starting at day 14 or day 16 post tumor induction or a combination of Sunitinib given daily from day 14 or day 16 post tumor induction in combination with a single dose of OXi4503 at day 16. Treatment was terminated at day 21 post tumor induction and its effects were assessed using stereological and immunohistochemical techniques. Long term effects were assessed in a survival study.ResultsCombination with long (7 day) Sunitinib treatment lead to liver toxicity but this was ameliorated in the shorter (5 day) treatment without significantly altering the effects on tumor reduction. Combination treatment resulted in significant reduction of viable tumor, reduction in tumor vasculature, reduction in tumor proliferation, increase in tumor apoptosis and prolonged mouse survival compared to control and single arm treatments. Complete tumor eradication was not achieved. Redistribution of E-cadherin and strong up regulation of ZEB1 and Vimentin were observed in the surviving tumor; indicative of epithelial to mesenchymal transition (EMT), a mechanism that could contribute to tumor resistance.ConclusionsCombination treatment significantly reduces viable tumor and prolongs animal survival. EMT in the surviving tumor may prevent total tumor eradication and could provide novel targets for a more lasting treatment.

【 授权许可】

CC BY   
© The Author(s). 2016