Tyrosine kinase inhibition of multiple angiogenic growth factor receptors improves survival in mice bearing colon cancer liver metastases by inhibition of endothelial cell survival mechanisms

Redundant mechanisms mediate colon cancer angiogenesis. Targeting multiple angiogenic factors simultaneously may improve survival of mice with colon c ancer metastases. BALB/c mice underwent splenic injection with CT-26 colon cancer cells to generate liver metastases and received administration of ei ther vehicle alone or a tyrosine kinase inhibitor for vascular endothelial growth factor, basic fibroblast growth factor, and platelet-derived growth factor receptors (SU6668). Mice were sacrificed when they became moribund a s determined by a blinded observer. In a parallel experiment, groups of mic e were sacrificed at earlier time points to better define the kinetics of t he effect of SU6668 on angiogenic parameters over time. SU6668 increased me dian survival by 58% (P < 0.001) and led to a progressive increase in tumor cell and endothelial cell apoptosis that increased over time. In addition, pericyte vessel coverage and tumor vascularity were significantly decrease d in mice treated with SU6668. Based on current knowledge of endothelial ce ll survival, these data suggest that SU6668 may prevent tumor endothelial c ell survival directly (vascular endothelial growth factor) and indirectly ( pericyte coverage) by affecting endothelial cell survival mechanisms.