Shaheen R M, Tseng W W, Davis D W, Liu W, Reinmuth N, Vellagas R, Wieczorek A A, Ogura Y, McConkey D J, Drazan K E, Bucana C D, McMahon G, Ellis L M
Department of Surgical Oncology, University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Cancer Res. 2001 Feb 15;61(4):1464-8.
Redundant mechanisms mediate colon cancer angiogenesis. Targeting multiple angiogenic factors simultaneously may improve survival of mice with colon cancer metastases. BALB/c mice underwent splenic injection with CT-26 colon cancer cells to generate liver metastases and received administration of either 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 as determined by a blinded observer. In a parallel experiment, groups of mice were sacrificed at earlier time points to better define the kinetics of the effect of SU6668 on angiogenic parameters over time. SU6668 increased median 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 decreased in mice treated with SU6668. Based on current knowledge of endothelial cell survival, these data suggest that SU6668 may prevent tumor endothelial cell survival directly (vascular endothelial growth factor) and indirectly (pericyte coverage) by affecting endothelial cell survival mechanisms.
冗余机制介导结肠癌血管生成。同时靶向多种血管生成因子可能会提高患有结肠癌转移的小鼠的存活率。BALB/c小鼠通过脾脏注射CT-26结肠癌细胞以产生肝转移，并接受单独给予载体或针对血管内皮生长因子、碱性成纤维细胞生长因子和血小板衍生生长因子受体的酪氨酸激酶抑制剂（SU6668）。当由一位不知情的观察者判定小鼠濒死时，将其处死。在一项平行实验中，在更早的时间点处死几组小鼠，以更好地确定SU6668对血管生成参数随时间变化的影响动力学。SU6668使中位生存期延长了58%（P < 0.001），并导致肿瘤细胞和内皮细胞凋亡随时间逐渐增加。此外，接受SU6668治疗的小鼠中周细胞血管覆盖和肿瘤血管形成显著减少。基于目前对内皮细胞存活的认识，这些数据表明SU6668可能通过影响内皮细胞存活机制直接（血管内皮生长因子）和间接（周细胞覆盖）地阻止肿瘤内皮细胞存活。
