Sweeney C J, Miller K D, Sissons S E, Nozaki S, Heilman D K, Shen J, Sledge G W
Indiana University, Department of Medicine, Indianapolis, IN 46202, USA.
Cancer Res. 2001 Apr 15;61(8):3369-72.
Numerous chemotherapeutic agents have been shown to have an inhibitory effect on endothelial cell proliferation and migration, and tubule formation. In this study, we examined the antiangiogenic activity of docetaxel. Docetaxel inhibited endothelial cell proliferation and tubule formation in vitro in a dose-dependent fashion. Docetaxel treatment also inhibited angiogenesis in an in vivo Matrigel plug assay. The endothelial stimulating factors, vascular endothelial cell growth factor (VEGF) and basic fibroblast growth factor are able to protect endothelial cells from the antiangiogenic properties of docetaxel. This protective effect can be overcome by a recombinant humanized monoclonal antibody directed against VEGF in both in vitro and in vivo models. Similarly, combination of docetaxel with the antiangiogenic agent 2-methoxyestradiol also overcomes the protective effect of VEGF in both in vitro and in vivo models. These data suggest that microenvironmental factors (e.g., local release of VEGF and basic fibroblast growth factor) could play a role in decreasing the antiangiogenic effects of docetaxel, whereas agents such as 2- methoxyestradiol and recombinant humanized monoclonal antibody directed against VEGF may reverse this protective effect.
许多化疗药物已被证明对内皮细胞增殖、迁移及小管形成具有抑制作用。在本研究中，我们检测了多西他赛的抗血管生成活性。多西他赛在体外以剂量依赖方式抑制内皮细胞增殖和小管形成。多西他赛治疗在体内基质胶栓试验中也抑制血管生成。内皮刺激因子，即血管内皮生长因子（VEGF）和碱性成纤维细胞生长因子，能够保护内皮细胞免受多西他赛的抗血管生成特性影响。在体外和体内模型中，针对VEGF的重组人源化单克隆抗体均可克服这种保护作用。同样，在体外和体内模型中，多西他赛与抗血管生成药物2-甲氧基雌二醇联合使用也可克服VEGF的保护作用。这些数据表明，微环境因素（如VEGF和碱性成纤维细胞生长因子的局部释放）可能在降低多西他赛的抗血管生成作用中发挥作用，而诸如2-甲氧基雌二醇和针对VEGF的重组人源化单克隆抗体等药物可能会逆转这种保护作用。
