Reynolds Andrew R, Hart Ian R, Watson Alan R, Welti Jonathan C, Silva Rita G, Robinson Stephen D, Da Violante Georges, Gourlaouen Morgane, Salih Mishal, Jones Matt C, Jones Dylan T, Saunders Garry, Kostourou Vassiliki, Perron-Sierra Françoise, Norman Jim C, Tucker Gordon C, Hodivala-Dilke Kairbaan M
Tumour Angiogenesis Group, The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
Nat Med. 2009 Apr;15(4):392-400. doi: 10.1038/nm.1941. Epub 2009 Mar 22.
Inhibitors of alpha(v)beta(3) and alpha(v)beta(5) integrin have entered clinical trials as antiangiogenic agents for cancer treatment but generally have been unsuccessful. Here we present in vivo evidence that low (nanomolar) concentrations of RGD-mimetic alpha(v)beta(3) and alpha(v)beta(5) inhibitors can paradoxically stimulate tumor growth and tumor angiogenesis. We show that low concentrations of these inhibitors promote VEGF-mediated angiogenesis by altering alpha(v)beta(3) integrin and vascular endothelial growth factor receptor-2 trafficking, thereby promoting endothelial cell migration to VEGF. The proangiogenic effects of low concentrations of RGD-mimetic integrin inhibitors could compromise their efficacy as anticancer agents and have major implications for the use of RGD-mimetic compounds in humans.
α(v)β(3)和α(v)β(5)整合素抑制剂已作为抗癌治疗的抗血管生成药物进入临床试验，但总体上未获成功。在此，我们提供体内证据表明，低（纳摩尔）浓度的RGD模拟α(v)β(3)和α(v)β(5)抑制剂反而会刺激肿瘤生长和肿瘤血管生成。我们发现，低浓度的这些抑制剂通过改变α(v)β(3)整合素和血管内皮生长因子受体-2的运输来促进VEGF介导的血管生成，从而促进内皮细胞向VEGF迁移。低浓度RGD模拟整合素抑制剂的促血管生成作用可能会损害其作为抗癌药物的疗效，并对RGD模拟化合物在人体中的应用产生重大影响。
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