Context-dependent role of angiopoietin-1 inhibition in the suppression of angiogenesis and tumor growth: implications for AMG 386, an angiopoietin-1/2-neutralizing peptibody.
Context-dependent role of angiopoietin-1 inhibition in the suppression of angiogenesis and tumor growth: implications for AMG 386, an angiopoietin-1/2-neutralizing peptibody.
复制标题
血管生成素-1抑制在抑制血管生成和肿瘤生长中的上下文依赖性作用：对AMG 386的影响，AMG 386，一种血管生成蛋白1/2中和肽。
DOI：
10.1158/1535-7163.mct-10-0213
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发表时间：
2010-10
影响因子：
5.7
通讯作者：
Oliner JD
中科院分区：
文献类型：
--
作者：
Coxon A;Bready J;Min H;Kaufman S;Leal J;Yu D;Lee TA;Sun JR;Estrada J;Bolon B;McCabe J;Wang L;Rex K;Caenepeel S;Hughes P;Cordover D;Kim H;Han SJ;Michaels ML;Hsu E;Shimamoto G;Cattley R;Hurh E;Nguyen L;Wang SX;Ndifor A;Hayward IJ;Falcón BL;McDonald DM;Li L;Boone T;Kendall R;Radinsky R;Oliner JD
AMG 386是一种研究中的首个肽-Fc融合蛋白（肽体），通过阻止血管生成素-1（Ang 1）和Ang 2与其受体Tie 2的相互作用来抑制血管生成。虽然阻断Ang 2的治疗价值已经在几种肿瘤发生和血管生成模型中显示，但Ang 1拮抗作用的潜在益处尚不清楚。为了研究Ang 1中和的后果，我们开发了有效的和选择性的肽体，其抑制Ang 1与其受体Tie 2之间的相互作用。尽管选择性Ang 1拮抗作用在血管生成相关疾病（癌症和糖尿病视网膜病变）模型中没有独立作用，但它在正常幼年大鼠中诱导卵巢萎缩，并在卵巢刺激诱导的排卵模型中抑制卵巢卵泡血管生成。令人惊讶的是，当与Ang 2抑制剂组合时，Ang 1抑制剂的活性似乎在一些疾病模型中被揭开，甚至在同时血管内皮生长因子抑制的情况下。使用AMG 386或Ang 1和Ang 2选择性肽体的组合双重抑制Ang 1和Ang 2协同抑制肿瘤异种移植物生长和卵巢滤泡血管生成;然而，Ang 1抑制未能增强Ang 2抑制对肿瘤内皮细胞增殖、角膜血管生成和氧诱导的视网膜血管生成的抑制作用。在任何情况下，Ang 1抑制均未显示出（a）赋予优于Ang 2抑制或双重Ang 1/2抑制的上级活性或（B）拮抗Ang 2抑制的功效。这些结果意味着Ang 1在促进出生后血管生成中起着环境依赖性作用，并且在某些出生后环境中，双重Ang 1/2抑制对于抑制血管生成而言上级于选择性Ang 2抑制。Mol Cancer Ther; 9（10）; 2641-51.
AMG 386 is an investigational first-in-class peptide-Fc fusion protein (peptibody) that inhibits angiogenesis by preventing the interaction of angiopoietin-1 (Ang1) and Ang2 with their receptor, Tie2. Although the therapeutic value of blocking Ang2 has been shown in several models of tumorigenesis and angiogenesis, the potential benefit of Ang1 antagonism is less clear. To investigate the consequences of Ang1 neutralization, we have developed potent and selective peptibodies that inhibit the interaction between Ang1 and its receptor, Tie2. Although selective Ang1 antagonism has no independent effect in models of angiogenesis-associated diseases (cancer and diabetic retinopathy), it induces ovarian atrophy in normal juvenile rats and inhibits ovarian follicular angiogenesis in a hormone-induced ovulation model. Surprisingly, the activity of Ang1 inhibitors seems to be unmasked in some disease models when combined with Ang2 inhibitors, even in the context of concurrent vascular endothelial growth factor inhibition. Dual inhibition of Ang1 and Ang2 using AMG 386 or a combination of Ang1- and Ang2-selective peptibodies cooperatively suppresses tumor xenograft growth and ovarian follicular angiogenesis; however, Ang1 inhibition fails to augment the suppressive effect of Ang2 inhibition on tumor endothelial cell proliferation, corneal angiogenesis, and oxygen-induced retinal angiogenesis. In no case was Ang1 inhibition shown to (a) confer superior activity to Ang2 inhibition or dual Ang1/2 inhibition or (b) antagonize the efficacy of Ang2 inhibition. These results imply that Ang1 plays a context-dependent role in promoting postnatal angiogenesis and that dual Ang1/2 inhibition is superior to selective Ang2 inhibition for suppression of angiogenesis in some postnatal settings. Mol Cancer Ther; 9(10); 2641–51.