Prediction of in vivo synergistic activity of antiangiogenic compounds by gene expression profiling.
Prediction of in vivo synergistic activity of antiangiogenic compounds by gene expression profiling.
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DOI：
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发表时间：
2002-12
期刊：
影响因子：
11.2
通讯作者：
E. Cline;S. Bicciato;C. Dibello;M. Lingen
中科院分区：
文献类型：
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作者：
E. Cline;S. Bicciato;C. Dibello;M. Lingen
血管生成是肿瘤形成的重要表型，需要肿瘤微环境中多个细胞的相互作用。因此，成功的抗血管生成治疗必须能够阻断肿瘤用来诱导新生血管的所有不同机制。开发这种方案的一个主要挑战是确定哪些药物在体内可能具有最高程度的协同活性。我们用六种血管生成抑制剂处理人微血管内皮细胞，并使用微阵列寻找暗示潜在协同作用的基因表达的不同模式。血栓反应蛋白模拟肽(DI-TSPa)和TNP-470(TNP)的表达谱非常相似，而内皮抑素的表达谱却截然不同。在体外，内皮抑素与TNP-470或DI-TSPa具有协同抗血管生成作用。在体内，携带Lewis肺癌细胞的小鼠联合使用内皮抑素和DI-TSPa或TNP-470，单独使用时剂量无效，导致显著的肿瘤生长抑制和肿瘤血管生成减少。相反，用DI-TSPa和TNP-470治疗的动物显示出对肿瘤生长和血管生成的温和影响。这些结果表明，即使在缺乏对这些抑制剂如何发挥作用的完整机制的了解的情况下，基因表达谱也可以用于预测协同抗血管生成活性，从而使其抗肿瘤效果最大化。
Angiogenesis, an essential phenotype for tumor formation, requires the interaction of many cells within the tumor microenvironment. Therefore, successful antiangiogenic therapies must be able to block all of the different mechanisms tumors use to induce neovascularization. A major challenge for developing such protocols is determining which agents are likely to have the highest degree of synergistic activity in vivo. We treated human microvascular endothelial cells with six inhibitors of angiogenesis and used microarrays to seek divergent patterns of gene expression suggestive of potential synergies. The expression profiles of a thrombospondin-mimetic peptide (DI-TSPa) and TNP-470 (TNP) were very similar, whereas endostatin had a dramatically different profile. In vitro, endostatin was synergistically antiangiogenic with either TNP-470 or DI-TSPa. In vivo, mice bearing Lewis lung carcinoma cells treated with a combination of endostatin and either DI-TSPa or TNP-470, at doses that were ineffective when used alone, resulted in a marked inhibition of tumor growth and decreased tumor angiogenesis. Conversely, animals treated with both DI-TSPa and TNP-470 demonstrated a modest effect on both tumor growth and angiogenesis. These results suggest that even in the absence of a complete mechanistic understanding of how these inhibitors work, gene expression profiling may be used to predict synergistic antiangiogenic activity and thus maximize their antitumor efficacy.