Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: Role of oxygenation, angiopoietin-1, and matrix metal loproteinases
Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: Role of oxygenation, angiopoietin-1, and matrix metal loproteinases
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DOI：
10.1016/s1535-6108(04)00305-8
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发表时间：
2004-12-01
期刊：
影响因子：
50.3
通讯作者：
Jain, RK
中科院分区：
文献类型：
--
作者：
Winkler, F;Kozin, SV;Jain, RK
最近具有里程碑意义的VEGF特异性抗体的III期临床试验表明，抗血管生成治疗必须与细胞毒性治疗相结合，用于治疗实体瘤。然而，没有指导这些治疗的最佳时间表。在这里，我们表明VEGFR 2阻断创造了一个“正常化窗口”-在此期间，联合放射治疗提供了最佳结果。该窗口的特征在于肿瘤氧合的增加，这是已知的增强辐射反应。在正常化窗口期间，但不是在其之前或之后，VEGFR 2阻断通过上调Ang 1增加脑肿瘤血管的周细胞覆盖，并通过MMP活化降解其病理性厚基底膜。
The recent landmark Phase III clinical trial with a VEGF-specific antibody suggests that antiangiogenic therapy must be combined with cytotoxic therapy for the treatment of solid tumors. However, there are no guidelines for optimal scheduling of these therapies. Here we show that VEGFR2 blockade creates a "normalization window" - a period during which combined radiation therapy gives the best outcome. This window is characterized by an increase in tumor oxygenation, which is known to enhance radiation response. During the normalization window, but not before or after it, VEGFR2 blockade increases pericyte coverage of brain tumor vessels via upregulation of Ang1 and degrades their pathologically thick basement membrane via MMP activation.