Vascular endothelial growth factor trap blocks tumor growth, metastasis formation, and vascular leakage in an orthotopic murine renal cell cancer model
Vascular endothelial growth factor trap blocks tumor growth, metastasis formation, and vascular leakage in an orthotopic murine renal cell cancer model
复制标题
DOI：
10.1158/1078-0432.ccr-06-2553
复制
发表时间：
2007-07-15
影响因子：
11.5
通讯作者：
Pili, Roberto
中科院分区：
文献类型：
--
作者：
Verheul, Henk M. W.;Hammers, Hans;Pili, Roberto
目的：血管生成抑制剂在晚期肾细胞癌患者中显示出临床获益，但需要进一步改进治疗。血管内皮生长因子（VEGF）Trap是一种新开发的VEGF阻断剂，具有比抗VEGF抗体贝伐单抗更强的亲和力和更广泛的活性。在这项研究中，我们测试了VEGF陷阱的活性在原位小鼠模型的肾癌与自发性肺transferation.Experimental设计：小鼠同基因肾细胞癌细胞（RENCA）转染的表达载体被注射到BALB/c小鼠的肾包膜。用VEGF Trap或对照蛋白i. p.处理（10或25 mg/kg，每周两次），以防止肿瘤发展（预防模型）或在建立的肿瘤形成后抑制肿瘤生长和转移形成结果：在预防模型中，与对照相比，VEGF Trap抑制肿瘤生长87 +/- 14%（P = 0.007），并显著延长生存期。在干预模型中，VEGF Trap抑制肿瘤生长74 +/- 9%（P < 0.001），抑制肺转移形成98%（P < 0.004）。由于VEGF Trap治疗，微血管密度降低了66%（P < 0.001）。此外，VEGF陷阱防止纤维蛋白原渗漏到肿瘤微环境代表减少血管渗漏所示的免疫组化staining.Conclusions：VEGF陷阱是一个有效的抑制剂RENCA肿瘤生长和转移的形成，并阻止VEGF在体内的生物学功能。这些结果支持VEGF Trap用于肾细胞癌和其他癌症类型的进一步临床开发。
Purpose: Angiogenesis inhibitors have shown clinical benefit in patients with advanced renal cell cancer, but further therapeutic improvement is needed. Vascular endothelial growth factor (VEGF) Trap is a newly developed VEGF-blocking agent with stronger affinity and broader activity than the anti-VEGF antibody bevacizumab. In this study, we tested the activity of VEGF Trap in an orthotopic murine model of renal cancer with spontaneous lung metastases.Experimental Design: Murine syngeneic renal cell carcinoma cells (RENCA) transfected with a luciferase-expressing vector were injected into the renal capsule of BALB/c mice. i.p. treatment with VEGF Trap or control protein (10 or 25 mg/kg twice weekly) was started shortly after tumor injection to prevent tumor development (prevention model) or after established tumors were formed to inhibit tumor growth and metastasis formation (intervention model).Results: In the prevention model,VEGF Trap inhibited tumor growth by 87 +/- 14% compared with control (P = 0.007) and significantly prolonged survival. In the intervention model, VEGF Trap inhibited tumor growth by 74 +/- 9% (P < 0.001) and the formation of lung metastases was inhibited by 98% (P < 0.004). Microvascular density was reduced by 66% due to VEGF Trap treatment (P < 0.001). In addition,VEGF Trap prevented fibrinogen leakage into the tumor microenvironment representative for reduced vascular leaking as shown by immunohistochemical staining.Conclusions: VEGF Trap is a potent inhibitor of RENCA tumor growth and metastasis formation and blocks the biological function of VEGF in vivo. These results support further clinical development of VEGF Trap for renal cell cancer and other cancer types.