Vascular disruption in combination with mTOR inhibition in renal cell carcinoma.
Vascular disruption in combination with mTOR inhibition in renal cell carcinoma.
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DOI：
10.1158/1535-7163.mct-11-0748
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发表时间：
2012-02
影响因子：
5.7
通讯作者：
Pili R
中科院分区：
文献类型：
--
作者：
Ellis L;Shah P;Hammers H;Lehet K;Sotomayor P;Azabdaftari G;Seshadri M;Pili R
肾细胞癌（RCC）是一种血管生成依赖性和缺氧驱动的恶性肿瘤。因此，人们越来越关注使用抗血管生成剂来治疗RCC患者。然而，肿瘤血管破坏剂（肿瘤-VDA）的活性还没有被广泛研究，对RCC。在这项研究中，我们研究了肿瘤-VDA ASA 404（DMXAA，5，6-二甲基氧杂蒽酮-4-乙酸或vadimezan）与mTOR抑制剂依维莫司（RAD 001）联合治疗RCC的疗效。使用人脐静脉内皮细胞进行体外研究，并使用原位RENCA肿瘤和免疫组织化学患者肿瘤来源的RCC异种移植物进行体内研究。MRI用于表征原位RENCA异种移植物对联合治疗的血管反应。通过肿瘤生长测量和组织病理学评价确定治疗效果。ASA 404/依维莫司组合导致在三维球体测定中增强的内皮细胞发芽抑制。原位RENCA异种移植物的MRI显示ASA 404治疗后4小时渗透性早期增加，但依维莫司治疗后未增加。给药后24小时，联合给药组观察到血容量显著减少。肿瘤切片的相关CD 31/NG 2染色证实了联合治疗后的显著血管损伤。组织学切片显示，与单独VDA治疗相比，联合治疗后广泛坏死和存活边缘减少。这些结果显示了在RCC中将肿瘤-VDA与mTOR抑制剂组合的潜力。对这种新的组合策略的进一步研究是必要的。
Renal cell carcinoma (RCC) is an angiogenesis-dependent and hypoxia-driven malignancy. As a result, there has been an increased interest in the use of antiangiogenic agents for the management of RCC in patients. However, the activity of tumor-vascular disrupting agents (tumor-VDA) has not been extensively examined against RCC. In this study, we investigated the therapeutic efficacy of the tumor-VDA ASA404 (DMXAA, 5,6-dimethylxanthenone-4-acetic acid, or vadimezan) in combination with the mTOR inhibitor everolimus (RAD001) against RCC. In vitro studies were carried out using human umbilical vein endothelial cells and in vivo studies using orthotopic RENCA tumors and immunohistochemical patient tumor-derived RCC xenografts. MRI was used to characterize the vascular response of orthotopic RENCA xenografts to combination treatment. Therapeutic efficacy was determined by tumor growth measurements and histopathologic evaluation. ASA404/everolimus combination resulted in enhanced inhibition of endothelial cell sprouting in the 3-dimensional spheroid assay. MRI of orthotopic RENCA xenografts revealed an early increase in permeability 4 hours posttreatment with ASA404, but not with everolimus. Twenty-four hours after treatment, a significant reduction in blood volume was observed with combination treatment. Correlative CD31/NG2 staining of tumor sections confirmed marked vascular damage following combination therapy. Histologic sections showed extensive necrosis and a reduction in the viable rim following combination treatment compared with VDA treatment alone. These results show the potential of combining tumor-VDAs with mTOR inhibitors in RCC. Further investigation into this novel combination strategy is warranted.