mTOR Inhibitor RAD001 (Everolimus) Has Antiangiogenic/Vascular Properties Distinct from a VEGFR Tyrosine Kinase Inhibitor
mTOR Inhibitor RAD001 (Everolimus) Has Antiangiogenic/Vascular Properties Distinct from a VEGFR Tyrosine Kinase Inhibitor
复制标题
DOI：
10.1158/1078-0432.ccr-08-2057
复制
发表时间：
2009-03-01
影响因子：
11.5
通讯作者：
O'Reilly, Terence
中科院分区：
文献类型：
--
作者：
Lane, Heidi A.;Wood, Jeanette M.;O'Reilly, Terence
用途：比较口服哺乳动物雷帕霉素靶（mTOR）抑制剂RAD 001（依维莫司）和血管内皮生长因子受体（VEGFR）抑制剂瓦他拉尼（PTK/ZK）的抗血管生成/血管特性。实验设计：在体外测量针对各种肿瘤组织型的抗增殖活性和对mTOR途径的下游效应。在体内，测量抗肿瘤活性、血浆和肿瘤RAD 001水平。结果：RAD 001在体外抑制肿瘤细胞增殖（IC_（50）值为1 μ mol/L），在敏感和不敏感的肿瘤细胞中，对pS 6激酶和4 E-BP_1均有抑制作用。体外活性与体内活性不相关，并且在肿瘤中观察到显著反应，其中IC 50值比肿瘤RAD 001浓度高>10倍。在体外，RAD 001抑制VEGF刺激的和成纤维细胞生长因子刺激的人内皮细胞的增殖，但不抑制真皮成纤维细胞的增殖，并损害敏感和不敏感肿瘤细胞的VEGF释放，但不抑制人内皮细胞的迁移。在体内，在来源于敏感或不敏感细胞的肿瘤模型中，RAD 001降低Tie-2水平、成熟和未成熟血管的量、总血浆和肿瘤VEGF。RAD 001不影响急性暴露于VEGF的正常脉管系统中的血管渗漏，也不影响通过动态对比增强磁共振成像测量的肿瘤血管渗透性（K-transs）。结论：VEGFR和mTOR抑制剂对肿瘤血管生物学具有相似但不同的作用，这对它们单独或联合应用的临床活性具有重要意义。
Purpose: Comparison of the antiangiogenic/vascular properties of the oral mammalian target of rapamycin (mTOR) inhibitor RAD001 (everolimus) and the vascular endothelial growth factor receptor (VEGFR) inhibitor vatalanib (PTK/ZK).Experimental Design: Antiproliferative activity against various tumor histotypes and downstream effects on the mTOR pathway were measured in vitro. In vivo, antitumor activity, plasma, and tumor RAD001 levels were measured. Activity in several different angiogenic/vascular assays in vitro and in vivo was assessed and compared with PTK/ZK.Results: RAD001 inhibited proliferation in vitro (IC50 values 1 mu mol/L), and in sensitive and insensitive tumor cells, pS6 kinase and 4E-BP1 were inhibited. Activity in vitro did not correlate with activity in vivo and significant responses were seen in tumors with IC50 values >10-fold higher than tumor RAD001 concentrations. In vitro, RAD001 inhibited the proliferation of VEGF-stimulated and fibroblast growth factor-stimulated human endothelial cells but not dermal fibroblasts and impaired VEGF release from both sensitive and insensitive tumor cells but did not inhibit migration of human endothelial cells. In vivo, in tumor models derived from either sensitive or insensitive cells, RAD001 reduced Tie-2 levels, the amount of mature and immature vessels, total plasma, and tumorVEGF. RAD001 did not affect blood vessel leakiness in normal vasculature acutely exposed to VEGF nor did it affect tumor vascular permeability (K-trans) as measured by dynamic contrast-enhanced magnetic resonance imaging. However, the pan-VEGFR inhibitor PTK/ZK inhibited endothelial cell migration and vascular permeability but had less effect on mature vessels compared with RAD001.Conclusions: VEGFR and mTOR inhibitors show similar but also distinct effects on tumor vascular biology, which has implications for their clinical activity alone or in combination.