Lane Heidi A, Wood Jeanette M, McSheehy Paul M J, Allegrini Peter R, Boulay Anne, Brueggen Joseph, Littlewood-Evans Amanda, Maira Sauveur-Michel, Martiny-Baron Georg, Schnell Christian R, Sini Patrizia, O'Reilly Terence
Oncology Research, Novartis Institutes for Biomedical Research, Basel, Switzerland.
Clin Cancer Res. 2009 Mar 1;15(5):1612-22. doi: 10.1158/1078-0432.CCR-08-2057. Epub 2009 Feb 17.
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).
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.
RAD001 inhibited proliferation in vitro (IC50 values<1 nmol/L to >1 micromol/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 tumor VEGF. RAD001 did not affect blood vessel leakiness in normal vasculature acutely exposed to VEGF nor did it affect tumor vascular permeability (Ktrans) 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.
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.
比较口服雷帕霉素哺乳动物靶点（mTOR）抑制剂RAD001（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。
在体外测量对各种肿瘤组织类型的抗增殖活性以及对mTOR通路的下游效应。在体内，测量抗肿瘤活性、血浆和肿瘤RAD001水平。评估并与PTK/ZK比较体外和体内几种不同血管生成/血管检测中的活性。
RAD001在体外抑制增殖（IC50值<1 nmol/L至>1 μmol/L），在敏感和不敏感肿瘤细胞中，pS6激酶和4E-BP1均受到抑制。体外活性与体内活性不相关，在IC50值比肿瘤RAD001浓度高10倍以上的肿瘤中观察到显著反应。在体外，RAD001抑制VEGF刺激和成纤维细胞生长因子刺激的人内皮细胞增殖，但不抑制真皮成纤维细胞，损害敏感和不敏感肿瘤细胞释放VEGF，但不抑制人内皮细胞迁移。在体内，在源自敏感或不敏感细胞的肿瘤模型中，RAD001降低Tie-2水平、成熟和未成熟血管数量、总血浆和肿瘤VEGF。RAD001对急性暴露于VEGF的正常脉管系统中的血管渗漏无影响，也不影响动态对比增强磁共振成像测量的肿瘤血管通透性（Ktrans）。然而，泛VEGFR抑制剂PTK/ZK抑制内皮细胞迁移和血管通透性，但与RAD001相比，对成熟血管的影响较小。
VEGFR和mTOR抑制剂对肿瘤血管生物学表现出相似但也不同的作用，这对它们单独或联合的临床活性具有重要意义。
