Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
Int J Cancer. 2012 Aug 15;131(4):E484-93. doi: 10.1002/ijc.26456. Epub 2011 Nov 8.
Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors are effective agents in the treatment of metastatic renal cell cancer (mRCC). We here investigated whether inhibition of VEGFR signalin by sunitinib causes changes in plasma proteins associated with tumor endothelium. Forty-three patients with mRCC received sunitinib 50 mg/day in a 4-weeks on 2-weeks off schedule. Sequential plasma samples were obtained before treatment (C1D1), on C1D14, on C1D28, and on C2D1 before start of cycle 2. Plasma levels were assessed for VEGF, soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular cell adhesion molecule-1 (sICAM-1), von Willebrand factor (vWF), circulating angiopoietin-2 (Ang-2) and soluble Tie-2 (sTie-2). Total tumor burden was calculated at baseline and at first evaluation. Progression-free survival (PFS) and overall survival (OS) were determined. Tumor burden was positively associated with baseline circulating Ang-2 [Spearman's rho (ρ) = 0.378, p = 0.028] and vWF (ρ = 0.417, p = 0.008). During sunitinib treatment, circulating Ang-2 and sTie-2 significantly decreased (p < 0.001 for both), plasma levels of sVCAM-1 and VEGF significantly increased (p = 0.022 and p < 0.001), whereas those of sICAM-1 and vWF remained stable. These protein changes had recovered on C2D1. The reduction in circulating Ang-2 levels on C1D28 was positively correlated with the percentage decrease in tumor burden (ρ = 0.605; p = 0.002). Baseline protein levels and subsequent changes were not associated with PFS or OS. In conclusion, sunitinib-induced changes in Ang-2, sTie-2, sVCAM-1 and VEGF are related to the administration schedule, while reduction in Ang-2 is also associated with decrease in tumor burden.
血管内皮生长因子受体 (VEGFR) 酪氨酸激酶抑制剂是转移性肾细胞癌 (mRCC) 治疗的有效药物。我们在这里研究了舒尼替尼对 VEGFR 信号的抑制是否会引起与肿瘤内皮相关的血浆蛋白变化。43 例 mRCC 患者接受舒尼替尼 50mg/天，每 4 周为一个周期，其中 2 周停药。在治疗前（C1D1）、C1D14、C1D28 和 C2D1 前开始第 2 周期时获得连续的血浆样本。评估血浆中 VEGF、可溶性血管细胞黏附分子-1 (sVCAM-1)、可溶性细胞间黏附分子-1 (sICAM-1)、血管性血友病因子 (vWF)、循环血管生成素-2 (Ang-2) 和可溶性 Tie-2 (sTie-2) 的水平。在基线和首次评估时计算总肿瘤负担。确定无进展生存期 (PFS) 和总生存期 (OS)。肿瘤负担与基线循环 Ang-2 呈正相关[Spearman's rho (ρ) = 0.378，p = 0.028]和 vWF (ρ = 0.417，p = 0.008)。在舒尼替尼治疗期间，循环 Ang-2 和 sTie-2 显著下降（两者均 p < 0.001），sVCAM-1 和 VEGF 显著升高（p = 0.022 和 p < 0.001），而 sICAM-1 和 vWF 保持稳定。这些蛋白变化在 C2D1 时已恢复。C1D28 时循环 Ang-2 水平的降低与肿瘤负担百分比的降低呈正相关（ρ = 0.605；p = 0.002）。基线蛋白水平和随后的变化与 PFS 或 OS 无关。结论：舒尼替尼诱导的 Ang-2、sTie-2、sVCAM-1 和 VEGF 的变化与给药方案有关，而 Ang-2 的减少也与肿瘤负担的减轻有关。
