Suppression of the nitric oxide pathway in metastatic renal cell carcinoma patients receiving vascular endothelial growth factor-signaling inhibitors.
Suppression of the nitric oxide pathway in metastatic renal cell carcinoma patients receiving vascular endothelial growth factor-signaling inhibitors.
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DOI：
10.1161/hypertensionaha.110.160481
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发表时间：
2010-12
期刊：
影响因子：
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通讯作者：
Humphreys BD
中科院分区：
文献类型：
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作者：
Robinson ES;Khankin EV;Choueiri TK;Dhawan MS;Rogers MJ;Karumanchi SA;Humphreys BD
靶向血管内皮生长因子（VEGF）通路的治疗可引起高血压，但其机制尚不清楚。这项横断面研究验证了VEGF抑制通过抑制VEGF介导的血管舒张途径引起高血压的假设。从2002-2009年的80例转移性肾细胞癌患者中收集尿液，其中40例在基线时，40例在VEGF抑制剂治疗期间。测量的尿生物标志物包括白蛋白、一氧化氮途径及其下游效应物的代谢物、cGMP和前列腺素途径生物标志物前列腺素E2、6-酮PGF 1α和cAMP，均标准化为尿肌酐。两组的平均年龄为61.8岁，76%为男性，接受VEGF抑制剂的患者尿白蛋白较高（中位数18.4mg/g vs. 4.6 mg/g; p=0.009）。在接受VEGF抑制剂的患者中，cGMP/Cr受到抑制（0.28 pmol/ug vs. 0.39 pmol/ug; p=0.01），硝酸盐/Cr有抑制趋势（0.46 umol/mg vs. 0.62 umol/mg; p=0.09）。当排除接受贝伐珠单抗治疗的患者，仅分析接受小分子酪氨酸激酶抑制剂治疗的患者时，两种比较均得到加强（cGMP/Cr，p=0.003;硝酸盐/Cr，p=0.01）。前列腺素E2、6-酮PGF 1 α和cAMP在组间无差异。这些结果表明，VEGF抑制剂诱导的高血压是通过抑制一氧化氮的产生介导的。需要进行前瞻性研究，以探讨这些生物标志物是否可能是接受VEGF靶向治疗的患者有效性的有用预测因子。
Therapies that target the vascular endothelial growth factor (VEGF) pathway cause hypertension but the mechanism remains unknown. This cross-sectional study tested the hypothesis that VEGF inhibition causes hypertension by suppressing VEGF-mediated vasodilatory pathways. Urine was collected from 80 patients with metastatic renal cell carcinoma from 2002–2009, 40 at baseline and 40 while on VEGF inhibitors. Measured urinary biomarkers include albumin, metabolites of the nitric oxide pathway and its downstream effector, cGMP, and prostaglandin pathway biomarkers prostaglandin E2, 6-keto PGF 1α, and cAMP, all normalized to urinary creatinine. The mean age in both groups was 61.8 years, 76% were male, and urinary albumin was higher in patients receiving VEGF inhibitors (median 18.4mg/g vs. 4.6 mg/g; p=0.009). cGMP/Cr was suppressed in patients on VEGF inhibitors (0.28 pmol/ug vs. 0.39 pmol/ug; p=0.01), with a trend toward suppression of nitrate/Cr (0.46 umol/mg vs. 0.62 umol/mg; p=0.09). Both comparisons were strengthened when patients on bevacizumab were excluded and only those receiving small molecule tyrosine kinase inhibitors were analyzed (cGMP/Cr, p=0.003; Nitrate/Cr, p=0.01). Prostaglandin E2, 6-keto PGF1α, and cAMP did not differ between groups. These results suggest that hypertension induced by VEGF inhibitors is mediated by suppression of nitric oxide production. Prospective studies are needed to explore whether these biomarkers may be useful predictors of efficacy in patients receiving VEGF-targeted therapies.