Lankhorst Stephanie, Danser A H Jan, van den Meiracker Anton H
Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
Am J Physiol Regul Integr Comp Physiol. 2016 Feb 1;310(3):R230-4. doi: 10.1152/ajpregu.00373.2015. Epub 2015 Oct 28.
Antiangiogenesis, targeting vascular endothelial growth factor (VEGF), has become a well-established treatment for patients with cancer. This treatment is associated with nitric oxide (NO) suppression and a dose-dependent activation of the endothelin system, resulting in preeclampsia-like features, particularly hypertension and renal injury. Studies in endothelium NO synthase (eNOS)-deficient mice and pharmacological treatment with endothelin receptor blockers and sildenafil indicate that an activated endothelin system, rather than NO suppression, mediates the side effects of angiogenesis inhibitors. Activation of the endothelin system is also observed in preeclamptic women, where it is related to the increased placental production of sFlt-1, the soluble form of the VEGF receptor-1. This receptor binds VEGF, thereby having the same consequences as antiangiogenic treatment with VEGF inhibitors. The side effects of antiangiogenic treatment in patients with cancer may be dose limiting, thereby impairing its therapeutic potential. In addition, because endothelin exerts proangiogenic effects, investigation of the effects of endothelin receptor blockade in patients with cancer treated with angiogenesis inhibitors is warranted.
靶向血管内皮生长因子（VEGF）的抗血管生成已成为癌症患者一种成熟的治疗方法。这种治疗与一氧化氮（NO）抑制以及内皮素系统的剂量依赖性激活有关，会导致子痫前期样症状，尤其是高血压和肾损伤。对内皮型一氧化氮合酶（eNOS）缺陷小鼠的研究以及使用内皮素受体阻滞剂和西地那非的药物治疗表明，激活的内皮素系统而非NO抑制介导了血管生成抑制剂的副作用。子痫前期女性中也观察到内皮素系统的激活，这与胎盘产生的可溶性VEGF受体-1即sFlt-1增加有关。该受体结合VEGF，从而产生与使用VEGF抑制剂进行抗血管生成治疗相同的后果。癌症患者抗血管生成治疗的副作用可能会限制剂量，从而损害其治疗潜力。此外，由于内皮素具有促血管生成作用，因此有必要研究内皮素受体阻滞剂对接受血管生成抑制剂治疗的癌症患者的影响。
