Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC University Medical Center, CA Rotterdam, The Netherlands.
Cardiovascular Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia.
Cardiovasc Res. 2019 Apr 15;115(5):904-914. doi: 10.1093/cvr/cvz022.
Since the formation of new blood vessels is essential for tumour growth and metastatic spread, inhibition of angiogenesis by targeting the vascular endothelial growth factor (VEGF) pathway is an effective strategy for various types of cancer, most importantly renal cell carcinoma, thyroid cancer, and hepatocellular carcinoma. However, VEGF inhibitors have serious side effects, most importantly hypertension and nephropathy. In case of fulminant hypertension, this may only be handled by lowering the dosage since the blood pressure rise is proportional to the amount of VEGF inhibition. These effects pathophysiologically and clinically resemble the most severe complication of pregnancy, preeclampsia, in which case an insufficient placenta leads to a rise in sFlt-1 levels causing a decrease in VEGF availability. Due to this overlap, studies in preeclampsia may provide important information for VEGF inhibitor-induced toxicity and vice versa. In both VEGF inhibitor-induced toxicity and preeclampsia, endothelin (ET)-1 appears to be a pivotal player. In this review, after briefly summarizing the anticancer effects, we discuss the mechanisms that potentially underlie the unwanted effects of VEGF inhibitors, focusing on ET-1, nitric oxide and oxidative stress, the renin-angiotensin-aldosterone system, and rarefaction. Given the salt sensitivity of this phenomenon, as well as the beneficial effects of aspirin in preeclampsia and cancer, we next provide novel treatment options for VEGF inhibitor-induced toxicity, including salt restriction, ET receptor blockade, and cyclo-oxygenase inhibition, in addition to classical antihypertensive and renoprotective drugs. We conclude with the recommendation of therapeutic drug monitoring to improve patient outcome.
由于新血管的形成对于肿瘤生长和转移扩散至关重要，因此靶向血管内皮生长因子（VEGF）途径抑制血管生成是治疗各种类型癌症的有效策略，尤其是肾细胞癌、甲状腺癌和肝细胞癌。然而，VEGF 抑制剂有严重的副作用，最重要的是高血压和肾病。在发生暴发性高血压的情况下，由于血压升高与 VEGF 抑制的量成正比，因此只能通过降低剂量来处理。这些作用在病理生理学和临床上类似于妊娠最严重的并发症子痫前期，在这种情况下，胎盘不足会导致 sFlt-1 水平升高，从而导致 VEGF 供应减少。由于这种重叠，子痫前期的研究可能为 VEGF 抑制剂诱导的毒性提供重要信息，反之亦然。在 VEGF 抑制剂诱导的毒性和子痫前期中，内皮素（ET）-1 似乎是一个关键因素。在这篇综述中，在简要总结抗癌作用之后，我们讨论了潜在导致 VEGF 抑制剂不良作用的机制，重点关注 ET-1、一氧化氮和氧化应激、肾素-血管紧张素-醛固酮系统和稀疏。鉴于这种现象的盐敏感性，以及阿司匹林在子痫前期和癌症中的有益作用，我们接下来提供了治疗 VEGF 抑制剂诱导的毒性的新治疗选择，包括盐限制、ET 受体阻断和环氧化酶抑制，以及经典的降压和肾保护药物。我们最后建议进行治疗药物监测以改善患者的预后。
