Abstract 1693: Bevacizumab acutely decreases endothelium dependent vasodilation in healthy volunteers
Authors: Anna M. Thijs, Carla M. van Herpen, Winette T. van der Graaf, Paul Smits, Gerard A. Rongen
Journal: Cancer Research (2012)

Abstract Introduction: Angiogenesis inhibitors have remarkably improved the outcome of patients with several types of cancer. One of the most reported side effects of angiogenesis inhibitors is hypertension. In patients treated with bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), hypertension has an overall incidence up to 32%. Understanding the pathogenesis of this side effect is essential for optimal treatment with this class of drugs. Microvascular endothelial dysfunction is involved in the pathogenesis of hypertension. Our hypothesis is that bevacizumab (BVZ) induced hypertension is caused by an acute reduction of endothelium-mediated vasodilation. Methods: BVZ was infused intra-arterially to separate direct local effects of VEGF inhibition from systemic actions, such as hypertension, that could indirectly interfere with endothelial function. At first, in seven volunteers the acute vasomotor effect of BVZ was studied. During 15 minutes BVZ 144 μg/dl forearm volume/min was infused in the brachial artery of the non-dominant arm while assessing forearm blood flow (FBF) with venous strain gauge plethysmography. During BVZ infusion venous blood was collected from both arms to measure local and systemic concentrations of BVZ. Subsequently the acute vasodilator response to intra-arterial acetylcholine (Ach, endothelium-dependent vasodilator) alone and during simultaneous infusion of BVZ was studied, in another group of 12 volunteers. Finally, the effect of BVZ on the response to an endothelium-independent vasodilator nitroprusside (SNP) was studied in a similar experimental set up, in a third group of 12 volunteers. Results: In the experimental arm during infusion BVZ reached a concentration of 135±10,7μg/ml (± SD; n=8), resembling systemic exposure to BVZ in patients treated with 5mg BVZ i.v./kg. BVZ concentration in the control arm was 6,7±1,1 μg/ml (n=10). Intra-arterial BVZ did not directly alter forearm vascular tone. Infusion of BVZ significantly reduced the percentage increase in forearm blood flow during infusion of two dosages of acetylcholine from (mean±SE) 440±157 and 926±252 to 169±154 and 612±40 (p&amp;lt;0,05, ANOVA for repeated measures on log-transformed data). In the absence of BVZ, the vasodilator response to SNP equaled the response to ACh. BVZ did not alter the percentage increase in forearm blood flow during infusion of SNP (n=12). Conclusion: Although BVZ did not alter baseline forearm vascular tone, it acutely and specifially reduced endothelium-mediated vasodilation. Although this observation suggests a minor role for the muscle vascular bed, a similar acute effect in other organs such as the kidney could very well be involved in the pathogenesis of BVZ-induced hypertension. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1693. doi:1538-7445.AM2012-1693