Contrary Effects of the Receptor Tyrosine Kinase Inhibitor Vandetanib on Constitutive and Flow-Stimulated Nitric Oxide Elaboration in Humans

Vascular endothelial growth factor regulates neoplastic angiogenesis through production of endothelium-derived NO. We performed a prospective evaluation of vascular function during treatment with vandetanib, a vascular endothelial growth receptor 2 and 3 receptor tyrosine kinase inhibitor, to determine the effects of vascular endothelial growth receptor signal interruption on endothelial function in humans. Seventeen patients with stage IV breast cancer received dose-escalated vandetanib in combination with low-dose oral chemotherapy. We measured blood pressure, systemic nitrate/nitrite levels, and brachial artery vascular function. In vitro analyses of cultured endothelial cells were performed to determine the effect of vandetanib on NO production, akt(473) phosphorylation, and endothelial NO synthase protein content and membrane localization. Vandetanib treatment for 6 weeks significantly increased blood pressure, decreased resting brachial artery diameter, and decreased plasma systemic nitrate/nitrite levels compared with baseline. Flow-mediated vasodilation was preserved, and no change was noted in nitroglycerin-mediated vasodilation. In vitro, endothelial cell nitrite levels and akt(473) phosphorylation were reduced and vascular endothelial growth receptor 2 levels did not change, but endothelial NO synthase membrane concentration doubled. Vandetanib reduces constitutive NO production and increases blood pressure, yet flow-stimulated NO bioavailability was preserved. Changes in vascular function with tyrosine kinase inhibition are complex and require further study in humans.