Molecular basis of hypertension side effects induced by sunitinib

Abstract

Over the past decade a number of vascular complications have emerged, such as newly developed or worsened hypertension, in patients who were administered with new cancer treatments for several types of cancer that were untreatable earlier. Hypertension is emerging as one of the most common adverse effects of therapy with angiogenesis inhibitors. Small-molecule inhibitors of vascular endothelial growth factor signalling are associated with a high proportion of patients with hypertension. The mechanisms underlying the development of hypertension are not well known, although there seem to be several mechanisms. Physiopathology of hypertension implicates abnormalities in endothelial function and angiogenesis. Several features of hypertensive patients are reduced number of arterioles and capillaries, alterations of the microvascular network, decrease in vascular wall compliance and flexibility, reduced nitric oxide bioactivity and increases in plasma vascular endothelial growth factor. Treatment with tyrosine kinase inhibitors (TKIs) is associated with a significant and sustained increase in blood pressure. We suspect that TKIs exert their hypertensive effects directly at the level of the microvascular network through processes such as vascular rarefaction, endothelial dysfunction and/or altered nitric oxide metabolism. This study shows the vascular complications of treatment with a TKI, sunitinib (SU11248), with special emphasis on hypertension.

Retrospective evaluation of toceranib phosphate (Palladia®) use in the treatment of inoperable, metastatic, or recurrent canine pheochromocytomas: 5 dogs (2014–2017)

“…The underlying pathogenesis of TKI-induced hypertension is unknown. Prevailing theories include: (1) VEGF blockade, which prevents nitric oxide synthetase production of nitric oxide, allowing endothelin driven vasoconstriction; (2) decreased VEGF which may remodel capillaries and lead to endothelial dysfunction; or perhaps (3) TKIs may induce tumor cell apoptosis, leading to release of stored catecholamines and thus hypertension [39]. Recently, it has been determined that the development of hypertension while on a TKI is a biomarker of efficacy in some human patients treated with sunitinib [40].…”

Evaluation of the adverse event profile and pharmacodynamics of toceranib phosphate administered to dogs with solid tumors at doses below the maximum tolerated dose

“…While the exact mechanism of hypertension associated with toceranib is not clear, it may be directly related to inhibition of VEGF signaling pathways [12]. Additionally, anti-angiogenic drugs used in human patients have been shown to induce increased concentrations of endothelin-1, and this may contribute to the observed hypertension [13-15]. …”

Life-threatening acute acalculous cholecystitis in a patient with renal cell carcinoma treated by sunitinib: a case report

“…On the other hand, sunitinib causes vascular adverse events by vascular endothelial dysfunction [6,7] resulting in myocardial ischemia [8] and proteinuria due to renal thrombotic microangiopathy [9]. Likewise, sunitinib-related acute cholecystitis might be caused by the antivascular effect of sunitinib rather than gallbladder stones although the detailed mechanism underlying this adverse event is unclear.…”