title: Treatment of sunitinib-induced hypertension in solid tumor by nitric oxide donors.
abstract: Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are overexpressed in the majority of renal cell carcinomas. This characteristic has supported the rationale of targeting VEGF-driven tumour vascularization, especially in clear cell RCC. VEGF-inhibiting strategies include the use of tyrosine kinase inhibitors (sunitinib, axitinib, pazopanib, and sorafenib) and neutralizing antibodies such as bevacizumab. Hypertension (HTN) is one of the most common adverse effects of angiogenesis inhibitors. HTN observed in clinical trials appears to correlate with the potency of VEGF kinase inhibitor against VEGFR-2: agents with higher potency are associated with a higher incidence of HTN. Although the exact mechanism by tyrosine kinase inhibitors induce HTN has not yet been completely clarified, two key hypotheses have been postulated. First, some studies have pointed to a VEGF inhibitors-induced decrease in nitric oxide synthase (NOS) and nitric oxide (NO) production, that can result in vasoconstriction and increased blood pressure. VEGF, mediated by PI3K/Akt and MAPK pathway, upregulates the endothelial nitric oxide synthase enzyme leading to up-regulation of NO production. So inhibition of signaling through the VEGF pathway would lead to a decrease in NO production, resulting in an increase in vascular resistance and blood pressure. Secondly a decrease in the number of microvascular endothelial cells and subsequent depletion of normal microvessel density (rarefaction) occurs upon VEGF signaling inhibition. NO donors could be successfully used not only for the treatment of developed angiogenesis-inhibitor-induced hypertension but also for preventive effects.
authors.affiliation: Servicio Galego de Saúde, Edificio Administrativo San Lázaro s/n, 15781 Santiago de Compostela, Spain. Electronic address: luis.leon.mateos@sergas.es.
authors.forename: L
authors.initials: L
authors.lastname: León-Mateos
authors.affiliation: Servicio de Oncología Médica, Complexo Hospitalario Universitario de A Coruña, c/ Xubias de Arriba, 84, 15006 Coruña, Spain. Electronic address: joaquin.mosquera.martinez@sergas.es.
authors.forename: J
authors.initials: J
authors.lastname: Mosquera
authors.affiliation: Servicio de Oncología Médica, Complexo Hospitalario Universitario de A Coruña, c/ Xubias de Arriba, 84, 15006 Coruña, Spain. Electronic address: luis.M.anton.aparicio@sergas.es.
authors.forename: L
authors.initials: L
authors.lastname: Antón Aparicio
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy*; D007211:Indoles / Q000009:adverse effects* / Q000627:therapeutic use; D020030:Nitric Oxide Donors / Q000494:pharmacology / Q000627:therapeutic use*; D011758:Pyrroles / Q000009:adverse effects* / Q000627:therapeutic use; D015398:Signal Transduction; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
chemical_list: D000959:Antihypertensive Agents; D000970:Antineoplastic Agents; D007211:Indoles; D020030:Nitric Oxide Donors; D011758:Pyrroles; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000077210:Sunitinib
keywords: Hypertension; Nitric oxide; Renal cell carcinoma; Sunitinib; Tyrosine kinase inhibitors; Vascular endothelial growth factor