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Published on: July 3, 2013
Treatment of sunitinib-induced hypertension in solid tumor by nitric oxide donors
L León-Mateos1, J Mosquera2, L Antón Aparicio2
1Servicio Galego de Saúde, Edificio Administrativo San Lázaro s/n, 15781 Santiago de Compostela, Spain.
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.
Insights
Vascular endothelial growth factor (VEGF) inhibitors used in cancer treatment can cause hypertension. This is linked to reduced nitric oxide production and blood vessel rarefaction, suggesting nitric oxide donors may help manage this side effect.
Area of Science:
- Oncology
- Cardiovascular Research
- Pharmacology
Background:
- Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are frequently overexpressed in renal cell carcinomas, making them targets for cancer therapy.
- VEGF-inhibiting drugs, including tyrosine kinase inhibitors and neutralizing antibodies, are used to target tumor vascularization, particularly in clear cell renal cell carcinoma (RCC).
- Hypertension (HTN) is a common adverse effect of these angiogenesis inhibitors, with incidence correlating to the potency of VEGF kinase inhibitors against VEGFR-2.
Purpose of the Study:
- To explore the mechanisms by which VEGF inhibitors induce hypertension.
- To investigate the potential therapeutic role of nitric oxide (NO) donors in managing or preventing this side effect.
Main Methods:
- Review of existing studies on VEGF inhibitors, hypertension, and nitric oxide pathways.
- Analysis of the correlation between VEGF inhibitor potency and hypertension incidence.
- Examination of proposed mechanisms involving nitric oxide synthase (NOS) and microvessel density.
Main Results:
- Two primary hypotheses for VEGF inhibitor-induced HTN: 1) decreased nitric oxide (NO) production due to inhibition of the PI3K/Akt and MAPK pathways, leading to vasoconstriction. 2) Reduced microvascular endothelial cell density (rarefaction).
- The potency of VEGF kinase inhibitors against VEGFR-2 correlates with the incidence of hypertension.
- Nitric oxide (NO) donors show potential for both treating and preventing hypertension induced by angiogenesis inhibitors.
Conclusions:
- VEGF inhibition in cancer therapy can lead to hypertension through mechanisms involving nitric oxide pathways and vascular rarefaction.
- Nitric oxide donors represent a promising therapeutic strategy for managing hypertension associated with VEGF-targeted cancer treatments.
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