Regorafenib induces rapid and reversible changes in plasma nitric oxide and endothelin-1 Journal Article


Authors: De Jesus-Gonzalez, N.; Robinson, E.; Penchev, R.; von Mehren, M.; Heinrich, M. C.; Tap, W.; Wang, Q.; Demetri, G.; George, S.; Humphreys, B. D.
Article Title: Regorafenib induces rapid and reversible changes in plasma nitric oxide and endothelin-1
Abstract: Background Hypertension is a toxicity of antiangiogenic therapies and a possible biomarker that identifies patients with superior cancer outcomes. Understanding its mechanism will aid in treatment and could lead to the development of other biomarkers for predicting toxicity and anticancer efficacy. Recent evidence implicates nitric oxide (NO) suppression and endothelin-1 (ET-1) stimulation as potential mechanisms leading to antiangiogenic therapy-induced hypertension. The aim of this study was to evaluate the effects of regorafenib, a novel broad-spectrum kinase inhibitor with activity against multiple targets, including vascular endothelial growth factor receptor 2 inhibition, on NO and ET-1 levels.MethodsRegorafenib was administered to 32 subjects with gastrointestinal stromal tumor on a 3-week-on, 1-week-off basis. Plasma levels of NO and ET-1 were measured at baseline, 2, 4, and 6 weeks of therapy. Data analysis was by Wilcoxon rank-sum and paired t-tests.ResultsTwenty subjects (63%) developed regorafenib-induced hypertension. Two weeks after starting regorafenib therapy, plasma ET-1 levels increased (25% increase, P 0.05) and NO was suppressed (20% decrease, P 0.05). These normalized after 1-week washout but ET-1 rose again by 30% (P 0.05) and NO fell by 50% (P 0.05) after restarting regorafenib.ConclusionsThese findings indicate that regorafenib induces a coordinated and reversible suppression of NO and stimulation of ET-1. Whether NO and ET-1 might predict therapeutic efficacy in these patients requires further study. © 2012 American Journal of Hypertension, Ltd.
Keywords: adult; clinical article; treatment response; middle aged; hypertension; treatment duration; pyridines; protein blood level; biological markers; gastrointestinal stromal tumor; gastrointestinal stromal tumors; drug effect; vasculotropin receptor 2; blood sampling; antiangiogenic therapy; open study; blood pressure; angiogenesis inhibitors; blood pressure measurement; mean arterial pressure; nitric oxide; endothelin 1; endothelin-1; regorafenib; phenylurea compounds
Journal Title: American Journal of Hypertension
Volume: 25
Issue: 10
ISSN: 0895-7061
Publisher: American Journal of Hypertension, Ltd  
Date Published: 2012-10-01
Start Page: 1118
End Page: 1123
Language: English
DOI: 10.1038/ajh.2012.97
PROVIDER: scopus
PUBMED: 22785409
PMCID: PMC3578478
DOI/URL:
Notes: --- - "Cited By (since 1996): 1" - "Export Date: 1 October 2012" - "CODEN: AJHYE" - "Source: Scopus"
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  1. William Douglas Tap
    122 Tap