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

Nilka De Jesus-Gonzalez, Emily Robinson, Radostin Penchev, Margaret Von Mehren, Michael C. Heinrich, William Tap, Qian Wang, George Demetri, Suzanne George, Benjamin D. Humphreys

    Research output: Contribution to journalArticle

    30 Scopus citations

    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.

    Original languageEnglish (US)
    Pages (from-to)1118-1123
    Number of pages6
    JournalAmerican Journal of Hypertension
    Volume25
    Issue number10
    DOIs
    StatePublished - Oct 2012

    Keywords

    • antiangiogenic therapy
    • blood pressure
    • endothelin-1
    • hypertension
    • nitric oxide

    ASJC Scopus subject areas

    • Internal Medicine

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    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. (2012). Regorafenib induces rapid and reversible changes in plasma nitric oxide and endothelin-1. American Journal of Hypertension, 25(10), 1118-1123. https://doi.org/10.1038/ajh.2012.97