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. METHODS: Regorafenib 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. RESULTS: Twenty 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. CONCLUSIONS: These 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.
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. METHODS:Regorafenib 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. RESULTS: Twenty 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. CONCLUSIONS: These 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.
Authors: George D Demetri; Allan T van Oosterom; Christopher R Garrett; Martin E Blackstein; Manisha H Shah; Jaap Verweij; Grant McArthur; Ian R Judson; Michael C Heinrich; Jeffrey A Morgan; Jayesh Desai; Christopher D Fletcher; Suzanne George; Carlo L Bello; Xin Huang; Charles M Baum; Paolo G Casali Journal: Lancet Date: 2006-10-14 Impact factor: 79.321
Authors: Andrew S Levey; Josef Coresh; Tom Greene; Jane Marsh; Lesley A Stevens; John W Kusek; Frederick Van Lente Journal: Clin Chem Date: 2007-03-01 Impact factor: 8.327
Authors: Mariëtte H W Kappers; Vincent J de Beer; Zhichao Zhou; A H Jan Danser; Stefan Sleijfer; Dirk J Duncker; Anton H van den Meiracker; Daphne Merkus Journal: Hypertension Date: 2011-11-28 Impact factor: 10.190
Authors: Maria Luisa Veronese; Ari Mosenkis; Keith T Flaherty; Maryann Gallagher; James P Stevenson; Raymond R Townsend; Peter J O'Dwyer Journal: J Clin Oncol Date: 2006-01-30 Impact factor: 44.544
Authors: James C Yang; Leah Haworth; Richard M Sherry; Patrick Hwu; Douglas J Schwartzentruber; Suzanne L Topalian; Seth M Steinberg; Helen X Chen; Steven A Rosenberg Journal: N Engl J Med Date: 2003-07-31 Impact factor: 91.245
Authors: Arvind K Pandey; Eric K Singhi; Juan Pablo Arroyo; Talat Alp Ikizler; Edward R Gould; Jonathan Brown; Joshua A Beckman; David G Harrison; Javid Moslehi Journal: Hypertension Date: 2017-12-26 Impact factor: 10.190
Authors: Stephen J H Dobbin; Alan C Cameron; Mark C Petrie; Robert J Jones; Rhian M Touyz; Ninian N Lang Journal: Heart Date: 2018-09-18 Impact factor: 5.994