Inhibition of protease-activated receptor 1 ameliorates intestinal radiation mucositis in a preclinical rat model.

International Journal of Radiation Oncology, Biology, Physics
Junru WangMartin Hauer-Jensen

Abstract

To determine, using a specific small-molecule inhibitor of protease-activated receptor 1 (PAR1) signaling, whether the beneficial effect of thrombin inhibition on radiation enteropathy development is due to inhibition of blood clotting or to cellular (PAR1-mediated) thrombin effects. Rats underwent fractionated X-irradiation (5 Gy×9) of a 4-cm small-bowel segment. Early radiation toxicity was evaluated in rats receiving PAR1 inhibitor (SCH602539, 0, 10, or 15 mg/kg/d) from 1 day before to 2 weeks after the end of irradiation. The effect of PAR1 inhibition on development of chronic intestinal radiation fibrosis was evaluated in animals receiving SCH602539 (0, 15, or 30 mg/kg/d) until 2 weeks after irradiation, or continuously until termination of the experiment 26 weeks after irradiation. Blockade of PAR1 ameliorated early intestinal toxicity, with reduced overall intestinal radiation injury (P=.002), number of myeloperoxidase-positive (P=.03) and proliferating cell nuclear antigen-positive (P=.04) cells, and collagen III accumulation (P=.005). In contrast, there was no difference in delayed radiation enteropathy in either the 2- or 26-week administration groups. Pharmacological blockade of PAR1 seems to reduce early radiation m...Continue Reading

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Citations

Nov 18, 2015·Cancer Metastasis Reviews·Marek Z WojtukiewiczKenneth V Honn
Aug 2, 2018·Cancers·Annalisa BrunoPaola Patrignani
Jan 13, 2017·Journal of Thrombosis and Haemostasis : JTH·C LinC A Spek
Nov 13, 2020·Biomarkers : Biochemical Indicators of Exposure, Response, and Susceptibility to Chemicals·Guanqun ChaoShuo Zhang

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