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Title: Inhibition of Protease-activated Receptor 1 Ameliorates Intestinal Radiation Mucositis in a Preclinical Rat Model

Abstract

Purpose: 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. Methods and Materials: Rats underwent fractionated X-irradiation (5 Gy Multiplication-Sign 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. Results: 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. Conclusion: Pharmacological blockade of PAR1 seems to reduce early radiation mucositis but does not affect the level of delayed intestinal radiation fibrosis. Early radiation enteropathy is related to activation ofmore » cellular thrombin receptors, whereas platelet activation or fibrin formation may play a greater role in the development of delayed toxicity. Because of the favorable side-effect profile, PAR1 blockade should be further explored as a method to ameliorate acute intestinal radiation toxicity in patients undergoing radiotherapy for cancer and to protect first responders and rescue personnel in radiologic/nuclear emergencies.« less

Authors:
;  [1];  [2];  [3];  [1]
  1. Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas (United States)
  2. Schering-Plough Research Institute, Kenilworth, New Jersey (United States)
  3. Nevada Cancer Institute, Las Vegas, Nevada (United States)
Publication Date:
OSTI Identifier:
22149735
Resource Type:
Journal Article
Journal Name:
International Journal of Radiation Oncology, Biology and Physics
Additional Journal Information:
Journal Volume: 85; Journal Issue: 1; Other Information: Copyright (c) 2013 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0360-3016
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; ANTIGENS; BLOOD COAGULATION; COLLAGEN; FIBRIN; FIBROSIS; INTESTINES; IRRADIATION; MEDICAL PERSONNEL; NEOPLASMS; PATIENTS; RADIATION INJURIES; RADIOTHERAPY; RATS; RECEPTORS; THROMBIN; TOXICITY

Citation Formats

Wang, Junru, Kulkarni, Ashwini, Chintala, Madhu, Fink, Louis M., Hauer-Jensen, Martin, and Surgery Service, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas. Inhibition of Protease-activated Receptor 1 Ameliorates Intestinal Radiation Mucositis in a Preclinical Rat Model. United States: N. p., 2013. Web. doi:10.1016/J.IJROBP.2012.02.007.
Wang, Junru, Kulkarni, Ashwini, Chintala, Madhu, Fink, Louis M., Hauer-Jensen, Martin, & Surgery Service, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas. Inhibition of Protease-activated Receptor 1 Ameliorates Intestinal Radiation Mucositis in a Preclinical Rat Model. United States. https://doi.org/10.1016/J.IJROBP.2012.02.007
Wang, Junru, Kulkarni, Ashwini, Chintala, Madhu, Fink, Louis M., Hauer-Jensen, Martin, and Surgery Service, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas. 2013. "Inhibition of Protease-activated Receptor 1 Ameliorates Intestinal Radiation Mucositis in a Preclinical Rat Model". United States. https://doi.org/10.1016/J.IJROBP.2012.02.007.
@article{osti_22149735,
title = {Inhibition of Protease-activated Receptor 1 Ameliorates Intestinal Radiation Mucositis in a Preclinical Rat Model},
author = {Wang, Junru and Kulkarni, Ashwini and Chintala, Madhu and Fink, Louis M. and Hauer-Jensen, Martin and Surgery Service, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas},
abstractNote = {Purpose: 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. Methods and Materials: Rats underwent fractionated X-irradiation (5 Gy Multiplication-Sign 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. Results: 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. Conclusion: Pharmacological blockade of PAR1 seems to reduce early radiation mucositis but does not affect the level of delayed intestinal radiation fibrosis. Early radiation enteropathy is related to activation of cellular thrombin receptors, whereas platelet activation or fibrin formation may play a greater role in the development of delayed toxicity. Because of the favorable side-effect profile, PAR1 blockade should be further explored as a method to ameliorate acute intestinal radiation toxicity in patients undergoing radiotherapy for cancer and to protect first responders and rescue personnel in radiologic/nuclear emergencies.},
doi = {10.1016/J.IJROBP.2012.02.007},
url = {https://www.osti.gov/biblio/22149735}, journal = {International Journal of Radiation Oncology, Biology and Physics},
issn = {0360-3016},
number = 1,
volume = 85,
place = {United States},
year = {Tue Jan 01 00:00:00 EST 2013},
month = {Tue Jan 01 00:00:00 EST 2013}
}