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- Title
Organotypical vascular model for characterization of radioprotective compounds: Studies on antioxidant 2,3-diaryl-substituted indole-based cyclooxygenase-2 inhibitors.
- Authors
Ullm, Sandra; Laube, Markus; Bechmann, Nicole; Kniess, Torsten; Pietzsch, Jens
- Abstract
Radiotherapy of various cancers is closely associated with increased cardiovascular morbidity and mortality. Arachidonic acid metabolites are supposed to play a key role in radiation-induced vascular dysfunction. This study was designed to evaluate the effects of novel, antioxidative 2,3-diaryl-substituted indole-based selective cyclooxygenase-2 (COX-2) inhibitors (2,3-diaryl-indole coxibs) on radiation-induced formation of arachidonic acid metabolites via COX-2 and oxidant stress pathways in an organotypical vascular model of rat aortic rings. Acute and subacute effects of X-ray radiation (4 and 10 Gy; 1 and 3 days post irradiation) with or without the presence of 1 μM of the 2,3-diaryl-indole coxib 2-[4-(aminosulfonyl)phenyl]-3-(4- methoxyphenyl)-1H-indole (C1) or celecoxib as reference compared to sham-irradiated controls were assessed. The following parameters were measured: metabolic activity of the aortic rings; induction and regulation of COX-2 expression; release of prostaglandin E2 and F2α-isoprostane. Irradiation without presence of coxibs resulted in a dose-dependent augmentation of all parameters studied. When aortic rings were exposed to the 2,3-diaryl-indole coxib 1 h before irradiation, metabolic activity was restored and the release of both prostaglandin and isoprostane was inhibited. The latter indicates a direct interaction with oxidant stress pathways. By contrast, celecoxib exhibited only slight effects on the formation of isoprostane. The reduction of radiation-induced vascular dysfunction by antioxidative coxibs may widen the therapeutic window of COX-2 targeted treatment.
- Subjects
CYCLOOXYGENASE 2; RADIOTHERAPY; CYCLOOXYGENASE inhibitors; CARDIOVASCULAR system; ARACHIDONIC acid; METABOLITES; PROSTAGLANDINS; ISOPROSTANES
- Publication
Clinical Hemorheology & Microcirculation, 2014, Vol 58, Issue 1, p281
- ISSN
1386-0291
- Publication type
Article
- DOI
10.3233/CH-141902