title: Organotypical vascular model for characterization of radioprotective compounds: studies on antioxidant 2,3-diaryl-substituted indole-based cyclooxygenase-2 inhibitors.
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.
authors.affiliation: Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden- Rossendorf, Dresden, Germany Department of Chemistry and Food Chemistry, Technische Universität Dresden, Dresden, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Ullm
authors.affiliation: Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden- Rossendorf, Dresden, Germany Department of Chemistry and Food Chemistry, Technische Universität Dresden, Dresden, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Laube
authors.affiliation: Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden- Rossendorf, Dresden, Germany Department of Chemistry and Food Chemistry, Technische Universität Dresden, Dresden, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Bechmann
authors.affiliation: Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden- Rossendorf, Dresden, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Kniess
authors.affiliation: Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden- Rossendorf, Dresden, Germany Department of Chemistry and Food Chemistry, Technische Universität Dresden, Dresden, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Pietzsch
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000737:chemistry*; D001011:Aorta / Q000187:drug effects / Q000378:metabolism*; D016718:Arachidonic Acid / Q000737:chemistry; D002318:Cardiovascular Diseases / Q000188:drug therapy; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry*; D007150:Immunohistochemistry; D007211:Indoles / Q000737:chemistry; D028421:Isoprostanes / Q000737:chemistry; D008297:Male; D008955:Models, Cardiovascular; D016877:Oxidants / Q000737:chemistry; D011453:Prostaglandins / Q000737:chemistry; D011837:Radiation-Protective Agents / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000975:Antioxidants; D052246:Cyclooxygenase 2 Inhibitors; D007211:Indoles; D028421:Isoprostanes; D016877:Oxidants; D011453:Prostaglandins; D011837:Radiation-Protective Agents; D016718:Arachidonic Acid; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat
keywords: Aortic ring model; adjuvant radioprotective therapy; cardiovascular disease; coxibs; normal tissue damage; prostanoids; radiation therapy