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Lookup NU author(s): Professor Alison Tyson-Capper, Emeritus Professor Nick Europe-Finner
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Increased expression of cyclooxygenase-2 (COX-2) has been implicated in the onset of both term and preterm labor. In this context, both selective and nonselective COX-2 inhibitors have been used in clinical trials to determine their efficacy in delaying preterm labor. However, recent evidence indicates that these tocolytics may have potentially adverse fetal and maternal side effects. Therefore, the development of more specific and nontoxic agents to inhibit COX-2 needs to be considered. We have evaluated whether antisense morpholino oligonucleotides have therapeutic potential in inhibiting COX-2 by specifically targeting both the 3′ and 5′ acceptor and donor sites of exon 4 of COX-2's pre-mRNA sequence. Confocal microscopy on "live" cells illustrated high levels of penetrance of antisense morpholino oligonucleotides using the Endo-Porter formula (Gene-Tools, LLC, Philomath, OR), with delivery efficiencies of 82 and 78%, respectively, in amnion-derived WISH and myometrial cells. Substantial inhibition by the morpholino oligonucleotides of COX-2 expression, induced by lipopolysaccharide administration, was observed at both the mRNA and protein levels. Loss of enzymic activity of COX-2 was confirmed using a sensitive COX enzyme activity assay, which reflects the rate of conversion of arachidonic acid to prostaglandin H2. Our results indicate that antisense morpholino oligonucleotides significantly inhibit expression and activity of this enzyme in in vitro cultures of amnion-WISH and myometrial cells. The potential thus exists that a similar approach can be mimicked in vivo to produce a highly specific and nontoxic strategy to inhibit COX-2 activity with its subsequent effects on the better management of preterm labor and other inflammatory conditions. Copyright © 2006 The American Society for Pharmacology and Experimental Therapeutics.
Author(s): Tyson-Capper AJ, Europe-Finner GN
Publication type: Article
Publication status: Published
Journal: Molecular Pharmacology
Year: 2006
Volume: 69
Issue: 3
Pages: 796-804
ISSN (print): 0026-895X
ISSN (electronic): 1521-0111
Publisher: American Society for Pharmacology and Experimental Therapeutics
URL: http://dx.doi.org/10.1124/mol.105.020529
DOI: 10.1124/mol.105.020529
PubMed id: 16354766
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