The COX-2 inhibitor nimesulide suppresses superoxide and 8-hydroxy-deoxyguanosine formation, and stimulates apoptosis in mucosa during early colonic inflammation in rats

As we have shown previously [Tardieu,D., Jaeg,J,P,, Cadet,J,, Embvani,E., C orpet,D.E. and Petit,C, (1998) Cancer Left, 134, 1-5], a 48-h treatment of 6% dextran sodium sulphate (DSS) in drinking water led to a reproducible 2- fold increase of the mutagenic oxidative lesion 8-oxo-7,8-dihydro-2'-deoxyg uanosine (8-oxodGuo) in colonic mucosa DNA of rats in vivo. The aim of this study was to test the effect of nimesulide, a preferential COX-2 inhibitor , on the DSS-induced 8-oxodGuo increase. We show that nimesulide when admin istered orally, simultaneously with DSS at 5 mg/kg/day, not only totally pr events 8-oxodGuo formation but also suppresses the 5-fold increase of super oxide induced by DSS in the colonic mucosa, This was measured by in vivo fo rmazan blue precipitation (P < 0.01 in the Wilcoxon test). Moreover, nimesu lide enhances apoptosis by similar to 30% as compared with the already high level induced by DSS treatment (P < 0.01), It is suggested that the signif icant increase in mutagenic oxidative DNA damage, produced by mild acute co lonic inflammation, could be important in the initiation of colon cancer in both animals and man. These effects may explain at least partly the well-d ocumented protective action towards colon cancer by preferential COX-2 inhi bitors, either xenobiotics such as nimesulide or natural nutrients.