STIMULUS DEPENDENCE OF NONSTEROIDAL ANTIINFLAMMATORY DRUG POTENCY IN A CELLULAR-ASSAY OF PROSTAGLANDIN-H SYNTHASE-2

The prostaglandin H synthase-2 selective non-steroidal antiinflammator y drugs nimesulide, NS-398 2-cyclohexyloxy-4-nitrophenyl)methanesulfon amide), flosulide and SC 58125 [4-(methylsulfonyl)phenyl]-3-(trifluoro methyl)-1H- pyrazole) as well as the non-selective non-steroidal antii nflammatory drugs indomethacin, meclofenamate and ibuprofen were compa red in a WISH (human amnionic epithelial cell) cellular assay of prost aglandin H synthase-2 activity. Varying amounts of prostaglandin E-2 w ere induced in WISH cells using either interleukin-1 beta, tumor necro sis factor-alpha or phorbol 12-myristate 13-acetate, alone or in combi nation, or with okadaic acid as stimulants. The results from these stu dies demonstrated that under conditions which generate greater amounts of prostaglandin E-2, the potency of both prostaglandin H synthase-2 selective and non-selective non-steroidal antiinflammatory drugs may b e reduced. Dexamethasone, a transcriptional inhibitor of prostaglandin H synthase-2, also became progressively less effective in cells activ ated by combinations of stimuli or with okadaic acid. We conclude that decreases in potency under conditions of high levels of prostaglandin H synthase-2 expression and prostaglandin E-2 production are observed equally with prostaglandin H synthase-2 selective and non-selective i nhibitors. (C) 1997 Elsevier Science B.V.