title: Gastric mucosal cell model for estimating relative gastrointestinal toxicity of non-steroidal anti-inflammatory drugs.
abstract: The study objective was to characterize the AGS human gastric mucosal cell line as a model for estimating gastrointestinal toxicity of COX-inhibiting compounds. Rofecoxib, celecoxib, nimesulide, ibuprofen, indomethacin, aspirin, salicylic acid, naproxen and acetaminophen were tested for inhibition of COX-2-mediated prostaglandin E2 synthesis in A549 and AGS cells. The IC50 ratio AGS/A549 was calculated as an estimate of the therapeutic index (TI) for gastrointestinal toxicity. Calculated IC50 values of non-steroidal anti-inflammatory drugs (NSAIDs) in A549 cells were in excellent agreement with published values (r = 0.996; P < 0.005). Calcium ionophore induction of arachidonic acid release in AGS cells provided TI similar to those using platelets and A549 cells (r = 0.918; P < 0.01). The AGS/A549 model exhibited lower TI than the platelet/A549 model. Spearman ranking correlated clinical NSAID gastropathy with lower AGS TI values. The AGS cell line has excellent potential to serve as a model for assessing the gastrointestinal effects of COX-inhibiting compounds.
authors.affiliation: Metagenics, 9770 44th Avenue, Gig Harbor, WA 98332, USA. amyhall@metagenics.com
authors.forename: A J
authors.initials: AJ
authors.lastname: Hall
authors.forename: M
authors.initials: M
authors.lastname: Tripp
authors.forename: T
authors.initials: T
authors.lastname: Howell
authors.forename: G
authors.initials: G
authors.lastname: Darland
authors.forename: J S
authors.initials: JS
authors.lastname: Bland
authors.forename: J G
authors.initials: JG
authors.lastname: Babish
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D001792:Blood Platelets / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000633:toxicity; D015232:Dinoprostone / Q000096:biosynthesis; D005753:Gastric Mucosa / Q000187:drug effects* / Q000473:pathology; D005767:Gastrointestinal Diseases / Q000139:chemically induced*; D006801:Humans; D020128:Inhibitory Concentration 50; D008954:Models, Biological
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D015232:Dinoprostone