Gastric mucosal cell model for estimating relative gastrointestinal toxicity of non-steroidal anti-inflammatory drugs.
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.
Hall
A J
AJ
Metagenics, 9770 44th Avenue, Gig Harbor, WA 98332, USA. amyhall@metagenics.com
Tripp
M
M
Howell
T
T
Darland
G
G
Bland
J S
JS
Babish
J G
JG
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
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D015232:Dinoprostone