Paradoxical effects of a selective cyclooxygenase-2 inhibitor, etodolac, on proliferative changes of forestomach in alloxan-induced diabetic rats

A single intravenous injection of alloxan, a non-genotoxic diabetogenic chemical, induces proliferative changes in forestomach mucosa of rats, and some lesions progress to squamous cell carcinoma accompanied with inflammatory change. The present study was conducted to examine the effects of a selective cyclooxygenase-2 (COX-2) inhibitor, etodolac, on the proliferative changes of forestomach mucosa in alloxan-induced diabetic rats. Alloxan-induced diabetic rats were fed a diet containing 0.01% etodolac (AL+Et group) and standard diet (AL group). They were sacrificed after 25 and 50 weeks of feeding, respectively. Squamous cell hyperplasia of forestomach was completely suppressed by etodolac after 25 weeks. After 50 weeks of treatment, the proliferative changes in forestomach developed in all rats of the AL+Et group, but in only 55.6% of the rats in the AL group. The severity of proliferative lesions was much enhanced in the AL+Et group compared to the AL group, and was parallel to the inflammatory changes in individual cases. Ulceration and erosion were more severe in the AL+Et group. These findings demonstrate that etodolac suppresses proliferative and inflammatory changes with COX-2 expression of forestomach in the early stage, but enhances them after 50 weeks.