Chemoprevention by nimesulide, a selective cyclooxygenase-2 inhibitor, of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced mammary gland carcinogenesis in rats

Breast cancer is common in women all over the world, and exploration of che mopreventive approaches to this cancer is very important. Nimesulide, a sel ective inhibitor of cyclooxygenase-2 (COX-2), is a good candidate as a chem opreventive agent with low toxicity, We examined its effects on mammary tum or development in female Sprague-Dawley rats induced with the environmental carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), Rats at 7 weeks of age received intragastric intubations of PhIP (85 mg/kg body we ight) 4 times weekly for 2 weeks and were maintained on control diet (high fat diet) or experimental diet (high fat diet supplemented with 400 ppm nim esulide) throughout the experiment, COX-2 protein was over-expressed in epi thelial cancer cells and stromal cells of the PhIP-induced mammary carcinom as, but was weak or not apparent in normal mammary gland cells. The develop ment of mammary carcinomas was clearly suppressed by administration of nime sulide, The carcinoma incidence was 51% as compared to 71% for the control diet group, The average multiplicity of carcinomas in the experimental diet group was 1.2+/-0.2 (P<0.05), significantly smaller than the control diet group value (2.6+/-0.5). The size of carcinomas was also clearly decreased; 1.1+/-0.4 cm(3)/rat in experimental diet group (P<0.05), 4.1+/-1.3 cm(3)/r at in the control diet group. The results therefore provide evidence that t he selective COX-2 inhibitor, nimesulide, possesses chemopreventive activit y against PhIP-induced mammary carcinogenesis in rats.