Comparative ability of ibuprofen and N-(4-hydroxyphenyl)retinamide to inhibit development of rat mammary adenocarcinomas associated with differentialinhibition of gene expression of cyclooxygenase isoforms

A rodent model of carcinogen-induced mammary tumorigenesis was used to dete rmine the comparative growth inhibitory effects of dietary administration o f either 1000 mg/kg of the non-steroidal antiinflammatory drug (NSAID) ibup rofen ol 1.5 mmol/kg of the synthetic retinoid N-(4-hydroxyphenyl)-retinami de (4-HPR). In addition, the effects of these compounds on gene expression and protein production of the two isoforms of the cyclooxygenase (COX) gene which are responsible for prostaglandin production were examined. Experime ntal diets were provided to mts beginning at 7 days prior to administration of a single intragastric dose of 15 mg dimethylbenz[a]anthracene (DMBA) an d diets were provided ad libitum until the study was terminated at 16 weeks later Ibuprofen significantly decreased levels of gene expression of both COX-I and COX-2 (p < 0.01). Although dietary 4-HPR did significantly dimini sh levels of COX-I gene expression (p < 0.01) in inf mammary adenocarcinoma s, this synthetic retinoid did not significantly inhibit COX-2 gene express ion. COX-I protein was localized to endothelial cells, infiltrating inflamm atory cells, and tumor cells, while COX-2 protein was detected primarily wi thin tumor cells. Although ibuprofen was more effective in inhibiting COX-2 gene expression than 4-HPR, ibuprofen and 4-HPR were equally effective in inhibiting development of carcinogen-induced mammary adenocarcinomas.