Chemoprevention and therapy of mammary carcinogenesis by prostaglandin H synthase-2 (COX-2) inhibition

A promising new lead for the control of breast cancer comes from recent epidemiological studies which suggest that regular intake of nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of human cancers, including breast cancer. The anticarcinogenic activity of NSAIDs appears to be related predominantly to their inhibitory effects on prostaglandin H synthase (COX) isoforms (COX-1 and COX-2) related mechanisms. A growing body of evidence has shown the inducible COX-2 gene to be overexpressed in several types of cancers, including breast cancer, and suggests an association between its blockade and inhibition of tumor development and growth.; In a series of studies, the chemopreventive and therapeutic potential of the selective COX-2 inhibitor, celecoxib, was investigated in chemically (DMBA)-induced rat mammary cancer model. Celecoxib significantly inhibited mammary tumor incidence, tumor multiplicity, tumor volume and increased tumor latency, in a dose-dependent manner; and the inhibition was approximately equal during the initiation or promotion phases of mammary carcinogenesis. The chemopreventive effects of celecoxib exceeded those obtained by the nonselective NSAID, ibuprofen, or the retinoid, 4-HPR, which were used for comparison in these experiments. No sign of toxicity was observed with celecoxib use during the experimental period. Also, the administration of celecoxib to animals with established DMBA-induced mammary tumors, caused reduction of the cancer load (CL), that is, regression of tumor volume as well as decrease in the total number of tumors. The chemotherapeutic effects of celecoxib exceeded those obtained by ibuprofen. On the other hand, the selective COX-1 inhibitor, SC560, did not cause any regression in tumor volume, and tumors continued to grow.; The results of these pre-clinical efficacy studies provide further evidence for the role of NSAIDs in chemoprevention and therapy of breast cancer, similar to what has been reported in colon cancer. The higher potency and lower toxicity of COX-2 inhibitors offer chemopreventive/chemotherapeutic advantage over the nonselective NSAIDs, and underscore their potential usefulness in the future for the prevention and therapy of human breast cancer.