Chemopreventive activity of celecoxib, a specific cyclooxygenase-2 inhibitor, and indomethacin against ultraviolet light-induced skin carcinogenesis

Epidemiological and dietary studies suggest that nonsteroidal anti-inflamma tory drugs (NSAIDs) reduce the risk of colon cancer, possibly through a mec hanism involving inhibition of cyclooxygenase (COX)-2, which is overexpress ed in premalignant adenomatous polyps and colon cancer. Because ultraviolet light (UV) can induce COX-2 and nonspecific NSAIDs can decrease UV-induced skin cancer, we evaluated the ability of two compounds, celecoxib (a speci fic COX-2 inhibitor) and indomethacin (a nonspecific NSAID), to block UV-in duced skin tumor development in SKH:HR-1-hrBr hairless mice. Mice fed 150 o r 500 ppm celecoxib showed a dose-dependent reduction (60% and 89%, respect ively) in tumor yield. Indomethacin (4 ppm) reduced tumor yield by 78%. Alt hough both acute and chronic UV exposure increased cell proliferation and e dema, neither compound reduced these parameters. In contrast, UV-induced pr ostaglandin synthesis in the epidermis was effectively blocked by both comp ounds. UV-induced increases in COX-2 expression in skin were also not alter ed in any of the treatment groups. Similarly, tumors that constitutively ex press high levels of COX-2 displayed no reduction by treatment with celecox ib or indomethacin. The dramatic protective effects of celecoxib suggests t hat specific COX-2 inhibitors may offer a way to safely reduce the risk of skin cancer in humans. (C) 1999 Wiley-Liss, Inc.