Rofecoxib (Vioxx), a specific cyclooxygenase-2 inhibitor, is chemopreventive in a mouse model of colon cancer.
The ApcDelta716 knockout mouse develops hundreds of intestinal polyps and smaller numbers in the colon because of the truncation of the suppressor protein Apc. We show inhibition of polyposis in the ApcDelta716 mouse by rofecoxib (Vioxx), a specific cyclooxygenase-2 (COX-2) inhibitor. Both the number and size of polyps in the ApcDelta716 mouse were markedly reduced by rofecoxib (Vioxx) treatment at plasma concentrations similar to those achieved in humans with antiinflammatory concentrations of Vioxx. Sulindac, a dual cyclooxygenase-1/2 inhibitor, also diminished size and number of polyps but to a lesser extent than rofecoxib. The protein expression of COX-1 or COX-2 was unchanged by treatment with rofecoxib or sulindac because these agents inhibit enzyme activity and prostaglandin product formation rather than transcription of the COX genes. The proangiogenic protein vascular derived endothelial growth factor was decreased in polyps treated with rofecoxib, whereas membrane-associated beta-catenin increased in rofecoxib-treated polyps. DNA proliferation was decreased in polyps by both rofecoxib and sulindac treatment. Rofecoxib (Vioxx) is used clinically for osteoarthritis and pain, and in addition the results described here suggest that Vioxx may be useful as a chemopreventive in humans at risk for colorectal neoplasia.
Evans
Jilly F
JF
Pharmacology Department, Merck Research Laboratories, Merck & Co., Inc., West Point, Pennsylvania, USA.
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000517:prevention & control*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D017491:Genes, APC; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D007783:Lactones / Q000627:therapeutic use*; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D011451:Prostaglandin-Endoperoxide Synthases; D013450:Sulfones; D013467:Sulindac / Q000627:therapeutic use
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D007783:Lactones; D013450:Sulfones; C116926:rofecoxib; D013467:Sulindac; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases