[COX inhibitor, suppression of polyposis, and chemoprevention].
Early experiments using carcinogen-induced rat intestinal tumor models demonstrated the inhibitory effects of non-steroidal anti-inflammatory drugs (NSAIDs) on intestinal tumorigenesis. Furthermore, epidemiological studies and clinical trials for familial adenomatous polyposis (FAP) patients supported the possibility that NSAIDs can be used as chemopreventive agents. The major target molecules of NSAIDs are cyclooxygenases (COX), which catalyze the rate-limiting step of prostaglandin biosynthesis. Two isoenzymes of COX have been identified: COX-1 and COX-2. Whereas COX-1 is expressed constitutively in most tissues and responsible for tissue homeostasis, COX-2 is inducible and plays an important role in inflammation and tumorigenesis. A genetic study using compound mutant mice of COX-2-/- and Apc delta 716, a model for human familial adenomatous polyposis (FAP), directly demonstrated that induction of COX-2 is critical for intestinal polyp formation. Numerous studies have also demonstrated that COX-2-selective inhibitors suppress intestinal polyp formation in Apc gene-mutant mice and xenografted cancer cell growths. In addition, stimulation of angiogenesis is one of the major effects by COX-2 expression that is induced in the polyp stromal cells. These data from animal model studies should be helpful in understanding the in vivo mechanism(s) of tumor suppression by NSAIDs or COX-2 inhibitors. Here, we review the animal studies that reported the suppression of intestinal tumor growths by NSAIDs or COX-2 inhibitors.
Oshima
Masanobu
M
Department of Pharmacology, Kyoto University Graduate School of Medicine, Yoshida-Konoe cho, Sakyo-ku, Kyoto 606-8501, Japan.
Taketo
Makoto M
MM
D011125:Adenomatous Polyposis Coli / Q000201:enzymology / Q000517:prevention & control*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D051546:Cyclooxygenase 2; D004195:Disease Models, Animal; D017491:Genes, APC; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D011451:Prostaglandin-Endoperoxide Synthases; D051381:Rats
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007527:Isoenzymes; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases