COX Selectivity and Animal Models for Colon Cancer

Early experiments performed during 1980s and 1990s 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 intestinal tumorigenesis. A genetic study using compound mutant mice of COX-2- / -, and ApcD716 which is 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. On the other hand, another study indicated that COX-1 also plays an important role in the early stage of intestinal tumorigenesis. 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 have been published as of August 2001, and reported to suppress intestinal tumor growths by NSAIDs or COX-2 inhibitors.