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 Apc(Delta716) 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.