The role of COX-2 in intestinal cancer

Cyclooxygenase (COX), the key regulatory enzyme for prostaglandin synthesis, is transcribed from two distinct genes. COX-1 is expressed constitutively in most tissues whereas COX-2 is induced by a wide variety of stimuli and was initially identified as an immediate-early growth response gene. In addition, COX-2 expression is markedly increased in 85-90% of human colorectal adenocarcinomas while COX-1 levels remain unchanged. Several epidemiological studies have reported a 40-50% reduction in the risk of developing colorectal cancer in persons who chronically take non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, which are classic inhibitors of COX. Genetic evidence also supports a role for COX-2, since mice null for COX-2 have an 86% reduction in tumour multiplicity in a background containing a mutated APC allele. These results strongly suggest that COX-2 contributes to the development of intestinal tumours and that inhibition of COX is chemopreventative. It is hoped that the chemopreventative effects of NSAIDs will be enhanced by the recent development of COX-2-specific inhibitors.