Cyclooxygenase-2 inhibitors in colorectal cancer.

Abstract

Cyclooxygenase (COX) enzyme-dependent arachidonic acid metabolites occupy key positions in important physiologic processes such as immunity, reproduction, and vascular integrity. Large retrospective and prospective population-based studies have shown that the use of both nonselective, nonsteroidal anti-inflammatory drugs and selective COX-2 inhibitors are associated with decreased colorectal cancer incidence and mortality rate. A majority of animal studies provide strong evidence that prevention of intestinal tumors is more efficiently accomplished by COX-2 selective inhibition rather than by COX-1 suppression. The inducible COX-2 isoform is overexpressed in colorectal tissues and is associated with critical events of tumorigenesis. COX-2 expression correlates with expression of angiogenic factors and new blood vessel formation. Inhibition of COX-2 favors apoptosis and causes a dose-dependent decline of tumor growth and metastasis in these models. These data, together with the fact that COX-2 inhibitors cause less toxic side effects compared with nonselective nonsteroidal anti-inflammatory drugs, render these new compounds promising candidates in chemoprevention and treatment of colorectal cancer. Results from initial clinical trials suggest that COX-2 inhibitors may be able to reduce the polyp burden in patients with familial polyposis coli. However, further clinical studies are needed to evaluate whether COX-2 inhibition will be effective in all types of colorectal tumor tissues. This is especially true for neoplastic lesions that express COX-2 at a lower level (eg, hereditary nonpolyposis colorectal cancer) and for colorectal tumors of patients with inflammatory bowel disease. In summary, COX-2 inhibitors represent a new and very promising group of chemotherapeutic agents with great potential for both colorectal cancer prevention and treatment.