Cyclooxygenase-2: a novel target for cancer chemotherapy?

Epidemiologic studies have documented a 40-50% reduction in incidence of co lorectal cancer in individuals taking nonsteroidal antiinflammatory drugs ( NSAIDs). Since NSAIDs are known to inhibit cyclo-oxygenases (COX-1, COX-2), the basic mechanism of their antitumor effects is conceivably the altered metabolism of arachidonic acid and, subsequently, prostaglandins (PGs). Alt hough COX-2, the inducible isoform, is regularly expressed at low levels in colonic mucosa, its activity increases dramatically following mutation of the APC (adenomatous polyposis coli) gene suggesting that beta -catenin/T-c ell factor mediated Wnt-signaling activity may regulate COX-2 gene expressi on. In addition, hypoxic conditions and sodium butyrate exposure may also c ontribute to COX-2 gene transcription in human cancers. The development of selective COX-2 inhibitors has made it possible to further evaluate the rol e of COX-2 activity in colorectal carcinogenesis. To date, at least five me chanisms by which COX-2 contributes to tumorigenesis and the malignant phen otype of tumor cells have been identified, including: (1) inhibition of apo ptosis; (2) increased angiogenesis; (3) increased invasiveness; (4) modulat ion of inflammation/immuno-suppression; and (5) conversion of procarcinogen s to carcinogens. A clear positive correlation between COX-2 expression and inhibition of apoptosis has been established, associated with increased PG E(2) levels resulting in modulation of pro- and anti-apoptotic factors (e.g ., bcl-2, MAKs/ras, caspase-3, Par-4). In terms of angiogenesis and invasiv eness, COX-2 activity was found to increase the expression of growth factor s (e.g., VDEG, PDGF, bFGF) and matrix metalloproteinases (MMPs). Since COX- 2 inhibitors have been demonstrated to interfere with tumorigenesis and apo ptosis, COX-2 and its gene product may be attractive targets for therapeuti c and chemoprotective strategies in colorectal cancer patients. This may le ad to new perspectives that by controlling the cancer phenotype, rather tha n attempting to eradicate all affected cells, may provide significant benef its to the cancer patient.