Prevention of colorectal cancer through the use of COX-2 selective inhibitors.
Colorectal cancer is a major cause of morbidity and mortality accounting for an estimated 550,000 deaths annually worldwide. Colonic neoplasia develops in a stepwise fashion progressing from normal mucosa to adenomatous polyps to carcinoma, a process that takes years, thereby providing a prime opportunity for intervention. Although early detection by fecal occult blood testing and sigmoidoscopy can decrease the risk of cancer-related death by 20-30%, most persons never undergo appropriate screening. Population-based studies have previously determined that long-term ingestion of aspirin or other nonsteroidal antiinflammatory drugs (NSAIDs) leads to a 40-50% reduction in mortality. from colorectal cancer. These observational studies fueled subsequent mechanistic investigations that led to the identification of a molecular target, cyclooxygenase-2 (COX-2). COX-2 has tumor-promoting properties. Expression of COX-2 is virtually undetectable in normal intestinal mucosa, but is increased in approximately 50% of colonic adenomas and in 90% of colorectal carcinomas. Experimental studies in mice have revealed that genetic ablation or pharmacologic inhibition of COX-2 attenuates the number and size of intestinal polyps that develop in animals harboring a mutation in Apc, which confers an increased risk for intestinal neoplasia. Recent clinical studies using specific COX-2 inhibitors have shown that these compounds can: (1) reduce intestinal polyp burden in patients with familial adenomatous polyposis; (2) prevent the occurrence and/ or recurrence of colorectal adenomas and cancers; and (3) negatively regulate angiogenesis in colorectal cancer liver metastases. Compared to nonselective NSAIDs, COX-2 specific inhibitors cause substantially fewer gastrointestinal side effects. These findings indicate that a widely used and relatively safe class of drugs may represent a viable and effective anticancer strategy for a disease that causes over a half-million deaths per year.
Division of Gastroenterology, Vanderbilt University School of Medicine, 1161 21st Avenue South, C-2104 Medical Center North, Nashville, TN 37232-2279, USA. richard.peek@vanderbilt.edu
Richard M
RM
Peek
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000517:prevention & control*; D051546:Cyclooxygenase 2; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D007417:Intestinal Polyps / Q000188:drug therapy; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012306:Risk
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases