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Prevention of colorectal cancer through the use of COX-2 selective inhibitors

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Abstract

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.

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  1. Division of Gastroenterology, Vanderbilt University School of Medicine, 1161 21st Avenue South, C-2104 Medical Center North, Nashville, TN 37232-2279, USA

    Richard M. Peek Jr

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Correspondence to Richard M. Peek Jr.

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This work was presented at the 19th Bristol-Myers Squibb Nagoya International Cancer Treatment Symposium, “State of the Arts for Digestive Organs”, 14–15 November 2003, Nagoya, Japan.

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Peek, R.M. Prevention of colorectal cancer through the use of COX-2 selective inhibitors. Cancer Chemother Pharmacol 54 (Suppl 1), S50–S56 (2004). https://doi.org/10.1007/s00280-004-0887-x

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