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Research suggests new avenue for stopping, preventing colon cancer

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"Our results identify PPARdelta as a critical downstream mediator in PGE2-stimulated promotion of colorectal tumor growth," the researchers concluded.

A drug that blocks PPARdelta has been developed in France, and the Vanderbilt researchers hope to test it in mice to see if it has the same effect as knocking out the gene. "We've been carefully examining drugs which inhibit COX-2," DuBois explained. "Now we can really focus on key components of the downstream pathway."

The research could lead to more specific and safer -- ways to prevent colorectal cancer. In addition to generating PGE2, the COX-2 enzyme produces another prostaglandin that blocks clot formation and dilates blood vessels. Long-term, high-dose use of the COX-2 inhibitor Vioxx has been linked to high blood pressure and an increased risk of serious heart problems in some patients.

Last month, researchers at the Salk Institute in La Jolla reported that activating PPARdelta in mice stimulated changes in muscle fibers that enabled the animals to run "marathons" and eat a high-fat diet without gaining weight. A drug that turns on PPARdelta is being tested in patients with fat metabolism disorders.

However, when the drug was given to a strain of mice with a genetic mutation that makes them susceptible to developing pre-cancerous intestinal polyps, both the number and size of polyps increased significantly, DuBois and his colleagues reported last February in Nature Medicine. The same mutation is found in 80 percent of patients with colorectal cancer.

The findings suggest that drugs that activate PPARdelta "may encourage abnormal cell growth in certain populations at risk for colorectal cancer," DuBois cautioned.

DuBois credited Sudhansu K. Dey, Ph.D., who directs the division of Reproductive and Developmental Biology at Vanderbilt, with maintaining the PPARdelta "knockout" mouse colony that made the study possible. Dey, DuBois and their colleagues previously have demo
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Contact: Cynthia Floyd Manley
cynthia.manley@vanderbilt.edu
615-936-5711
Vanderbilt University Medical Center
20-Sep-2004


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