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Activation of receptor ups development of precancerous intestinal polyps

NASHVILLE, Tenn. -- Vanderbilt-Ingram Cancer Center researchers have provided the first evidence that activation of a particular cellular receptor dramatically increases the development of precancerous polyps in the intestine. The findings suggest a new strategy for preventing colorectal cancer by blocking activation of this receptor.

However, they also raise caution about an increased risk of colorectal cancer among people who take drugs that activate this receptor. Such drugs are currently in clinical development to treat obesity and atherosclerosis.

The researchers report their findings Feb. 2 in the online version of the journal Nature Medicine. The paper is scheduled for publication in the print edition next month.

The work was funded in part by the National Colorectal Cancer Research Alliance (NCCRA), an initiative led by NBC's Katie Couric, Lily Tartikoff and the Entertainment Industry Foundation. Other support came from the T.J. Martell Foundation for Leukemia, and the National Cancer Institute.

The group found that among mice with a specific genetic mutation - one that is found among 80 percent of human patients with colorectal cancer - the incidence of larger colon polyps increased fivefold with treatment of a compound known to bind very specifically to the peroxisome proliferator-activated receptor delta (PPAR-delta).

"This is extremely significant because it is these larger polyps that are most likely to develop into intestinal cancer," said Raymond N. DuBois, MD, PhD, Hortense B. Ingram Professor of Molecular Oncology, a professor of Medicine, and associate director of cancer prevention, control and population-based research at Vanderbilt-Ingram.

The team became interested in PPAR-delta's potential role in colorectal cancer development after the observation that the receptor is overexpressed in most colorectal cancer tumors. As part of the lab'
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Contact: Cynthia Floyd Manley
cynthia.manley@vanderbilt.edu
615-838-0280
Vanderbilt University Medical Center
1-Feb-2004


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