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Paired Drug Combination Kills Precancerous Colon Polyps

A two-drug combination destroys precancerous colon polyps with no effect on normal tissue, opening a new potential avenue for chemoprevention of colon cancer, according to a team of scientists at The University of Texas M.D. Anderson Cancer Center and INCELL Corporation. The drug regimen, tested so far in mouse models and on human colon cancer tissue in the laboratory, appears to address a problem with chemopreventive drugs--they must be taken continuously long term to be effective, exposing patients to possible side effects, said senior author Dr. Xiangwei Wu, associate professor in M.D. Anderson's Department of Head and Neck Surgery. "This combination can be given short term and periodically to provide a long-term effect, which would be a new approach to chemoprevention," Dr. Wu said. The team found that a combination of Vitamin A acetate (RAc) and TRAIL, (tumor necrosis factor-related apoptosis-inducing ligand), kills precancerous polyps and inhibits tumor growth in mice that have deficiencies in a tumor-suppressor gene. That gene, adenomatous polyposis coli (APC) and its downstream signaling molecules, are mutated or deficient in 80 percent of all human colon cancers, Dr. Wu said. Early experiments with APC-deficient mice showed that the two drugs combined or separately did not harm normal colon epithelial cells. Separately, they showed no effect on premalignant polyps. RAc and TRAIL together killed premalignant polyps, causing programmed cell death known as apoptosis. RAc, researchers found, sensitizes polyp cells to TRAIL. The scientists painstakingly tracked the molecular cascade caused by APC deficiencies, and found that insufficient APC sensitizes cells to TRAIL and RAc by suppressing a protein that blocks TRAIL. Before human clinical trials can be considered, Dr. Wu noted, the team will conduct additional research to understand potential side effects and will also try to develop an injectable version of the drug combination, which is administered intravenously now. Today, concerns about cardiovascular side effects limit chemopreventive agents for colon cancer mainly to high-risk patients, Dr. Wu said. "We hope this combination, if it proves to lack toxicities, might be available as a chemopreventive agent to a broader, general population." The article was published online on March 28, 2010 in Nature. [Press release] [Nature abstract]