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A combination of two drugs destroys precancerous polyps in the colon without effects on normal tissues, which opens a new avenue for chemoprevention of colon cancer, a team of scientists from the University of Texas MD Anderson progress report of the Cancer Center Publishing online edition of Nature. The system, as tested in mouse models and human colon cancer tissues in the laboratory, appears to be a problem with chemopreventive agents – must take the long term remains effective, exposing patients to the possible effects side, said lead author Wu Xiangwei, Phil. D., Associate Professor at the MD Anderson Department of Head and Neck Surgery.

“This combination may be of short duration and periodically to provide long term, which would be a new approach to chemotherapy,” said Wu

The team found that the combination of vitamin A acetate (RAC) and Camino, the absence of tumor necrosis factor apoptosis-inducing ligand to kill pre-cancerous polyps and inhibits tumor growth in mice that are deficient in the tumor suppressor gene. This gene, familial adenomatous polyposis (APC) and its downstream signaling molecules, are mutated or deficient in 80 percent of all cancers of the colon of man, “Wu said

Failing to separate, all powerful

The first experiments with mice deficient in APC showed the two drugs in combination or separately, does not affect normal cells in the epithelium of the colon. On the other hand, showed no effect on precancerous polyps called adenomas.

ROAD CAR and dead cells of adenomas, knowing the causes cell death or apoptosis. RAC, the researchers found, sensitizes cells to TRAIL polyps.

The researchers tracked the molecular cascade of failures caused by the APC and found that the absence of APC to sensitize cells to TRAIL and RAC remove a protein that blocks TRAIL.

The reduction in polyps, and improved survival

APC-deficient mice were treated with 15 cycles of the combination of TRAIL RAC over six weeks. Others have welcomed the RAC or a path and a control group received nothing. A month later, the control mice and those treated with a drug on average between 35 and 42 polyps, whereas those who received the combination of an average of 10.

To test the potential of the combination of a short-term therapy, APC-deficient mice were treated with two cycles of the combination in a week, causing a reduction of 69 percent of polyps two weeks later. A 10-fold increase of mice treated with the left, only 10 percent of polyps in the controls.

A long-term test of survival to five treatments over four months to improve the survival of 186 days for control beyond 213 days for mice treated with five of the seven treated mice living more than eight months.

Cell death in human colon polyps

Then the researchers treated the biopsy samples of normal tissue and tumor regions of patients with familial adenomatous polyposis – an inherited disease that inevitably leads to colon cancer if the colon is not removed. Treatment of normal tissues caused little cell death, while 57 percent of the cells of the polyps were killed by apoptosis.

Current treatments aim to block some aspects of tumor growth increasingly, Wu said, while the CAR and TRAIL directly kill all precancerous polyps. Since APC is mutated or deficient in other types of cancer, combined therapy could become a drug in general.

Before human clinical trials can be considered, said Wu, the team will conduct further research to understand the possible side effects and is also developing an injectable version of the association, which now is administered intravenously.

One of the genes activated by the poor form of the APC, β-catenin, is involved in stem cell self-renewal and maintenance of adult tissues. The team conducted a series of experiments and determined that the RAC / TRAIL does not affect stem cells in mice.

Today, concerns about side effects, cardiovascular agents limit the chemoprevention of colon cancer patients, especially high risk, “Wu said” We hope this combination, if it is a lack of toxicity may be available as a chemopreventive agent elderly population in general. ”

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