Paired drugs kill precancerous colon polyps, spare normal tissue

Paired drugs kill precancerous colon polyps, spare normal tissue

A two-drug combination destroys precancerous colon polyps with no effect on normal tissue, opening a new potential avenue for chemoprevention of colon cancer, a team of scientists at The University of Texas M. D. Anderson Cancer Center reports in the advance online edition of the journal Nature.

The regimen, tested so far in mouse models and on human colon cancer tissue in the lab, 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 Xiangwei Wu, Ph.D., 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," Wu said.

The team found that a combination of Vitamin A acetate (RAc) and TRAIL, short for tumour necrosis factor-related apoptosis-inducing ligand, kills precancerous polyps and inhibits tumour growth in mice that have deficiencies in a tumour-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, Wu said.

Ineffective separately, powerful together
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 called adenomas.

RAc and TRAIL together killed adenoma cells, causing programmed cell suicide know 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.