Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Paired drugs kill precancerous colon polyps, spare normal tissue

29.03.2010
Combination could provide chemoprevention via short-term therapy, long-term effect

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 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, 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.

Reductions in polyps, improved survival

APC-deficient mice were treated with 15 cycles of the RAc/TRAIL combination over six weeks. Others received either RAc or TRAIL and a control group received nothing. One month later, control mice and those treated with one of the drugs averaged between 35 and 42 polyps, while those receiving the combination averaged 10.

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

A longer term test of relative survival using five treatments over four months improved survival from 186 days for controls to beyond 213 days for treated mice, with five of seven treated mice living more than eight months.

Cell death in human colon polyps

Next, the researchers treated biopsy samples of normal tissue and tumor regions from patients with familial adenomatous polyposis - an inherited condition that inevitably leads to colon cancer if the colon is not removed. Treatment of normal tissue caused little cell death, while 57 percent of polyp cells were killed via apoptosis.

Targeted therapies today aim at blocking some aspect of the tumor that drives its growth, Wu said, whereas RAc and TRAIL together kill precancerous polyps outright. Since APC is deficient or mutated in other types of cancer, the combination therapy could become a more general drug.

Before human clinical trials can be considered, Wu said, the team will conduct additional research to understand potential side effects and also will try to develop an injectable version of the combination, which is administered intravenously now.

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

Today, concerns about cardiovascular side effects limit chemopreventive agents for colon cancer mainly to high-risk patients, Wu said. "We hope this combination, if it proves to lack toxicities, might be available as a chemopreventive agent to a broader, general population."

Wu's research was funded by a National Institutes of Health grant, M. D. Anderson institutional funds, and a grant from the Alliance of Cardiovascular Researchers.

Co-authors with Wu are co-first authors Ling Zhang, Ph.D., and Xiaoyang Ren, M.D., Shaoyi Huang, Zhengming Xu, and Xian-Feng Wen, Ph.D., all of M. D. Anderson's Department of Head and Neck Surgery; Eckhard Alt, M.D., and Xiaowen Bai, Ph.D., of the Department of Molecular Pathology; Patrick Lynch, M.D., of the Department of Gastroenterology, Hepatology and Nutrition. Wu also is affiliated with the Department of Molecular and Cellular Oncology. Co-author

About M. D. Anderson

The University of Texas M. D. Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. M. D. Anderson is one of only 40 comprehensive cancer centers designated by the National Cancer Institute. For six of the past eight years, including 2009, M. D. Anderson has ranked No. 1 in cancer care in "America's Best Hospitals," a survey published annually in U.S. News & World Report.

Scott Merville | EurekAlert!
Further information:
http://www.mdanderson.org

More articles from Health and Medicine:

nachricht Researchers release the brakes on the immune system
18.10.2017 | Rheinische Friedrich-Wilhelms-Universität Bonn

nachricht Norovirus evades immune system by hiding out in rare gut cells
12.10.2017 | University of Pennsylvania School of Medicine

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Neutron star merger directly observed for the first time

University of Maryland researchers contribute to historic detection of gravitational waves and light created by event

On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...

Im Focus: Breaking: the first light from two neutron stars merging

Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.

Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....

Im Focus: Smart sensors for efficient processes

Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).

When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...

Im Focus: Cold molecules on collision course

Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.

How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...

Im Focus: Shrinking the proton again!

Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.

It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ASEAN Member States discuss the future role of renewable energy

17.10.2017 | Event News

World Health Summit 2017: International experts set the course for the future of Global Health

10.10.2017 | Event News

Climate Engineering Conference 2017 Opens in Berlin

10.10.2017 | Event News

 
Latest News

Terahertz spectroscopy goes nano

20.10.2017 | Information Technology

Strange but true: Turning a material upside down can sometimes make it softer

20.10.2017 | Materials Sciences

NRL clarifies valley polarization for electronic and optoelectronic technologies

20.10.2017 | Interdisciplinary Research

VideoLinks
B2B-VideoLinks
More VideoLinks >>>