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!
Scientists learn more about how gene linked to autism affects brain
19.06.2018 | Cincinnati Children's Hospital Medical Center
Overdosing on Calcium
19.06.2018 | Albert-Ludwigs-Universität Freiburg im Breisgau
Scientists from the University of Freiburg and the University of Basel identified a master regulator for bone regeneration. Prasad Shastri, Professor of...
Moving into its fourth decade, AchemAsia is setting out for new horizons: The International Expo and Innovation Forum for Sustainable Chemical Production will take place from 21-23 May 2019 in Shanghai, China. With an updated event profile, the eleventh edition focusses on topics that are especially relevant for the Chinese process industry, putting a strong emphasis on sustainability and innovation.
Founded in 1989 as a spin-off of ACHEMA to cater to the needs of China’s then developing industry, AchemAsia has since grown into a platform where the latest...
The BMBF-funded OWICELLS project was successfully completed with a final presentation at the BMW plant in Munich. The presentation demonstrated a Li-Fi communication with a mobile robot, while the robot carried out usual production processes (welding, moving and testing parts) in a 5x5m² production cell. The robust, optical wireless transmission is based on spatial diversity; in other words, data is sent and received simultaneously by several LEDs and several photodiodes. The system can transmit data at more than 100 Mbit/s and five milliseconds latency.
Modern production technologies in the automobile industry must become more flexible in order to fulfil individual customer requirements.
An international team of scientists has discovered a new way to transfer image information through multimodal fibers with almost no distortion - even if the fiber is bent. The results of the study, to which scientist from the Leibniz-Institute of Photonic Technology Jena (Leibniz IPHT) contributed, were published on 6thJune in the highly-cited journal Physical Review Letters.
Endoscopes allow doctors to see into a patient’s body like through a keyhole. Typically, the images are transmitted via a bundle of several hundreds of optical...
Light detection and control lies at the heart of many modern device applications, such as smartphone cameras. Using graphene as a light-sensitive material for...
13.06.2018 | Event News
08.06.2018 | Event News
05.06.2018 | Event News
19.06.2018 | Physics and Astronomy
19.06.2018 | Life Sciences
19.06.2018 | Physics and Astronomy