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Researchers at Vanderbilt have discovered that a drug being tested as a chemoprevention agent for several types of cancer had more than one trick in its bag in cancer prevention. ;stomach.
The researchers found that in addition to its known ability to block the production of cell growth compounds, the drug DFMO (difluoromethylornithine) acts directly on the bacterium Helicobacter pylori to reduce its virulence. H. pylori the infection is the main cause of gastric cancer.
The conclusions, published in the March 12 issue of Proceedings of the National Academy of Sciences, supporting new DFMO studies for the prevention of stomach cancer, the third leading cause of cancer deaths worldwide.
H. pylori infects the stomach of half of the human population, but only about 1% of those infected develop stomach cancer. Although it is possible to treat the infection to prevent stomach cancer, it is difficult to know who to treat. In addition, the virus can have beneficial effects – esophageal reflux disease, asthma and other allergic disorders occur more frequently in people who are not infected. H. pylori.
"H. pylori has been co-evolved with humans for at least 60,000 years, probably more, and trying to prevent stomach cancer by eliminating infection through widespread use of antibiotics is not necessarily a good idea, "he said. Keith Wilson, MD, Thomas F. Frist Sr. Professor of Medicine and Professor of Pathology, Microbiology and Immunology.
"Our study suggests that it would be possible to reduce the virulence of the bacteria without having to eliminate it." It's a speculative and unusual way of thinking about an infection, but this could be an interesting strategy . "
Wilson, who also runs the Vanderbilt Center for Inflammation and Mucosal Cancer, and his team have previously linked the production of cell growth compounds called polyamines to the development of cancer. Stomach in H. pyloriinfected animal model. They demonstrated that animal treatment with DFMO, which inhibits an enzyme essential for the production of polyamines, prevents cancer of the stomach.
Their findings are at the basis of an ongoing clinical trial of DFMO for the prevention of stomach cancer in Honduras and Puerto Rico.
Patients with pre-malignant lesions in the stomach, determined by endoscopy, are included in the DFMO trial and will be studied for progression of the disease.
To deepen the functioning of DFMO, J. Carolina Sierra, PhD, professor of medical research, has collected H. pyloriinfected animal bacteria treated or not treated with DFMO. Using an in vitro test, she evaluated the activity of one of the main H. pylori virulence factors, a protein called CagA. CagA is "injected" into the epithelial cells of the stomach, where it contributes to oncogenic signaling pathways.
"What we have noticed is that bacterial strains from animals treated with DFMO have a reduced ability to displace this virulence factor in epithelial cells," Sierra said.
The researchers found that DFMO treatment – in animals or in vitro – caused mutations in the H. pylori gene that encodes CagY, part of the translocation machinery that injects CagA into the cells.
They demonstrated that animals infected with H. pylori Strains containing mutations in the CagY gene did not develop stomach cancer.
This result, Wilson said, supports the use of DFMO or other tools to reduce H. pylori virulence for cancer prevention.
"This drug (DFMO), which inhibits a very specific enzymatic pathway, also has what some might call" non-targeted "effects: it causes mutations in a H. pylori gene that affects the translocation of CagA, "Wilson said. The vast majority of gastric cancers are badociated with positive strains for CagA. If this drug interferes with the activity of CagA, it's an added bonus. "
Investigators will badyze H. pylori strains isolated from DFMO trial participants in Honduras and Puerto Rico to determine if there is a similar reduction in bacterial virulence in humans.
This research was funded by the National Institutes of Health (grants CA190612, CA116087, CA028842, AT004821, AT006896), a merit award for veterans, the American Heart Association, the Thomas F Foundation Frist Sr. and the Vanderbilt Center for mucosal inflammation and cancer.
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