Novel Intervention for Helicobacter pylori-Induced Stomach Cancer: Chemoprevention by Scavengers of Electrophiles
Abstract
Our Peer Reviewed Cancer Topic Area is Stomach Cancer and Military Relevance Focus Areas are Military-relevant risk factors associated with cancer -- Infectious agents; and Gaps in cancer prevention. Stomach cancer is a serious and very common disease. According to the latest available cancer statistics, there were 952,000 new cases of stomach cancer in 2012, accounting for 6.8% of all cancers, and it is the fifth most common cancer and the third leading cause of cancer deaths in the world. The main cause of this form of cancer is infection of the stomach by a type of bacteria called Helicobacter pylori. H. pylori is usually acquired early in life and typically lives in the stomach for the life of infected individuals; it is estimated that more than half of the world’s population is currently infected. The chronic infection with H. pylori causes inflammation of the stomach lining, called gastritis, which continues for decades and has the potential to evolve through various stages of damage until cancer develops. Very often this infection is clinically silent, such that damage is ongoing and the patient is unaware. As such, once stomach damage has progressed to a precancerous state, benefits of using antibiotics are unproven. Moreover, antibiotic regimens to treat the infection are expensive and complicated. In areas of the world where infection is very common, people so treated often develop recurrence of the infection. Also, the bacteria are frequently resistant to the antibiotics; guidelines have very recently changed to suggest that doctors should use various combinations of three different antibiotics, which will make the bacteria even harder to treat in the future. We desperately need to understand more about how cells in the stomach lining become cancerous and to use this knowledge to develop new ways to prevent this infection-associated cancer. Our previous work has shown that during the process of inflammation caused by the infection, there can be damage to the DNA of cells. DNA is the genetic code that is the building block of life. When there are abnormalities in the DNA (mutations) this can lead to cancer. This project brings a new perspective in which we will study a specific form of injurious agents, called electrophiles, which we have now shown, for the first time, to be produced in the stomach as a result of oxidative stress. These electrophiles can react with important molecules, such as DNA, and therefore transform normal cells into cancerous cells. We will determine if electrophiles could be responsible for development of stomach cancer due to H. pylori infection, and if we can block their damaging effects. We have developed a compound, 5-ethylsalicylamine (called EtSA), which is well tolerated in animals, that acts to remove the electrophiles. We will use two animal models: gerbils and a specific type of mouse; these animals develop gastric inflammation, precancerous lesions, and finally cancer when they are infected with H. pylori, mimicking the human disease process. By comparing mice and gerbils treated with EtSA or not, we will establish the effect of the drug on the severity and characteristics of the inflammation, and formation of cancerous lesions in the stomach. We will analyze the effect of EtSA on damage to the DNA caused by oxidative stress, and on DNA mutations, the end result of such damage, which are associated with malignancies. Our studies are proof-of-principle investigations in animal models. In the future, our work could help patients infected with H. pylori infection in which the stomach lining shows signs of cellular changes that have been shown to have a higher likelihood of progressing on to cancer. This study will not involve human subjects, but our outcomes will provide essential information about toxic electrophiles during infection-associated inflammation, precancer, and cancer; their ability to damage DNA; and the effect of a new drug on the disease p
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810301
Entities
People
- Keith T. Wilson
Organizations
- United States Army
- Vanderbilt University