For the 14,400 patients per year diagnosed with head and neck cancer, scientists from URMC’s Eastman Institute for Oral Health may have some good news.
Most head and neck cancer patients will undergo radiation therapy to treat the cancer. More than 90 percent of them will also experience an unpleasant parched sensation in their mouth — a side effect of the radiation treatment called xerostomia, or dry mouth. For most of these patients, the persistent dryness becomes a permanent part of their lives, causing difficulty with eating and speaking, oral infections, dental caries, tissue inflammation, and decreased quality of life.
This common scenario has led scientists to investigate what causes dry mouth. They have found that cells in the salivary gland are extremely sensitive to radiation exposure. As a result of the radiation therapy to treat the cancer, salivary gland cells activate an age-old suicide response called “apoptosis”, which is a Greek word that literally means, “as petals falling from a rose.” The response starts with an increased production of specific proteins that direct the death of the cell. As more cells die, the salivary gland’s ability to make saliva permanently diminishes.
These basic findings have raised a major clinical research question: If the process of cell death is blocked in the salivary glands during radiation treatment, can xerostomia be prevented?
A team of scientists from the Center for Oral Biology, part of the Eastman Institute for Oral Health, report initial success in reducing apoptosis and decreased saliva production in mice, by treating the salivary gland before radiation exposure. Their research, which is supported by the National Institute of Dental and Craniofacial Research, is published in the June issue of Molecular Therapy.
The team, led by Catherine Ovitt, Ph.D., associate professor in the Department of Biomedical Genetics, devised a method to temporarily block the expression of a protein causing the cell death. “Two issues are paramount for success,” Ovitt explained. “One is efficient delivery into the cell and the other is specifically targeting the protein to obtain the desired outcome.” They used short interfering RNAs (siRNAs), small molecules that can be introduced into the salivary gland cells to target and prevent the increased production of the protein during the radiation treatment. They coupled the siRNAs to nanoparticles developed in the laboratory of Danielle Benoit, Ph.D., assistant professor in Biomedical Engineering. The nanoparticles carry the siRNAs into the salivary gland cells. In order to specifically protect the salivary glands, Szilvia Arany, Ph.D., injected the siRNA-nanoparticle complexes retroductally into the mouse salivary gland excretory ducts before treating the mice with radiation.
Ovitt and her team soon determined that the siRNAs hit their mark, greatly reducing the amount of pro-apoptotic protein after radiation treatment. Immediately after radiation, the treated mice showed less salivary gland cell death, and after three months, they retained over 50 percent more salivary flow than control mice.
“Our results suggest that this approach could be an effective means of protecting salivary glands during radiation treatment of head and neck cancer,” Ovitt said. She also pointed out that the approach has significant advantages over alternative methods, as it is limited to the salivary glands, does not involve viruses, and only temporarily blocks the protein expression. The group is continuing their investigations to determine whether the siRNA-nanoparticle complexes are effective in fractionated radiation treatments, such as are administered to human patients.
The article is titled, “Nanoparticle-mediated gene silencing confers radioprotection to salivary glands in vivo.” The other authors include Szilvia Arany, Ph.D, Danielle SW Benoit, Ph.D, and Stephen Dewhurst, Ph.D.