July 14, 2023
Standard of care for patients with head and neck cancer can include surgery, radiation therapy, chemotherapy, targeted therapy or a combination of these treatments. With the current standard of care, nearly 70% of patients experience irreparable damage to healthy tissue adjacent to the treatment area. Salivary parenchyma is highly sensitive to this type of damage, which can lead to hyposalivation for many patients.
"Dry mouth is probably the No. 1 concern we see from patients," says Jeffrey R. Janus, M.D., an otolaryngologist with Mayo Clinic Comprehensive Cancer Center and chair of Otolaryngology at Mayo Clinic in Jacksonville, Florida. "It's one of the toughest side effects our patients deal with."
In recent research, putative stem cells have been found in the submandibular glands of mice and humans. These cells can be transplanted into the radio-ablated glands of recipient mice to restore salivary gland function. Experts at Mayo Clinic, however, have noted a need to develop an in vivo assay to measure quality and quantity of regenerative outcomes in transplant experiments. Results of their research in this space were published in the September 2022 edition of Radiation Research.
Developing a standardized preclinical model
The researchers evaluated highly immunodeficient mice and sought to validate saliva collection by Schirmer test strips. Forty young mice with equal sex representation were evaluated. The highly immunodeficient mice underwent opposing beam stereotactic radiation doses of 0, 2.5, 5, and 7.5 gray at a rate of 5 gray per minute. It also is important to note that a 5-gray whole-body dose of radiation is lethal to these mice. The team developed the first brain-sparing salivary ablative precision radiation model.
Current radiation salivary ablative doses in preclinical models vary widely. While there is some consensus around a dose of 15 gray for immunocompetent mice, this study's focus on a smaller range of doses for the immunodeficient mice provides an excellent model that replicated reduced saliva flow experienced by the patients undergoing head and neck radiotherapy.
"The study provided unprecedented insights into the intricate dynamics of radiation-induced injury in salivary glands, and also highlighted the profound sex- and age-specific differences in such responses," says Nagarajan Kannan, Ph.D., M.S., a researcher with Mayo Clinic's Center for Regenerative Biotherapeutics and Mayo Clinic Comprehensive Cancer Center in Rochester, Minnesota. Dr. Kannan also is the director of the Stem Cell and Cancer Biology Laboratory at Mayo Clinic.
Researchers stimulated saliva production with cholinergic drugs, and reflex saliva was collected every five minutes for up to 30 minutes using a Schirmer test strip. The strips were measured both gravimetrically and using the migration under the capillary action of the strip. In all groups, saliva was measured at three-week intervals up to six months after radiation.
The mice tolerated radiation doses of 2.5 to 7.5 gray, but doses greater than 5 gray led to chronic alopecia in the mandibular region. While different study groups showed saliva fluctuations early on, all groups' stimulated-saliva flow stabilized after five months. Researchers found that Schirmer test strips provided an accurate measure of salivation.
Use of the model going forward
The establishment of a standardized preclinical model represents a significant milestone toward effective testing of salivary stem cell treatments. The research team is optimizing techniques for isolating human salivary stem cells, with the aim of laying a solid foundation for translational studies. The team is hopeful that their efforts will have a meaningful impact on patients with head and neck cancer who endure radiation side effects on a daily basis.
For more information
Musheer Aalam SM, et al. Characterization of transgenic NSG-SGM3 mouse model of precision radiation-induced chronic hyposalivation. Radiation Research. 2022;198:243.
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