Abstract
BackgroundRadiotherapy for head and neck cancer results in severe and chronic salivary gland dysfunction in most individuals. This results in significant side effects including xerostomia, dysphagia, and malnutrition which are linked to significant reductions in patients' quality of life. Currently there are few xerostomia treatment approaches that provide long-term results without significant side effects. To address this problem we investigated the potential for post-therapeutic IGF-1 to reverse radiation-induced salivary gland dysfunction.MethodsFVB mice were treated with targeted head and neck radiation and significant reductions in salivary function were confirmed 3 days after treatment. On days 4-8 after radiation, one group of mice was injected intravenously with IGF-1 while a second group served as a vehicle control. Stimulated salivary flow rates were evaluated on days 30, 60, and 90 and histological analysis was performed on days 9, 30, 60, and 90.ResultsIrradiated animals receiving vehicle injections have 40-50% reductions in stimulated salivary flow rates throughout the entire time course. Mice receiving injections of IGF-1 have improved stimulated salivary flow rates 30 days after treatment. By days 60-90, IGF-1 injected mice have restored salivary flow rates to unirradiated control mice levels. Parotid tissue sections were stained for amylase as an indicator of functioning acinar cells and significant reductions in total amylase area are detected in irradiated animals compared to unirradiated groups on all days. Post-therapeutic injections of IGF-1 results in increased amylase-positive acinar cell area and improved amylase secretion. Irradiated mice receiving IGF-1 show similar proliferation indices as untreated mice suggesting a return to tissue homeostasis.ConclusionsPost-therapeutic IGF-1 treatment restores salivary gland function potentially through normalization of cell proliferation and improved expression of amylase. These findings could aid in the rational design of therapy protocols or drugs for the treatment of radiation-induced salivary gland dysfunction in patients who have completed their anti-cancer therapies.
Highlights
Radiotherapy for head and neck cancer results in severe and chronic salivary gland dysfunction in most individuals
Stimulated salivary flow rates are restored in mice receiving post therapy IGF-1 FVB mice exposed to a single radiation dose exhibit significant (P
Administration of recombinant IGF-1 to unirradiated FVB mice on days 4-8 did not show significant changes in salivary flow rates at any of the time points evaluated (85-100% of untreated controls) indicating that IGF-1 does not with a single 5 Gy dose that received vehicle injections. This reduction was significantly different from untreated FVB, IGF-1 injected, and irradiated mice receiving post therapy IGF-1 (P
Summary
Radiotherapy for head and neck cancer results in severe and chronic salivary gland dysfunction in most individuals This results in significant side effects including xerostomia, dysphagia, and malnutrition which are linked to significant reductions in patients’ quality of life. It has been shown in humans that radiationinduced defects in amylase production by the parotid acinar cells lead to significant decreases in amylase concentration in stimulated saliva [9]. These immediate pathophysiological and structural changes may contribute to the development of chronic symptoms such as malnutrition, mucositis, and permanent reduction in saliva flow rates based on acinar cell attrition and replacement with fibrotic tissue [10,11,12]
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