ArticleAdvances in radiation oncology2026
Systemic Copper Chelation Reduces Collagen Deposition and Preserves Secretory Function in Irradiated Mouse Salivary Glands.
Article in Advances in radiation oncology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Purpose: Radiation therapy (RT) for head and neck cancer commonly causes fibrosis of the salivary gland (SG) and loss of secretory function. We previously demonstrated that transdermal injection of the copper chelator tetrathiomolybdate into irradiated submandibular glands reduced the early deposition of fibrillar collagen and preserved their integrity and function. Although these studies identified copper metabolism as a novel therapeutic target to control RT-induced damage to the SG, local delivery of copper chelators in human SG presents clinical hurdles including specialized personnel and equipment needed for administration together with the discomfort felt by patients upon receiving this treatment. To overcome these issues, the current study investigated whether systemic administration of tetrathiomolybdate (TTM) via drinking water could similarly reduce collagen deposition and preserve secretory function. Methods and Materials: Mice received TTM in drinking water (0.1 mg/mL) beginning 7 days before and continuing through 7 days after a single 15-Gy dose of RT to the neck. Systemic TTM exposure and copper bioavailability were assessed by measuring molybdenum and copper levels and serum ceruloplasmin activity. RT-induced SG injury was evaluated by collagen deposition, histopathology, epithelial integrity, and stimulated saliva secretion. Results: Systemically administered TTM reached the submandibular gland and reversibly reduced copper bioavailability, as demonstrated by increased molybdenum levels, reduced copper-to-molybdenum ratios, and suppression of serum ceruloplasmin activity. Moreover, TTM treatment attenuated RT-induced collagen deposition and epithelial damage and promoted recovery of ZO-1 expression. Finally, at 30 days after RT, stimulated saliva flow was significantly higher in TTM-treated irradiated mice than in irradiated mice receiving regular water. Conclusion: Systemic TTM administration reduces copper bioavailability, attenuates RT-induced collagen deposition and epithelial injury, and preserves SG secretory function. These findings support systemic copper chelation as a less invasive alternative to local TTM delivery for limiting RT-induced SG damage.
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