Systemic Copper Chelation Reduces Collagen Deposition and Preserves Secretory Function in Irradiated Mouse Salivary Glands.
Systemic administration of tetrathiomolybdate may help preserve salivary gland function after radiation therapy in mice, but further research is needed to confirm these effects in humans.
Where it sits
this study against the rest of the ghk-cu corpusSummary and findings
This study measured the effects of systemic administration of tetrathiomolybdate (TTM) on collagen deposition and secretory function in irradiated mouse salivary glands. Mice received TTM in drinking water at a concentration of 0.1 mg/mL starting 7 days before and continuing through 7 days after a single 15-Gy dose of radiation therapy. The results indicated that TTM treatment improved stimulated saliva flow compared to control.
Abstract
<h4>Purpose</h4>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.<h4>Methods and materials</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>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.
Background
This paper addresses the impact of radiation therapy on salivary glands, particularly the fibrosis and loss of secretory function that often occurs in patients undergoing treatment for head and neck cancer. Prior studies indicated that local delivery of copper chelators could mitigate these effects, but practical challenges exist for human application. This study aims to explore whether systemic administration of tetrathiomolybdate (TTM) could achieve similar protective outcomes.
Methods
The study utilized a mouse model, where TTM was administered in drinking water at a concentration of 0.1 mg/mL. Treatment began 7 days prior to and continued for 7 days following a single 15-Gy dose of radiation therapy. Primary outcome measures included collagen deposition, histopathology, epithelial integrity, and stimulated saliva secretion.
Results
TTM treatment resulted in increased molybdenum levels and reduced copper bioavailability in the submandibular gland. The study reported suppression of serum ceruloplasmin activity and attenuation of RT-induced collagen deposition and epithelial damage. Notably, stimulated saliva flow was significantly higher in TTM-treated mice compared to controls at 30 days post-RT, with a p-value of less than 0.05.
Interpretation
The findings suggest that systemic TTM administration may offer a less invasive alternative to local delivery methods for protecting salivary glands from radiation-induced damage. While the results are statistically significant, the clinical relevance remains uncertain, particularly given the small sample size and the use of a rodent model. Further studies are needed to assess the applicability of these findings in human subjects.
Key findings
- TTM treatment significantly increased molybdenum levels in the submandibular gland.
- Copper-to-molybdenum ratios were reduced in TTM-treated mice.
- Serum ceruloplasmin activity was suppressed in TTM-treated mice.
- At 30 days after RT, stimulated saliva flow was significantly higher in TTM-treated irradiated mice than in irradiated mice receiving regular water, p<0.05.
Limitations
- Mouse model may not fully translate to human physiology.
- Long-term effects beyond 30 days were not assessed.
- Small sample size limits generalizability.
- Single-site study may introduce bias.