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Published on: March 20, 2018
Induction of covalent DNA adducts in rodents by tamoxifen
1Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston 77550-2782.
Abstract:
The antiestrogen tamoxifen, increasingly used as adjuvant treatment for breast cancer, has been found to covalently modify DNA of rodents. For instance, the liver DNA of female Sprague-Dawley rats treated with a single injection of tamoxifen contained two DNA adducts. Four additional DNA adducts were formed and adduct concentrations increased 5- 7- and 10-15-fold after three and six tamoxifen injections, respectively, from levels observed after a single dose. The accumulation of DNA adducts with repeated administrations of tamoxifen to rodents may make this drug a poor choice for the chronic preventative treatment of breast cancer.
Insights
The antiestrogen tamoxifen can damage rodent DNA, forming adducts that increase with repeated doses. This DNA modification suggests tamoxifen may not be suitable for long-term breast cancer prevention.
Area of Science:
- Pharmacology
- Toxicology
- Genetics
Background:
- Tamoxifen is a widely used adjuvant treatment for breast cancer.
- Concerns exist regarding the potential genotoxicity of tamoxifen.
- Rodent studies have indicated tamoxifen's interaction with DNA.
Purpose of the Study:
- To investigate the DNA adduct formation in rodents following tamoxifen administration.
- To assess the impact of repeated tamoxifen doses on DNA adduct levels.
Main Methods:
- Female Sprague-Dawley rats were administered tamoxifen.
- Liver DNA was analyzed for the presence and concentration of DNA adducts.
- Adduct levels were quantified after single and multiple injections.
Main Results:
- Two distinct DNA adducts were identified in the liver DNA of rats after a single tamoxifen injection.
- Repeated administrations (three and six injections) led to the formation of four additional DNA adducts.
- Adduct concentrations increased significantly (5-7-fold and 10-15-fold, respectively) with repeated dosing compared to single-dose levels.
Conclusions:
- Tamoxifen causes covalent modification of rodent DNA.
- The accumulation of DNA adducts with repeated tamoxifen exposure is dose-dependent.
- These findings raise concerns about the long-term safety of tamoxifen for chronic preventative use in breast cancer treatment.
