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Tamoxifen DNA damage detected in human endometrium using accelerator mass spectrometry
Elizabeth A Martin1, Karen Brown, Margaret Gaskell
1Cancer Biomarkers and Prevention Group, University of Leicester, Leicester, United Kingdom. elizabeth.martin@astrazeneca.com
Abstract:
This study was aimed to establish whether tamoxifen binds irreversibly to uterine DNA when given to women. Patients were given a single therapeutic dose of [(14)C]tamoxifen citrate orally (20 mg, 0.37 or 1.85 MBq) approximately 18 h prior to hysterectomy or breast surgery. Nonmalignant uterine tissue was separated into myometrium and endometrium. DNA and protein were isolated and bound radiolabel determined by the sensitive technique of accelerator mass spectrometry. Levels of irreversible DNA binding of tamoxifen in the endometrium of treated patients were 237 +/- 77 adducts/10(12) nucleotides (mean +/- SE, n = 10). In myometrial tissues, a similar extent of DNA binding was detected (492 +/- 112 adducts/10(12) nucleotides). Binding of tamoxifen to endometrial and myometrial proteins was 10 +/- 3 and 20 +/- 4 fmol/mg, respectively. In breast tissue, sufficient DNA could not be extracted but protein binding was an order of magnitude higher than that seen with endometrial proteins (358 +/- 81 fmol/mg). These results demonstrate that after oral administration, tamoxifen forms adducts in human uterine DNA but at low numbers relative to those previously reported in women after long-term tamoxifen treatment where levels, when detected, ranged from 15000 to 130000 adducts/10(12) nucleotides. Our findings support the hypothesis that the low level of DNA adducts in human uterus is unlikely to be involved with endometrial cancer development.
Insights
Tamoxifen forms low levels of DNA adducts in the human uterus after a single oral dose. These findings suggest tamoxifen-induced uterine DNA adducts are unlikely to cause endometrial cancer.
Area of Science:
- Pharmacology
- Toxicology
- Oncology
Background:
- Tamoxifen is a widely used medication for breast cancer treatment.
- Concerns exist regarding tamoxifen's potential genotoxicity and carcinogenicity, particularly in the uterus.
Purpose of the Study:
- To investigate the irreversible binding of tamoxifen to uterine DNA following a single oral dose in women.
- To quantify tamoxifen-DNA adducts in endometrial and myometrial tissues.
Main Methods:
- Patients received a single oral dose of [(14)C]tamoxifen citrate.
- Uterine tissues (endometrium and myometrium) were collected via hysterectomy.
- Accelerator mass spectrometry was used to determine levels of tamoxifen-DNA adducts and protein binding.
Main Results:
- Low levels of tamoxifen-DNA adducts were detected in both endometrial (237 +/- 77 adducts/10(12) nucleotides) and myometrial tissues (492 +/- 112 adducts/10(12) nucleotides).
- Protein binding was observed in uterine tissues and was significantly higher in breast tissue.
- Adduct levels were substantially lower than those reported after long-term tamoxifen treatment.
Conclusions:
- Single-dose tamoxifen administration results in low-level DNA adduct formation in the human uterus.
- The low incidence of these adducts supports the hypothesis that they are not a significant factor in endometrial cancer development.