Abstract
Tamoxifen is widely prescribed for the treatment of breast cancer and is also licensed in the United States for the prevention of this disease. However, tamoxifen therapy is associated with an increased occurrence of endometrial cancer in women, and there is also evidence that it may elevate the risk of colorectal cancer. The underlying mechanisms responsible for tamoxifen-induced carcinogenesis in women have not yet been elucidated, but much interest has focused on the role of DNA adduct formation. We investigated the propensity of tamoxifen to bind irreversibly to colorectal DNA when given to 10 women as a single [14C]-labeled therapeutic (20 mg) dose, ∼18 h before undergoing colon resections. Using the sensitive technique of accelerator mass spectrometry, coupled with high-performance liquid chromatography separation of enzymatically digested DNA, a peak corresponding to authentic dG-N 2-tamoxifen adduct was detected in samples from three patients, at levels ranging from 1 to 7 adducts/109 nucleotides. No [ 14C]-radiolabel associated with tamoxifen or its major metabolites was detected. The presence of detectable CYP3A4 protein in all colon samples suggests that this tissue has the potential to activate tamoxifen to α-hydroxytamoxifen, in addition to that occurring in the systemic circulation, and direct interaction of this metabolite with DNA could account for the binding observed. Although the level of tamoxifen-induced damage displayed a degree of interindividual variability, when present, it was ∼10 to 100 times higher than that reported for other suspect human colon carcinogens such as 2-amino-1-methyl-6-phenyimidazo[4,5-b]pyridine. These findings provide a mechanistic basis through which tamoxifen could increase the incidence of colon cancers in women.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 6995-7002 |
| Number of pages | 8 |
| Journal | Cancer Research |
| Volume | 67 |
| Issue number | 14 |
| DOIs | |
| State | Published - Jul 15 2007 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
Tamoxifen forms DNA adducts in human colon after administration of a single [14C]-labeled therapeutic dose. / Brown, Karen; Tompkins, Elaine M.; Boocock, David J.; Martin, Elizabeth A.; Farmer, Peter B.; Turteltaub, Ken W; Ubick, Esther; Hemingway, David; Horner-Glister, Emma; White, Ian N H.
In: Cancer Research, Vol. 67, No. 14, 15.07.2007, p. 6995-7002.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Tamoxifen forms DNA adducts in human colon after administration of a single [14C]-labeled therapeutic dose
AU - Brown, Karen
AU - Tompkins, Elaine M.
AU - Boocock, David J.
AU - Martin, Elizabeth A.
AU - Farmer, Peter B.
AU - Turteltaub, Ken W
AU - Ubick, Esther
AU - Hemingway, David
AU - Horner-Glister, Emma
AU - White, Ian N H
PY - 2007/7/15
Y1 - 2007/7/15
N2 - Tamoxifen is widely prescribed for the treatment of breast cancer and is also licensed in the United States for the prevention of this disease. However, tamoxifen therapy is associated with an increased occurrence of endometrial cancer in women, and there is also evidence that it may elevate the risk of colorectal cancer. The underlying mechanisms responsible for tamoxifen-induced carcinogenesis in women have not yet been elucidated, but much interest has focused on the role of DNA adduct formation. We investigated the propensity of tamoxifen to bind irreversibly to colorectal DNA when given to 10 women as a single [14C]-labeled therapeutic (20 mg) dose, ∼18 h before undergoing colon resections. Using the sensitive technique of accelerator mass spectrometry, coupled with high-performance liquid chromatography separation of enzymatically digested DNA, a peak corresponding to authentic dG-N 2-tamoxifen adduct was detected in samples from three patients, at levels ranging from 1 to 7 adducts/109 nucleotides. No [ 14C]-radiolabel associated with tamoxifen or its major metabolites was detected. The presence of detectable CYP3A4 protein in all colon samples suggests that this tissue has the potential to activate tamoxifen to α-hydroxytamoxifen, in addition to that occurring in the systemic circulation, and direct interaction of this metabolite with DNA could account for the binding observed. Although the level of tamoxifen-induced damage displayed a degree of interindividual variability, when present, it was ∼10 to 100 times higher than that reported for other suspect human colon carcinogens such as 2-amino-1-methyl-6-phenyimidazo[4,5-b]pyridine. These findings provide a mechanistic basis through which tamoxifen could increase the incidence of colon cancers in women.
AB - Tamoxifen is widely prescribed for the treatment of breast cancer and is also licensed in the United States for the prevention of this disease. However, tamoxifen therapy is associated with an increased occurrence of endometrial cancer in women, and there is also evidence that it may elevate the risk of colorectal cancer. The underlying mechanisms responsible for tamoxifen-induced carcinogenesis in women have not yet been elucidated, but much interest has focused on the role of DNA adduct formation. We investigated the propensity of tamoxifen to bind irreversibly to colorectal DNA when given to 10 women as a single [14C]-labeled therapeutic (20 mg) dose, ∼18 h before undergoing colon resections. Using the sensitive technique of accelerator mass spectrometry, coupled with high-performance liquid chromatography separation of enzymatically digested DNA, a peak corresponding to authentic dG-N 2-tamoxifen adduct was detected in samples from three patients, at levels ranging from 1 to 7 adducts/109 nucleotides. No [ 14C]-radiolabel associated with tamoxifen or its major metabolites was detected. The presence of detectable CYP3A4 protein in all colon samples suggests that this tissue has the potential to activate tamoxifen to α-hydroxytamoxifen, in addition to that occurring in the systemic circulation, and direct interaction of this metabolite with DNA could account for the binding observed. Although the level of tamoxifen-induced damage displayed a degree of interindividual variability, when present, it was ∼10 to 100 times higher than that reported for other suspect human colon carcinogens such as 2-amino-1-methyl-6-phenyimidazo[4,5-b]pyridine. These findings provide a mechanistic basis through which tamoxifen could increase the incidence of colon cancers in women.
UR - http://www.scopus.com/inward/record.url?scp=34547105315&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34547105315&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-07-0913
DO - 10.1158/0008-5472.CAN-07-0913
M3 - Article
C2 - 17638912
AN - SCOPUS:34547105315
VL - 67
SP - 6995
EP - 7002
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0099-7013
IS - 14
ER -