Tamoxifen forms DNA adducts in human colon after administration of a single [14C]-labeled therapeutic dose

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 ris...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2007-07, Vol.67 (14), p.6995-7002
Main Authors: BROWN, Karen, TOMPKINS, Elaine M, BOOCOCK, David J, MARTIN, Elizabeth A, FARMER, Peter B, TURTELTAUB, Kenneth W, UBICK, Esther, HEMINGWAY, David, HORNER-GLISTER, Emma, WHITE, Ian N. H
Format: Article
Language:English
Subjects:
ACCELERATORS
ADDUCTS
Adult
Aged
Aged, 80 and over
Antineoplastic agents
Antineoplastic Agents, Hormonal - pharmacology
BASIC BIOLOGICAL SCIENCES
Biological and medical sciences
Carbon Radioisotopes - chemistry
CARCINOGENESIS
CARCINOGENS
Chromatography, High Pressure Liquid
Colon - pathology
Colonic Neoplasms - drug therapy
Cytochrome P-450 CYP3A
Cytochrome P-450 Enzyme System - metabolism
DNA
DNA ADDUCTS
Endometrial Neoplasms - etiology
Endometrial Neoplasms - pathology
Female
HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY
Humans
LARGE INTESTINE
MAMMARY GLANDS
MASS SPECTROSCOPY
Medical sciences
METABOLITES
Middle Aged
NEOPLASMS
NUCLEOTIDES
PATIENTS
Pharmacology. Drug treatments
PROTEINS
TAMOXIFEN
Tamoxifen - administration & dosage
THERAPY
Tumors
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Summary: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 [(14)C]-labeled therapeutic (20 mg) dose, approximately 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/10(9) nucleotides. No [(14)C]-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 alpha-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 approximately 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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-07-0913