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Tamoxifen Forms DNA Adducts in Human Colon after Administration of a Single [¹⁴C]-Labeled Therapeutic Dose

¹ Cancer Biomarkers and Prevention Group and ² MRC Molecular Endocrinology Group, Reproductive Sciences, Department of Cancer Studies and Molecular Medicine, University of Leicester, and ³ Leicester Royal Infirmary, Leicester, United Kingdom; ⁴ Genetic Toxicology, AstraZeneca, Alderley Park, Cheshire, United Kingdom; and ⁵ Lawrence Livermore National Laboratory, Livermore, California

Requests for reprints: Karen Brown, Department of Cancer Studies and Molecular Medicine, Robert Kilpatrick Clinical Sciences Building, University of Leicester, Leicester, LE2 7LX, United Kingdom. Phone: 44-116-2231824; Fax: 44-116-2231840; E-mail: kb20{at}le.ac.uk.

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-N²-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 -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. [Cancer Res 2007;67(14):6995–7002]

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