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JNCI Journal of the National Cancer Institute 2004 96(14):1099-1104; doi:10.1093/jnci/djh195
© 2004 by Oxford University Press
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© 2004 Oxford University Press

ARTICLE

Electrospray Ionization–Tandem Mass Spectrometry and 32P-Postlabeling Analyses of Tamoxifen–DNA Adducts in Humans

Frederick A. Beland, Mona I. Churchwell, Daniel R. Doerge, Daniel R. Parkin, Danuta Malejka-Giganti, Alan Hewer, David H. Phillips, Paul L. Carmichael, Gonçalo Gamboa da Costa, M. Matilde Marques

Affiliations of authors: Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR (FAB, MIC, DRD); Veterans Affairs Medical Center, Minneapolis, MN (DRP, DMG); Institute of Cancer Research, Surrey, U.K. (AH, DHP); Imperial College London, Biological Chemistry, Faculty of Medicine, London, U.K. (PLC); Centro de Química Estrutural, Complexo I, Instituto Superior Técnico, Lisboa, Portugal (GGC, MMM)

Correspondence to: Frederick A. Beland, PhD, Division of Biochemical Toxicology, HFT-110, National Center for Toxicological Research, 3900 NCTR Rd., Jefferson, AR 72079 (e-mail: fbeland{at}nctr.fda.gov)

Background: Although the nonsteroidal antiestrogen tamoxifen is used as an adjuvant chemotherapeutic agent to treat hormone-dependent breast cancer and as a chemopreventive agent in women with elevated risk of breast cancer, it has also been reported to increase the risk of endometrial cancer. Reports of low levels of tamoxifen–DNA adducts in human endometrial tissue have suggested that tamoxifen induces endometrial cancer by a genotoxic mechanism. However, these findings have been controversial. We used electrospray ionization–tandem mass spectrometry (ES-MS/MS) and 32P-postlabeling analyses to investigate the presence of tamoxifen–DNA adducts in human endometrial tissue. Methods: Endometrial DNA from eight tamoxifen-treated women and eight untreated women was hydrolyzed to nucleosides and assayed for (E)-{alpha}-(deoxyguanosin-N2-yl)-tamoxifen (dG-Tam) and (E)-{alpha}-(deoxyguanosin-N2-yl)-N-desmethyltamoxifen (dG-desMeTam), the two major tamoxifen–DNA adducts that have been reported to be present in humans and/or experimental animals treated with tamoxifen, using on-line sample preparation coupled with high-performance liquid chromatography (HPLC) and ES-MS/MS. The same DNA samples were assayed for the presence of dG-Tam and dG-desMeTam by 32P-postlabeling methodology, using two different DNA digestion and labeling protocols, followed by both thin-layer chromatography and HPLC. Results: We did not detect either tamoxifen–DNA adduct by HPLC–ES-MS/MS analyses (limits of detection for dG-Tam and dG-desMeTam were two adducts per 109 nucleotides and two adducts per 108 nucleotides, respectively) or by 32P-postlabeling analyses (limit of detection for both adducts was one adduct per 109 nucleotides) in any of the endometrial DNA samples. Conclusion: The initiation of endometrial cancer by tamoxifen is probably not due to a genotoxic mechanism involving the formation of dG-Tam or dG-desMeTam.


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