26 research outputs found
Raised Late Pregnancy Glucose Concentrations in Mice Carrying Pups With Targeted Disruption of H19Δ13
Nitroreduction of Environmental Nitrofluorenes by Enzymes and Rat Mammary Gland In Vitro
Electrospray ionization-tandem mass spectrometry and P-32-postlabeling analyses of tamoxifen-DNA adducts in humans
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 (32)p- 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-N-2-yl)-tamoxifen (dG-Tam) and (E)-alpha-(deoxyguanosin-N-2-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 dGdesMeTam by P-32-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 dGdesMeTam were two adducts per 10(9) nucleotides and two adducts per 10(8) nucleotides, respectively) or by P-32- 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