Determination of Tamoxifen-DNA Adducts in Leukocytes from Breast Cancer Patients Treated with Tamoxifen
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- 作者：Atsushi Umemoto ; Yasumasa Monden ; Chun-Xing Lin ; Md. Abdul Momen ; Yuji Ueyama ; Kansei Komaki ; Y. R. Santosh Laxmi ; and Shinya Shibutani
- 刊名：Chemical Research in Toxicology
- 出版年：2004
- 出版时间：December 2004
- 年：2004
- 卷：17
- 期：12
- 页码：1577 - 1583
- 全文大小：250K
- 年卷期：v.17,no.12(December 2004)
- ISSN：1520-5010
文摘
Tamoxifen (TAM), a widely used antiestrogen for breast cancer therapy and chemoprevention,increases the incidence of endometrial cancer in women. The formation of DNA adducts inducedby tamoxifen may initiate endometrial cancer. To evaluate the genotoxic risk of TAM, theformation of DNA adducts in leukocytes was examined. Blood samples were collected from 47breast cancer patients (61.7 ± 12.5 years) taking TAM (20 mg/day; average duration untilsampling, ~37 months) and 20 untreated patients (58.2 ± 12.3 years), and their leukocyteDNA was analyzed by 32P-postlabeling/HPLC analysis. This assay resolves synthetic standards,trans- and cis-diastereoisomers of 
pha.gif" BORDER=0>-(N2-deoxyguanosinyl)tamoxifen 3'-monophosphate (dG3'P-N2-TAM), pha.gif" BORDER=0>-(N2-deoxyguanosinyl)-N-desmethyltamoxifen 3'-monophosphate (dG3'P-N2-N-dMeTAM), and pha.gif" BORDER=0>-(N2-deoxyguanosinyl)tamoxifen N-oxide 3'-monophosphate', and is capableof determining TAM adducts quantitatively. The detection limit of this assay is 0.6 adducts/109 nucleotides. trans-dG3'P-N2-TAM (fr-2; one of the two trans-isomers) was detected in six of47 breast cancer patients treated with TAM. Among them, trans-dG3'P-N2-N-dMeTAM (fr-2)was also detected in two patients. The total amounts of TAM-DNA adducts in the positivepatients were 2.6 ± 3.0 adducts/109 nucleotides. No adducts were detected in the controls.The presence of TAM-DNA adducts in the leukocyte DNA samples was confirmed using several32P-postlabeling/HPLC systems.
pha.gif" BORDER=0>-(N2-deoxyguanosinyl)tamoxifen 3'-monophosphate (dG3'P-N2-TAM), pha.gif" BORDER=0>-(N2-deoxyguanosinyl)-N-desmethyltamoxifen 3'-monophosphate (dG3'P-N2-N-dMeTAM), and pha.gif" BORDER=0>-(N2-deoxyguanosinyl)tamoxifen N-oxide 3'-monophosphate', and is capableof determining TAM adducts quantitatively. The detection limit of this assay is 0.6 adducts/109 nucleotides. trans-dG3'P-N2-TAM (fr-2; one of the two trans-isomers) was detected in six of47 breast cancer patients treated with TAM. Among them, trans-dG3'P-N2-N-dMeTAM (fr-2)was also detected in two patients. The total amounts of TAM-DNA adducts in the positivepatients were 2.6 ± 3.0 adducts/109 nucleotides. No adducts were detected in the controls.The presence of TAM-DNA adducts in the leukocyte DNA samples was confirmed using several32P-postlabeling/HPLC systems.