Determination of tamoxifen--DNA adducts in leukocytes from breast cancer patients treated with tamoxifen.
Determination of tamoxifen--DNA adducts in leukocytes from breast cancer patients treated with tamoxifen.
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测定他莫昔芬——接受他莫昔芬治疗的乳腺癌患者白细胞中的 DNA 加合物。
DOI：
10.1021/tx049930c
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Shibutani,Shinya
中科院分区：
文献类型：
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作者：
Umemoto,Atsushi;Monden,Yasumasa;Lin,Chun-Xing;Abdul-Momen,Md;Ueyama,Yuji;Komaki,Kansei;Laxmi,YRSantosh;Shibutani,Shinya
他莫昔芬（TAM）是一种广泛用于乳腺癌治疗和化学预防的抗雌激素，可增加女性子宫内膜癌的发病率。他莫昔芬诱导的DNA加合物的形成可能引发子宫内膜癌。为了评估TAM的遗传毒性风险，检测了白细胞中DNA加合物的形成。采集了47例（61.7±12.5岁）服用TAM （20mg /天，平均持续时间为~ 37个月）的乳腺癌患者（61.7±12.5岁）和20例（58.2±12.3岁）未治疗的患者（58.2±12.3岁）的血液样本，并采用32p -后标记/HPLC分析其白细胞DNA。该方法可分离合成标准物α-（n2 -脱氧鸟苷基）他莫昔芬3 ' -单磷酸（dG3'P-N2-TAM）、α-（n2 -脱氧鸟苷基）- n -去甲基他莫昔芬3 ' -单磷酸（dG3'P-N2-N-dMeTAM）和α-（n2 -脱氧鸟苷基）他莫昔芬n -氧化物3 ' -单磷酸)的反式和顺式非对映异构体，并能定量测定TAM加合物。检测限为0.6加合物/109个核苷酸。47例接受TAM治疗的乳腺癌患者中有6例检测到反式dg3′p - n2 -TAM （fr-2，两种反式异构体之一）。其中2例患者还检测到trans-dG3'P-N2-N-dMeTAM （fr-2）。阳性患者的TAM - DNA加合物总量为2.6±3.0加合物/109核苷酸。对照组未检测到加合物。白细胞DNA样品中TAM - DNA加合物的存在通过多个32p后标记/HPLC系统得到证实。
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 induced by tamoxifen may initiate endometrial cancer. To evaluate the genotoxic risk of TAM, the formation of DNA adducts in leukocytes was examined. Blood samples were collected from 47 breast cancer patients (61.7 ± 12.5 years) taking TAM (20 mg/day; average duration until sampling, ∼37 months) and 20 untreated patients (58.2 ± 12.3 years), and their leukocyte DNA was analyzed by32P-postlabeling/HPLC analysis. This assay resolves synthetic standards,trans- andcis-diastereoisomers of α-(N2-deoxyguanosinyl)tamoxifen 3‘-monophosphate (dG3‘P-N2-TAM), α-(N2-deoxyguanosinyl)-N-desmethyltamoxifen 3‘-monophosphate (dG3‘P-N2-N-dMeTAM), and α-(N2-deoxyguanosinyl)tamoxifenN-oxide 3‘-monophosphate‘, and is capable of determining TAM adducts quantitatively. The detection limit of this assay is 0.6 adducts/109nucleotides.trans-dG3‘P-N2-TAM (fr-2; one of the twotrans-isomers) was detected in six of 47 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 positive patients were 2.6 ± 3.0 adducts/109nucleotides. 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.