Tamoxifen-DNA adducts detected in the endometrium of women treated with tamoxifen.
Tamoxifen-DNA adducts detected in the endometrium of women treated with tamoxifen.
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DOI：
10.1021/tx990033w
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发表时间：
1999-06
影响因子：
4.1
通讯作者：
S. Shibutani;N. Suzuki;I. Terashima;Steven Sugarman;A. P. Grollman;Michael L. Pearl
中科院分区：
文献类型：
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作者：
S. Shibutani;N. Suzuki;I. Terashima;Steven Sugarman;A. P. Grollman;Michael L. Pearl
使用他莫昔芬治疗乳腺癌的妇女患子宫内膜癌的风险增加。这种致癌作用被归因于雌激素刺激和/或该药物的遗传毒性作用。为了检测遗传毒性，我们建立了子宫内膜组织中他莫昔芬-DNA加合物的(32)P-后标记TLCL/HPLC定量分析方法。这项试验比以前用于此目的的方法灵敏几个数量级；使用它，我们可以检测10(11)个碱基中的五个三苯氧胺-DNA加合物。子宫内膜组织取自接受三苯氧胺治疗的妇女和未经治疗的对照组受试者。在他莫昔芬治疗组的13名患者中，有6名患者检测到DNA加合物，被鉴定为α-(N(2)-脱氧鸟苷)他莫昔芬的反式和顺式同分异构体。反式加合物和顺式加合物的水平分别为0.5~8.3和0.4~4.8加合物/10(8)核苷酸。在对照组的子宫内膜组织中未检测到他莫昔芬-DNA加合物。本研究的结论是，一个或多个他莫昔芬代谢产物与子宫内膜脱氧核糖核酸反应形成共价加合物，证实了该药物对女性的潜在遗传毒性，并建议将-脱氧核糖核酸加合物作为生物标志物用于研究他莫昔芬诱发的子宫内膜癌。
Women treated for breast cancer with tamoxifen are at increased risk of developing endometrial cancer. This carcinogenic effect has been attributed to estrogenic stimulation and/or to a genotoxic effect of this drug. To examine genotoxicity, we developed a (32)P-postlabeling TLCL/HPLC procedure for quantitative analysis of tamoxifen-DNA adducts in endometrial tissue. This assay is several orders of magnitude more sensitive than those previously used for this purpose; with it, we can detect five tamoxifen-DNA adducts in 10(11) bases. Endometrial tissue was obtained from women undergoing tamoxifen therapy and from untreated control subjects. DNA adducts, identified as trans and cis epimers of alpha-(N(2)-deoxyguanosinyl)tamoxifen, were detected in six of thirteen patients in the tamoxifen-treated group. Levels of trans and cis adducts ranged from 0.5 to 8.3 and from 0.4 to 4.8 adducts/10(8) nucleotides, respectively. Tamoxifen-DNA adducts were not detected in endometrial tissue obtained from the control subjects. We conclude from this study that one or more tamoxifen metabolites react with endometrial DNA to form covalent adducts, establishing the potential genotoxicity of this drug for women and suggesting the use of TAM-DNA adducts as biomarkers for investigations of tamoxifen-induced endometrial cancer.