Identification of tamoxifen-DNA adducts in the endometrium of women treated with tamoxifen.
Identification of tamoxifen-DNA adducts in the endometrium of women treated with tamoxifen.
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DOI：
10.1093/carcin/21.5.461
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发表时间：
2000-08
期刊：
影响因子：
4.7
通讯作者：
S. Shibutani;Ravinder Nath ANISETTI;N. Suzuki;I. Terashima;S. Sugarman;A. Grollman;M. Pearl
中科院分区：
文献类型：
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作者：
S. Shibutani;Ravinder Nath ANISETTI;N. Suzuki;I. Terashima;S. Sugarman;A. Grollman;M. Pearl
接受他莫昔芬（TAM）治疗的女性患子宫内膜癌的风险显著增加；本研究旨在探讨这种致癌作用的机制。子宫内膜组织取自接受不同时间TAM治疗的16名妇女和15名未接受治疗的对照组。DNA分析采用（32）P-post-labeling/HPLC在线监测法，可检测2.5加合物/10（10）个核苷酸。使用这种敏感和特异性的分析，在8名妇女中检测到TAM-DNA加合物。发现的主要加合物是α -（N(2)-脱氧鸟苷基）他莫昔芬（dG-N(2)- tam）的反式和顺式外显体；含量分别在0.2-12和1.6-8.3加合物/10(8)个核苷酸之间。顺式加合物和反式加合物的相对含量存在显著的个体间差异。1例患者检测到低水平（0.74-1.1加合物/10(8)个核苷酸）反式和顺式dG-N(2)-TAM n -氧化物。从4-羟他莫昔芬醌甲醚中未观察到DNA加合物。我们从这一分析中得出结论，反式和顺式dG-N(2)- tam在许多（但不是全部）接受这种药物治疗的妇女的子宫内膜中大量积累。所发现的加合物水平，加上先前对其致突变性的证明[Cancer Res., 59, 2091, 1999]，表明基因毒性机制可能是tam诱发子宫内膜癌的原因。
The risk of developing endometrial cancer increases significantly for women treated with tamoxifen (TAM); the present study was designed to investigate the mechanism of this carcinogenic effect. Endometrial tissue was obtained from 16 women treated for varying lengths of time with TAM and from 15 untreated control subjects. DNA was analyzed with a (32)P-post-labeling/HPLC on-line monitoring assay capable of detecting 2.5 adducts/10(10) nucleotides. Using this sensitive and specific assay, TAM-DNA adducts were detected in eight women. The major adducts found were trans and cis epimers of alpha-(N(2)-deoxyguanosinyl) tamoxifen (dG-N(2)-TAM); levels ranged between 0.2-12 and 1.6-8.3 adducts/10(8) nucleotides, respectively. There was marked inter-individual variation in the relative amounts of cis and trans adducts present. Low levels (0.74-1.1 adducts/10(8) nucleotides) of trans and cis forms of dG-N(2)-TAM N-oxide were detected in one patient. DNA adducts derived from 4-hydroxytamoxifen quinone methide were not observed. We conclude from this analysis that trans and cis dG-N(2)-TAMs accumulate in significant amounts in the endometrium of many, but not all, women treated with this drug. The level of adducts found, coupled with the previous demonstration of their mutagenicity [Cancer Res., 59, 2091, 1999], suggest that a genotoxic mechanism may be responsible for TAM-induced endometrial cancer.