Carmichael P L, Sardar S, Crooks N, Neven P, Van Hoof I, Ugwumadu A, Bourne T, Tomas E, Hellberg P, Hewer A J, Phillips D H
Imperial College School of Medicine, Division of Biomedical Sciences, Molecular Toxicology, London, UK.
Carcinogenesis. 1999 Feb;20(2):339-42. doi: 10.1093/carcin/20.2.339.
Tamoxifen is associated with an increased incidence of endometrial cancer in women. It is also a potent carcinogen in rat liver and forms covalent DNA adducts in this tissue. A previous study exploring DNA adducts in human endometria, utilizing thin layer chromatography 32P-postlabelling, found no evidence for adducts in tamoxifen-treated women [Carmichael,P.L., Ugwumadu,A.H.N., Neven,P., Hewer,A.J., Poon,G.K. and Phillips,D.H. (1996) Cancer Res., 56, 1475-1479]. However, subsequent work utilizing HPLC 32P-post-labelling [Hemminki,K., Ranjaniemi,H., Lindahl,B. and Moberger,B. (1996) Cancer Res., 56, 4374-4377] suggested that very low levels could be detected. We have sought to investigate this question further by reproducing the HPLC methodology at two centres, and analysing endometrial DNA from 20 patients treated with 20 mg/day tamoxifen for between 22 and 65 months. Liver DNA isolated from tamoxifen-treated rats was used as a positive control. We found no convincing evidence for tamoxifen-derived DNA adducts in human endometrium. HPLC elution profiles of post-labelled DNA from tamoxifen-treated women were indistinguishable from those obtained with DNA from 14 untreated women and from six women taking toremifene, an analogue of tamoxifen.
他莫昔芬与女性子宫内膜癌发病率的增加有关。它在大鼠肝脏中也是一种强效致癌物，并在该组织中形成共价DNA加合物。先前一项利用薄层层析32P后标记法探索人类子宫内膜中DNA加合物的研究，未发现他莫昔芬治疗女性中有加合物的证据[卡迈克尔，P.L.，乌格武马杜，A.H.N.，内文，P.，休厄尔，A.J.，潘，G.K.和菲利普斯，D.H.（1996年）《癌症研究》，56，1475 - 1479]。然而，随后利用高效液相色谱32P后标记法的研究[赫明基，K.，兰亚涅米，H.，林达尔，B.和莫伯格，B.（1996年）《癌症研究》，56，4374 - 4377]表明可以检测到极低水平的加合物。我们试图通过在两个中心重现高效液相色谱方法，并分析20例接受每日20毫克他莫昔芬治疗22至65个月的患者的子宫内膜DNA，进一步研究这个问题。从他莫昔芬治疗的大鼠中分离的肝脏DNA用作阳性对照。我们没有发现令人信服的证据表明人类子宫内膜中存在他莫昔芬衍生的DNA加合物。他莫昔芬治疗女性的后标记DNA的高效液相色谱洗脱图谱与14名未治疗女性以及6名服用托瑞米芬（他莫昔芬类似物）女性的DNA所获得的洗脱图谱无法区分。
