Sargent L M, Dragan Y P, Sattler C, Bahnub N, Sattler G, Martin P, Cisneros A, Mann J, Thorgeirsson S, Jordan V C, Pitot H C
National Cancer Institute, Laboratory of Experimental Carcinogenesis, Bethesda, MD, USA.
Carcinogenesis. 1996 May;17(5):1051-6. doi: 10.1093/carcin/17.5.1051.
Since tamoxifen is efficacious for the prevention of second primary breast neoplasms in humans and has a low reported incidence of acute side effects, several structurally related compounds have been developed for the treatment of breast cancer including toremifene and idoxifene. We have compared the karyotypic alterations that occur after a single per os administration of 35 mg/kg of tamoxifen, toremifene or idoxifene to female Sprague-Dawley rats. One day following treatment, the rats were sacrificed and the hepatocytes isolated and cultured. After 47 h in culture, colcemid was added for 3 h prior to harvest of the hepatocytes for karyotypic evaluation. At least 100 metaphase spreads were examined for each of five rats per treatment. Toremifene resulted in aneuploidy in 50 +/- 7% of the cells examined and idoxifene induced a 57 +/- 4% aneuploidy compared with the 85 +/- 7% level induced by tamoxifen. Since the level of aneuploidy in solvent-treated rats was 3 +/- 3 %, the induction of aneuploidy in at least 50% of the cells from rats treated with tamoxifen, toremifene or idoxifene was highly significant. Analysis of electron micrographs of cultures treated with these antiestrogens demonstrated a range of phenotypes including multipolar spindles in toremifene-treated rats and condensed chromosomes in the presence of an intact nuclear envelope in occasional idoxifene-treated rat hepatocytes. The exclusion of chromosomes from the spindle apparatus and the lagging of some chromosomes on the metaphase plate correlate with the high rate of induction of aneuploidy in the rat liver as determined by karyotypic analysis of hepatocytes from rats treated with these triphenylethylenes.
由于他莫昔芬对预防人类第二原发性乳腺肿瘤有效且急性副作用发生率较低，已开发出几种结构相关的化合物用于治疗乳腺癌，包括托瑞米芬和艾多昔芬。我们比较了对雌性斯普拉格-道利大鼠单次口服35 mg/kg他莫昔芬、托瑞米芬或艾多昔芬后发生的核型改变。治疗后一天，处死大鼠并分离培养肝细胞。培养47小时后，在收获肝细胞进行核型评估前3小时加入秋水仙酰胺。每种处理的五只大鼠中，每只至少检查100个中期分裂相。与他莫昔芬诱导的85±7%的非整倍体水平相比，托瑞米芬使50±7%的检查细胞出现非整倍体，艾多昔芬诱导的非整倍体率为57±4%。由于溶剂处理大鼠的非整倍体水平为3±3%，他莫昔芬、托瑞米芬或艾多昔芬处理的大鼠至少50%的细胞中诱导出非整倍体具有高度显著性。对用这些抗雌激素处理的培养物的电子显微镜照片分析显示了一系列表型，包括托瑞米芬处理的大鼠中的多极纺锤体以及偶尔用艾多昔芬处理的大鼠肝细胞中在完整核膜存在下的浓缩染色体。纺锤体装置排斥染色体以及一些染色体在中期板上滞后与用这些三苯乙烯处理的大鼠肝细胞核型分析确定的大鼠肝脏中非整倍体的高诱导率相关。
