Toxicity of antiestrogens.
Toxicity of antiestrogens.
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DOI：
10.1046/j.1524-4741.2002.08204.x
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发表时间：
2002-03-01
期刊：
影响因子：
--
通讯作者：
Mantyla, Eero
中科院分区：
文献类型：
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作者：
Hirsimaki, Pirkko;Aaltonen, Annukka;Mantyla, Eero
本文的目的是简要回顾一些抗雌激素药物的临床前和临床安全性。他莫昔芬、托瑞米芬、屈洛昔芬和艾多昔芬是聚苯乙烯类抗雌激素，而纯抗雌激素ICI 182，780或法仕得以及雷洛昔芬具有不同的结构。在几项研究中，他莫昔芬已被证明具有遗传毒性。在体外可诱导大鼠肝细胞的程序外DNA合成和MCL-5a细胞的微核。他莫昔芬在体内也可诱导大鼠肝脏的非整倍体和小鼠骨髓的染色体畸变和微核。托瑞米芬也显示出遗传毒性，但程度要低得多，体外诱导MCL-5 a细胞微核和体内诱导大鼠肝脏非整倍体。在至少四项独立的长期研究中，他莫昔芬已被证明在大鼠中具有肝癌原性。大鼠肿瘤的发生是细胞色素P450同工酶代谢活化为亲电试剂（与DNA不可逆结合）的结果。其他抗雌激素在啮齿类动物中未显示致癌性。在几项独立的临床研究中，接受他莫昔芬治疗的妇女患子宫内膜癌的风险增加。在审查了现有数据后，国际癌症研究机构得出结论，有足够的证据表明他莫昔芬是一类人类致癌物。子宫内膜癌的风险增加主要发生在50岁或50岁以上的妇女中，并且已经用他莫昔芬治疗。目前尚不清楚子宫肿瘤的形成是否是遗传机制的结果，类似于在大鼠肝脏中观察到的那些或由于他莫昔芬的雌激素激动剂作用。然而，其他具有或多或少相似的内在雌激素潜力的抗雌激素尚未被证明对人类致癌。
The object of this article is to review briefly the preclinical and clinical safety of some antiestrogens. Tamoxifen, toremifene, droloxifene, and idoxifene are polyphenylethylene antiestrogens, whereas the pure antiestrogen, ICI 182,780 or faslodex, as well as raloxifene, is of a different structure. Tamoxifen has been shown to be genotoxic in several studies. It induces unscheduled DNA synthesis in rat hepatocytes and micronuclei in MCL-5 a cells in vitro. Tamoxifen also induces aneuploidy in rat liver in vivo and chromosome aberrations and micronuclei in mouse bone marrow. Toremifene has also shown to be genotoxic, but to a far lower extent, by inducing micronuclei in MCL-5 a cells in vitro and by inducing aneuploidy in rat liver in vivo. Tamoxifen has been shown to be hepatocarcinogenic in the rat in at least four independent long-term studies. The initiation of tumors in the rat is the result of metabolic activation by cytochrome P450 isoenzymes to an electrophile(s) that binds irreversibly to DNA. The other antiestrogens have not been shown to be carcinogenic in rodents. In several independent clinical studies, the risk of endometrial cancer has increased among tamoxifen-treated women. After reviewing the available data, the International Agency for Research on Cancer concluded that there was sufficient evidence to show that tamoxifen is a class I human carcinogen. The increased risk for endometrial cancer occurs predominantly among women who are 50 years old or older and who have been treated with tamoxifen. It is not yet clear whether the uterine tumor formation is a result of genetic mechanisms, analogous to those seen in the rat liver or due to the estrogen agonist action of tamoxifen. However, the other antiestrogens with a more or less similar intrinsic estrogenic potential have not been shown to be carcinogenic in humans.