Studies on the Effects of Carcinogenic Synthetic Estrogens on Microtubules

致癌合成雌激素对微管影响的研究

基本信息

批准号：
61571064
负责人：
SATO Yoshihiro
金额：
$ 1.09万
依托单位：
Kyoritsu College of Pharmacy
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1986
资助国家：
日本
起止时间：
1986 至 1988
项目状态：
已结题

项目摘要

A synthetic estrogen, diethylstilbestrol(DES), is not only chinically effective in chemotherapy but also carcinogenic in humans. We have proved that DES is active to inhibit in vitro microtubule polymerization. Microtubules are the cytoskelton in eucaryotes and also the important component of spindles. Consequently, vincristine, the compound which disrupts microtubules, is known as an anticarcinogenic agent. Present investigation was performed to clarify the mechanism of DES carcinognenesis using des derivatives by analyzing their effects on microtubule assembly and Chinese hamster V79 cells.DES and meso-hexestrol were starting meterials for the synthesis of DES derivatives. From microtubule proteins of porcine brains, PC-tubulin, S-tubulin, MAP2 and tau were obtained. The effects of the synthetic estrogens on reconstituted systems were analyzed by turbidity mesurement and electron microscopy. The results indicated that meso-hexestrol and E,E-dienestrol have activities to induce ribbon structures from microtubule proteins. The stereoisomers, dl-, (+)- and (-)-hexestrols showed some differences in their activity. Further, effects on plating efficiency and chromosomes of Chinese hamster V79 cells were examined by some DES derivatives, demonstrating the structure-activity relationship.Recently, it was indicated that peroxidative metabolism of DES might be the bases of DES induced cell transformation. Our present investigation would make an another important breakthough to solve DES carcinogenesis.

己烯雌酚（DES）是一种合成雌激素，不仅在化学治疗中有效，而且对人类具有致癌性。我们已经证明DES在体外具有抑制微管聚合的活性。微管是真核生物的细胞骨架，也是纺锤体的重要组成部分。因此，长春新碱（一种破坏微管的化合物）被称为抗癌剂。本研究通过分析DES衍生物对微管组装和中国仓鼠V79细胞的影响，阐明DES致癌机制。DES和内消旋己雌酚是合成DES衍生物的起始原料。从猪脑的微管蛋白中获得PC-微管蛋白、S-微管蛋白、MAP2和tau。通过浊度测量和电子显微镜分析合成雌激素对重构系统的影响。结果表明，内消旋己雌酚和E,E-二烯雌酚具有诱导微管蛋白带状结构的活性。立体异构体dl-、(+)-和(-)-己雌酚在活性上表现出一些差异。此外，还研究了一些DES衍生物对中国仓鼠V79细胞铺板效率和染色体的影响，证明了其构效关系。最近的研究表明，DES的过氧化代谢可能是DES诱导细胞转化的基础。我们目前的研究将在解决 DES 致癌方面取得另一个重要突破。