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

• 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
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-61571064/
• 关键词: Synthetic estrogen; diethylstilbestrol; microtubules; PC-tubulin; microtubule proteins; turbidity measurement; electron microscopy; meso-Hexestrol; S-tubulin; trans-DES-epoxide; 4-Hydroxy-meso-hexestral; Synthetic estrogen; diethylstilbestrol; microtubules; PC-tubulin; microtubule proteins; turbidity measurement; electron microscopy; meso-Hexestrol; S-tubulin; trans-DES-epoxide; 4-Hydroxy-meso-hexestral

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.

合成雌激素，二乙基甲醇（DES），不仅在化学疗法中有效，而且在人类中也有效。我们已经证明，DES具有抑制体外微管聚合的活跃。微管是桉树中的细胞分子，也是纺锤体的重要组成部分。因此，破坏微管的Vincristine被称为抗癌剂。通过分析其对微管组装的作用和中国仓鼠V79细胞的影响，进行了目前的研究，以阐明DES癌的机制。从猪大脑的微管蛋白，PC-微管蛋白，S-微管蛋白，MAP2和TAU获得。合成雌激素对重构系统的影响通过浊度和电子显微镜分析。结果表明，中己酚和E，E-二烯酚具有从微管蛋白诱导色带结构的活性。立体异构体DL-，（+） - 和（ - ） - 己洛斯在其活性上显示出一些差异。此外，某些DES衍生物对中国仓鼠V79细胞的电镀效率和染色体的影响进行了检查，证明了结构活性关系。据表明，DES的过氧化代谢可能是DES诱导的细胞转化的基础。我们目前的研究将是解决癌变的另一个重要突破。