Studies on the Effects of Carcinogenic Synthetic Estrogens on Microtubules

己烯雌酚（diethylstilbestrol，DES）是一种人工合成的雌激素，它不仅在临床上对化疗有效，而且在人体内具有致癌性。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，破坏微管的化合物长春新碱被称为抗癌剂。本研究以己烯雌酚（DES）和内消旋己雌酚（meso-hexestrol）为起始原料，通过分析DES衍生物对微管组装和中国仓鼠V79细胞的影响，探讨DES衍生物的致癌作用机制。从猪脑微管蛋白中分离得到PC微管蛋白、S微管蛋白、MAP 2和tau蛋白。通过浊度测定和电镜观察分析了合成雌激素对重组体系的影响。结果表明，meso-己雌酚和E，E-双烯雌酚具有诱导微管蛋白形成带状结构的活性。立体异构体dl-、（+）-和（-）-己烯雌酚在活性上显示出一些差异。进一步研究了DES衍生物对中国仓鼠V79细胞的转化率和染色体的影响，证实了DES衍生物的构效关系，最近的研究表明DES的过氧化代谢可能是其诱导细胞转化的基础。本研究为DES致癌机制的研究提供了又一重要突破。

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.