Studies on the Effects of Carcinogenic Synthetic Estrogens on Microtubules

一种合成的雌激素，己烯雌酚(DES)，不仅在临床上对化疗有效，而且对人类也是致癌的。我们已经证明DES具有抑制体外微管聚合的活性。微管是真核生物中的细胞质，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，被认为是一种抗癌药物。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，阐明了DES衍生物的致癌机理。DES和Meso-heestrol是合成DES衍生物的起始原料。从猪脑微管蛋白中分离得到PC-微管蛋白、S微管蛋白、MAP2和tau蛋白。用浊度测量和电子显微镜分析了合成雌激素对重组体系的影响。结果表明，Meso-己雌醇和E，E-二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(-)-己内酯的活性有所不同。进一步考察了DES衍生物对中国仓鼠V79细胞培养效率和染色体的影响，证实了DES的构效关系，提示DES的过氧化代谢可能是DES诱导细胞转化的基础。我们的研究将在解决DES致癌问题上取得又一重大突破。

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.