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Effect on the carcinogenesis of male rat bladder cancer of antiandrogen and 5_<alpha>-reductase inhibitor

抗雄激素及5_α-还原酶抑制剂对雄性大鼠膀胱癌癌变的影响

基本信息

批准号：
05671298
负责人：
AKAZA Hideyuki
金额：
$ 1.28万
依托单位：
University of Tsukuba
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1993
资助国家：
日本
起止时间：
1993 至 1994
项目状态：
已结题

项目摘要

It has been reported that blocking of androgen inhibits bladder carcinogenesis in male rats. However, the mechanism of action of androgen in bladder carcinogenesis is not known. To investigate this problem, we designed the following study using three antiandrogen drugs that have different mechanisms.We administered 0.05% BBN orally to 117 Wistar rats for 10 weeks, and divided them into 7 treatment groups (control, surgical castration, finasteride, LH-RH agonist, flutamide, LH-RH agonist + finasteride and LH-RH agonist + flutamide). Rats were cystectomized in the 21st week and speciments were examined histopathologically. Results demonstrated that surgical castration and LH-RH agonist treatment (three groups) reduced the incidence of carcinoma significantly and that surgical castration had a greater inhibitory effect than the LH-RH agonist. These observations suggest that androgen acts directly on the bladder mucosa. On the other hand, LH-RH agonist + flutamide showed greater inhibition than LH-RH agonist + finasteride, suggesting that testosterone combines directly with androgen receptor without conversion to DHT.We also investigated the presence of androgen receptors in rat and mouse bladder mucosa using monclonal and polyclonal antibodies and western blotting after homogenation. Results confirmed the existence of monoclonal antibody overlapping nuclei in mouse and rat bladder mucosa, as in accessory sex organs, and recognition of a protein corresponding to the molecular weight of the androgen receptor.

已有报道阻断雄激素可抑制雄性大鼠膀胱癌的发生。然而，雄激素在膀胱癌发生中的作用机制尚不清楚。为了研究这一问题，我们设计了三种不同作用机制的抗雄激素药物。给117只Wistar大鼠灌胃0.05%BBN 10周，并将其分为7个处理组(对照组、手术去势组、非那雄胺组、促黄体生成素激动剂组、氟他胺组、促黄体生成素激动剂+非那雄胺组和促黄体生成素激动剂+氟他胺组)。术后第21周行大鼠膀胱切除，取标本进行组织病理学检查。结果表明，手术去势和促黄体生成素释放激素激动剂治疗(三组)均可显著降低肿瘤发生率，且手术去势对肿瘤的抑制作用大于促黄体生成素释放激素激动剂。这些观察表明，雄激素直接作用于膀胱粘膜。另一方面，促黄体生成素受体激动剂+氟他胺的抑制作用强于促黄体生成素受体激动剂+非那雄胺，表明睾酮直接与雄激素受体结合，而不转化为雄激素受体。此外，我们还利用单抗和多克隆抗体以及匀浆后的免疫印迹技术研究了大鼠和小鼠膀胱粘膜中雄激素受体的存在。结果证实，在小鼠和大鼠膀胱粘膜中存在与附性器官相同的重叠核，并识别与雄激素受体分子量相对应的蛋白质。