Pan H J, Wilding G, Uno H, Inui S, Goldsmith L, Messing E, Chang C
Department of Pathology, University of Rochester Medical Center, NY 14642, USA.
Endocrine. 1998 Aug;9(1):39-43. doi: 10.1385/ENDO:9:1:39.
The effect of androgen receptor transcriptional activation by RU58841, a nonsteroidal anti-androgen, was studied in the human prostate cancer PC3 cell line by cotransfection with wild-type androgen receptor (wt AR) and an androgen-responsive reporter (MMTV-ARE-CAT) construct. Anti-and rogens, hydroxyflutamide, and Casodex, and the antiestrogen, genistein, were studied in parallel for comparison with RU58841. The wt AR was activated only by the androgen dihydrotestosterone (DHT). Neither the anti-androgens nor antiestrogen can enhance AR transcriptional activity at 10(-11)-10(-7)M in PC3 cells. Hydroxyflutamide, RU58841, and Casodex, but not genistein, displayed competitively suppressive effects on DHT activation of wt AR. The potency of RU58841 was comparable to that of hydroxyflutamide. From this result, topical application of RU58841, which is considered to be a potential therapy for skin diseases, may induce systemic side effects. However, RU58841, on topical application, revealed a potent increase in density, thickening, and length of hair in the macaque model of androgenetic alopecia, whereas no systemic effects were detected. Together our results suggest that RU58841 may have potent antagonism to the wt AR and could be considered as a topically applied active anti-androgen for the treatment of androgen-dependent skin disorders, such as acne, androgenetic alopecia, and hirsutism.
通过与野生型雄激素受体（wt AR）和雄激素反应性报告基因（MMTV-ARE-CAT）构建体共转染，在人前列腺癌PC3细胞系中研究了非甾体类抗雄激素RU58841对雄激素受体转录激活的作用。同时研究了抗雄激素药物氟他胺和比卡鲁胺以及抗雌激素染料木黄酮，以便与RU58841进行比较。wt AR仅被雄激素双氢睾酮（DHT）激活。在PC3细胞中，抗雄激素和抗雌激素在10^(-11)-10^(-7)M浓度下均不能增强AR转录活性。氟他胺、RU58841和比卡鲁胺对wt AR的DHT激活表现出竞争性抑制作用，而染料木黄酮则无此作用。RU58841的效力与氟他胺相当。由此结果可知，被认为是一种潜在皮肤病治疗药物的RU58841局部应用可能会引起全身副作用。然而，在雄激素性脱发的猕猴模型中，RU58841局部应用可使毛发密度显著增加、变厚并增长，且未检测到全身效应。我们的研究结果共同表明，RU58841可能对wt AR具有强效拮抗作用，可被视为一种局部应用的活性抗雄激素药物，用于治疗雄激素依赖性皮肤病，如痤疮、雄激素性脱发和多毛症。
