THE PROLIFERATIVE EFFECT OF ANTI-ANDROGENS ON THE ANDROGEN-SENSITIVE HUMAN PROSTATE TUMOR-CELL LINE LNCAP
THE PROLIFERATIVE EFFECT OF ANTI-ANDROGENS ON THE ANDROGEN-SENSITIVE HUMAN PROSTATE TUMOR-CELL LINE LNCAP
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DOI：
10.1210/endo-126-3-1457
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发表时间：
1990-03-01
期刊：
影响因子：
4.8
通讯作者：
SONNENSCHEIN, C
中科院分区：
文献类型：
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作者：
OLEA, N;SAKABE, K;SONNENSCHEIN, C
使用炭-葡聚糖剥离的补充人血清的培养基研究了甾体和非甾体“抗雄激素”对培养物中雄激素敏感的LNCaP-FGC人前列腺肿瘤细胞增殖能力的影响。环丙孕酮和醋酸甲羟孕酮、氟氯孕酮、羟基氟氯孕酮和anandron（R23908）单独给药，浓度为3 × 10 - 4。10-12和3 ×10-6 M.结果表明，尽管甲羟孕酮在3 × 10 - 6时诱导最大增殖，10-9 M时，其它“抗雄激素”（除了无效的氟替卡松外）在3 × 10 - 6时有效。10-8 M和更高浓度;这些化合物引起的增殖反应的幅度与雌二醇-17 β引起的相当。（比对照高3至5倍）。测试的抗雄激素药物均未触发雄激素作用的关闭效应特征。当3次时同时给予10-10 M DHT和上述抗雄激素，观察到协同作用模式;相反，3 × 10 - 10 M DHT和上述抗雄激素同时给予，观察到协同作用模式。10-8当同时给药时，M DHT取消了每种抗雄激素的增殖作用。这些抗雄激素与LNCaP-FGC细胞中存在的雄激素受体的相对结合亲和力与其增殖效率没有很好的相关性。在阴性对照假设的前提下解释所收集的数据，以调节后生动物的细胞增殖。在这些前提下，结果变得兼容的概念，第一，“抗雄激素”引起的雄激素敏感细胞的增殖，通过中和血清中的抑制剂（androcolyone-I）的影响，这一事件似乎不是由雄激素受体介导的。第二，抗雄激素不像雄激素那样引发增殖性关闭反应，即抗雄激素诱导的增殖模式与雌激素和孕激素引起的增殖模式相当。第三，当同时给予3 × 10 - 3个剂量时，10-10 M DHT，抗雄激素有协同作用。第四，当单独添加时，DHT诱导的阻断作用一致地超过抗雄激素和雌激素产生的增殖作用。最后，综合这些结果提出了关于抗雄激素在前列腺癌中的治疗作用的重要问题。
The effect of steroidal and nonsteroidal "antiandrogens" on the proliferative capacity of androgen-sensitive LNCaP-FGC human prostate tumor cells in culture was studied using charcoal-dextran stripped human serum-supplemented media. Cyproterone and medroxyprogesterone acetates, flutamide, hydroxyflutamide, and anandron (R23908) were administered alone at concentrations between 3 .times. 10-12 and 3 .times. 10-6 M. Results indicated that although medroxyprogesterone induced maximal proliferation at 3 .times. 10-9 M, the other "anti-androgens" (with the exception of flutamide that was ineffective) were effective at 3 .times. 10-8 M and higher concentrations; the amplitude of the proliferative response by these compounds was comparable to that elicited by estradiol-17.beta. (3 to 5-fold over control). None of the anti-androgens tested triggered the shutoff effect characteristic of androgen action. When 3 .times. 10-10 M DHT and the above mentioned anti-androgens were administered simultaneously, a synergistic pattern was seen; on the contrary, 3 .times. 10-8 M DHT cancelled the proliferative effect of each of the anti-androgens when administered simultaneously. The relative binding affinity of these anti-androgens to androgen receptors present in LNCaP-FGC cells did not correlate well with their proliferative efficiency. The data collected were interpreted within the premises of the negative control hypotheses for the regulation of cell proliferation in metazoans. Within those premises, results became compatible with the notion that first, "anti-androgens" elicited the proliferation of androgen-sensitive cells by neutralizing the effect of a serum-borne inhibitor (androcolyone-I); this event seems not to be mediated by androgens receptors. Second, anti-androgens did not trigger a proliferative shutoff response like androgens do, i.e. the proliferative pattern induced by anti-androgens was comparable to that elicited by estrogens and progestins. Third, when administered simultaneously with 3 .times. 10-10 M DHT, anti-androgens behaved synergistically. Fourth, the DHT-induced shutoff effect consistently overrode the proliferative effect generated by anti-androgens and estrogens when added alone. Finally, taken together these results raise important questions regarding the therapeutic role of anti-androgens in prostate cancer.