Labrie C, Simard J, Zhao H F, Pelletier G, Labrie F
Medical Research Council Group in Molecular Endocrinology, Laval University Medical Center, Quebec, Canada.
Mol Cell Endocrinol. 1990 Jan 22;68(2-3):169-79. doi: 10.1016/0303-7207(90)90190-j.
In order to assess the intrinsic androgenic activity of the synthetic progestins currently used as antiandrogens for the treatment of prostate cancer and other androgen-sensitive diseases, cyproterone acetate (CPA), medroxyprogesterone acetate (MPA) and megestrol acetate (MEG) were administered for 4 days to adult rats castrated 4 days previously. The effects of these compounds were measured on highly specific and sensitive markers of androgen action in the rat ventral prostate, namely the levels of messenger RNAs encoding the C1 (PBP-C1) and C3 (PBP-C3) components of rat prostatic binding protein (PBP). Steady-state mRNA levels were measured by dot-blot hybridization as well as by in situ hybridization. Treatment with CPA or MEG, at the twice daily dose of 10 mg, caused respective 2- and 4.5-fold increases in the steady-state levels of mRNA encoding PBP-C1. MPA, at the dose of 0.45 mg, twice daily, was approximately 40 times as potent as MEG, leading to an 8-fold increase in PBP-C1 mRNA levels. While the pure nonsteroidal antiandrogen flutamide (10 mg, twice daily) did not cause accumulation of PBP mRNAs when administered to castrated rats, it completely reversed the stimulatory effects of the synthetic progestins CPA, MPA and MEG. The results obtained by in situ hybridization were similar to those obtained by dot-blot analysis. Moreover, the synthetic progestins caused similar androgenic effects on PBP-C3 mRNA levels. The present data indicate that all three synthetic progestins currently used for the treatment of prostate cancer possess significant intrinsic androgenic activity as evidenced by their stimulatory effects on the accumulation of mRNAs sensitive to androgen action. Consequently, as indicated by this sensitive and androgen-specific in vivo rat model, such compounds are not recommended for the treatment of conditions requiring an optimal blockade of androgens, especially prostate cancer.
为了评估目前用作抗雄激素药物治疗前列腺癌和其他雄激素敏感疾病的合成孕激素的内在雄激素活性，对4天前已阉割的成年大鼠给予醋酸环丙孕酮（CPA）、醋酸甲羟孕酮（MPA）和醋酸甲地孕酮（MEG），持续4天。检测这些化合物对大鼠腹侧前列腺中雄激素作用的高度特异性和敏感性标志物的影响，即编码大鼠前列腺结合蛋白（PBP）的C1（PBP-C1）和C3（PBP-C3）成分的信使核糖核酸水平。通过斑点杂交以及原位杂交测量稳态信使核糖核酸水平。以每日两次、每次10 mg的剂量给予CPA或MEG治疗，导致编码PBP-C1的信使核糖核酸稳态水平分别增加2倍和4.5倍。每日两次、每次0.45 mg剂量的MPA，其效力约为MEG的40倍，导致PBP-C1信使核糖核酸水平增加8倍。当给阉割大鼠施用纯非甾体抗雄激素氟他胺（每日两次、每次10 mg）时，不会导致PBP信使核糖核酸积累，但它完全逆转了合成孕激素CPA、MPA和MEG的刺激作用。原位杂交获得的结果与斑点印迹分析获得的结果相似。此外，合成孕激素对PBP-C3信使核糖核酸水平产生类似的雄激素作用。目前的数据表明，目前用于治疗前列腺癌的所有三种合成孕激素都具有显著的内在雄激素活性，这可由它们对雄激素作用敏感的信使核糖核酸积累的刺激作用证明。因此，如这个敏感且雄激素特异性的体内大鼠模型所示，不建议将此类化合物用于需要最佳阻断雄激素的疾病治疗，尤其是前列腺癌。
