MacIndoe J H, West E R, Petrow V
J Steroid Biochem. 1984 May;20(5):1095-100. doi: 10.1016/0022-4731(84)90349-2.
We have compared the inhibitory effects of six synthetic steroid analogs (17 beta-carboxy-4-androsten-3-one benzylanilide (VP-1), 17 alpha-acetoxy-6-methylene-4-pregnene-3,20-dione (VP-2), 6-methylene-4-pregnene-3,20-dione (VP-3), 17 beta-acetoxy-6-methylene-4-androsten-3-one (VP-4), 17 beta-acetoxy-16,16-dimethyl-6-methylene-4-androsten-3-one (VP-5), and 3 beta-hydroxy-16-methylene-5-androsten-17-one (VP-6) ) upon 5 alpha-reductase activity within MCF-7 human breast cancer cells and rat prostate. Enzyme assays were performed by quantifying the amounts of [3H]5 alpha-androstan-3 alpha-17 beta-diol and/or [3H]dihydrotestosterone formed from 40 nM [3H]testosterone within each system. Five microM concentrations of VP-2 and VP-3 inhibited prostatic 5 alpha-reductase by 55 and 65%, respectively, whereas the other analogs showed little activity. In contrast, each of the six analogs was active against MCF-7 homogenate 5 alpha reductase activity. VP-2 and VP-4 demonstrated approx 65 and 70% inhibitions, respectively, whereas the other four compounds inhibited enzyme activity by 40-55% in this system. These results suggest that rat prostate and MCF-7 cells contain different 5 alpha-reductase isozymes. When these agents were examined for 5 alpha-reductase inhibitory activity following 1 h preincubations with intact MCF-7 cultures, VP-1 and 3 demonstrated potencies similar to those in MCF-7 homogenate. The other compounds, however, were far less active under these conditions. Longer culture preincubations (16 h) were associated with substantially increased VP-6 potency, moderate increases for VP-4 and 5, but no change in VP-2 activity. Additional studies examining the abilities of these agents to bind to MCF-7 androgen receptor (AR) and progesterone receptor (PR) revealed moderate AR binding activities of VP-2, 3, and 4, and substantial PR binding for VP-2 and 3. Finally, VP-4 failed to inhibit estrogen-dependent MCF-7 PR synthesis, suggesting that it has no androgenic activity despite its ability to interact with MCF-7 AR.
我们比较了六种合成类固醇类似物（17β-羧基-4-雄烯-3-酮苄基苯胺（VP-1）、17α-乙酰氧基-6-亚甲基-4-孕烯-3,20-二酮（VP-2）、6-亚甲基-4-孕烯-3,20-二酮（VP-3）、17β-乙酰氧基-6-亚甲基-4-雄烯-3-酮（VP-4）、17β-乙酰氧基-16,16-二甲基-6-亚甲基-4-雄烯-3-酮（VP-5）和3β-羟基-16-亚甲基-5-雄烯-17-酮（VP-6））对MCF-7人乳腺癌细胞和大鼠前列腺中5α-还原酶活性的抑制作用。通过定量每个系统中由40 nM [3H]睾酮形成的[3H]5α-雄甾烷-3α-17β-二醇和/或[3H]二氢睾酮的量来进行酶活性测定。5 microM浓度的VP-2和VP-3分别抑制前列腺5α-还原酶55%和65%，而其他类似物活性较低。相比之下，六种类似物均对MCF-7匀浆的5α-还原酶活性有抑制作用。VP-2和VP-4分别表现出约65%和70%的抑制率，而其他四种化合物在该系统中抑制酶活性40 - 55%。这些结果表明大鼠前列腺和MCF-7细胞含有不同的5α-还原酶同工酶。当在完整的MCF-7培养物中预孵育1小时后检测这些药物的5α-还原酶抑制活性时，VP-1和3的效力与在MCF-7匀浆中的效力相似。然而，在这些条件下其他化合物的活性要低得多。更长时间的培养预孵育（16小时）与VP-6效力的显著增加、VP-4和5效力的适度增加相关，但VP-2的活性没有变化。进一步研究这些药物与MCF-7雄激素受体（AR）和孕激素受体（PR）结合能力的实验表明，VP-2、3和4具有中等的AR结合活性，VP-2和3与PR有大量结合。最后，VP-4未能抑制雌激素依赖性的MCF-7 PR合成，这表明尽管它能够与MCF-7 AR相互作用，但它没有雄激素活性。
