雄激素拮抗效应estramustine磷酸(EMP)代谢产物对野生型和突变雄激素受体。

文章的细节

引用

复制到剪贴板

王LG,刘XM,克瑞斯W, Budman博士

雄激素拮抗效应estramustine磷酸(EMP)代谢产物对野生型和突变雄激素受体。

生物化学杂志。1998年5月1日,55(9):1427 - 33所示。

PubMed ID

10076535 (在PubMed

]

文摘

磷酸Estramustine频繁使用,单独或与其他抗肿瘤药物相结合,治疗hormone-refractory前列腺癌。Estramustine磷酸代谢激活体内,其代谢物,Estramustine, estromustine,雌激素酮,beta雌二醇抑制微管的组装(审查看:克瑞斯W:概念、机制、和新目标化疗(Ed Muggia FM), 163 - 184页。Kluwer学术出版商,波士顿,1995]。我们调查,通过位移[3 h] methyltrienolone出现2.5毫米在曲安奈德,estramustine磷酸盐及其代谢物的绑定,estramustine, estromustine,雌激素酮,beta雌二醇,以及其他抗雄激素药物包括alpha-estradiol bicalutamide,和hydroxyflutamide突变雄激素受体(m-AR) LNCaP野生型雄激素受体的细胞和野生型AR cDNA表达质粒(w-pAR0) cDNA-transfected海拉细胞。类似于抗雄激素,bicalutamide hydroxyflutamide,绑定的磷酸estramustine代谢物观察雄激素受体。EC50值(microM)是:estramustine磷酸盐> 10;estramustine, 3.129 + / - 0.312;estromustine;2.612 + / - 0.584;雌激素酮,0.800 + / - 0.090; alpha-estradiol, 1.051 +/- 0.096; beta-estradiol, 0.523 +/- 0.028; bicalutamide, 4.920 +/- 0.361; and hydroxyflutamide, 0.254 +/- 0.012. The transactivation assay demonstrated that, analogous to bicalutamide, estramustine could not induce luciferase activity in either w-pAR0 or m-pARL transfected HeLa cells. In contrast, a strong induction of the reporter activity by dihydrotestosterone was observed. Down-regulation of prostate-specific antigen (PSA) expression, an AR-target gene, by estramustine and bicalutamide was accompanied by the blockade of the mutated androgen receptor. Exposure of LNCaP cells to estramustine for 24 hr caused transcriptional inhibition of PSA in a concentration-dependent manner. The levels of PSA mRNA decreased 56 and 90% when LNCaP cells were treated with 5 and 10 microM of estramustine, respectively (IC50 = 10.97 +/- 1.68 microM). Binding of hydroxyflutamide to m-AR in LNCaP cells resulted in a concentration-dependent stimulation of PSA expression, suggesting that hydroxyflutamide acted as an agonist of the m-AR. Our data indicate that estramustine phosphate metabolites perform as androgen antagonists of AR, an additional mechanism involved in the therapeutic effect of estramustine phosphate in patients with prostate cancer.

DrugBank数据引用了这篇文章

药物靶点

药物	目标	类	生物	药理作用	行动
Bicalutamide	雄性激素受体	蛋白质	人类	是的	拮抗剂	细节