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抗雌激素药理学与作用机制。

Antiestrogen pharmacology and mechanism of action.

作者信息

Katzenellenbogen B S, Miller M A, Eckert R L, Sudo K

出版信息

J Steroid Biochem. 1983 Jul;19(1A):59-68.

PMID:6887873
Abstract

Antiestrogens are nonsteroidal compounds that are capable of antagonizing many of the actions of estrogens. They have long half-lives in serum, and during their action in vivo, the antiestrogens C1628, U23,469 and tamoxifen undergo bioactivation to more polar forms that have a higher affinity for the estrogen receptor. Utilizing the high affinity antiestrogens C1628M and trans-hydroxytamoxifen in radiolabeled form, we find differences in the interaction of the estradiol receptor complex and antiestrogen receptor complex with DNA cellulose and differences in their association in the nucleus. In MCF-7 human breast cancer cells, there are marked differences in the sedimentation rate and chromatographic properties of the nuclear estrogen receptor when complexed with antiestrogen (5.5 +/- 0.06 s, 5.93 +/- 0.20 nm Stokes radius, 137,000 mol. wt) as opposed to estrogen (4.1 +/- 0.03 s, 4.84 +/- 0.20 nm Stokes radius, 83,000 mol. wt). Our data are consistent with the association of the antiestrogen receptor with an additional nuclear protein of approx. 55,000 mol. wt. This antiestrogen promoted change in receptor association with another cellular component, which may function as a possible nuclear "blocking protein" and the alterations in antiestrogen-receptor association with DNA and nuclei, may be important aspects of the estrogen antagonist and growth inhibiting properties of these compounds. In addition to binding directly to the estrogen receptor, antiestrogens can be found associated with binding sites that are distinct from the estrogen receptor. These sites are present in a wide variety of estrogen target and non-target tissues in the rat, and in estrogen receptor positive and negative human breast cancer cell lines (MCF-7, T47D, MDA-MD-231) that differ markedly in their sensitivity to antiestrogens. These sites have a subcellular distribution and ligand binding specificity very different from those of the estrogen receptor. While their wide distribution and order of binding affinities for different antiestrogens raise questions about their role in mediating directly the classically recognized estrogen antagonism of antiestrogens, these sites might alter the apparent distribution volume of antiestrogens and hence their biological potency and pharmacokinetics.

摘要

抗雌激素是一类非甾体化合物,能够拮抗雌激素的多种作用。它们在血清中的半衰期较长,在体内发挥作用时,抗雌激素C1628、U23469和他莫昔芬会发生生物活化,转变为对雌激素受体具有更高亲和力的极性更强的形式。利用放射性标记的高亲和力抗雌激素C1628M和反式羟基他莫昔芬,我们发现雌二醇受体复合物和抗雌激素受体复合物与DNA纤维素的相互作用存在差异,并且它们在细胞核中的结合也存在差异。在MCF-7人乳腺癌细胞中,与抗雌激素结合时(沉降系数5.5±0.06 s,斯托克斯半径5.93±0.20 nm,分子量137,000),核雌激素受体的沉降速率和色谱性质与与雌激素结合时(沉降系数4.1±0.03 s,斯托克斯半径4.84±0.20 nm,分子量83,000)相比存在显著差异。我们的数据与抗雌激素受体与一种分子量约为55,000的额外核蛋白结合一致。这种抗雌激素促进了受体与另一种细胞成分结合的变化,该细胞成分可能作为一种潜在的核“阻断蛋白”发挥作用,而抗雌激素-受体与DNA和细胞核结合的改变,可能是这些化合物具有雌激素拮抗和生长抑制特性的重要方面。除了直接与雌激素受体结合外,还发现抗雌激素与不同于雌激素受体的结合位点相关联。这些位点存在于大鼠的多种雌激素靶组织和非靶组织中,以及对抗雌激素敏感性差异显著的雌激素受体阳性和阴性人乳腺癌细胞系(MCF-7、T47D、MDA-MD-231)中。这些位点的亚细胞分布和配体结合特异性与雌激素受体非常不同。虽然它们的广泛分布以及对不同抗雌激素的结合亲和力顺序引发了关于它们在直接介导抗雌激素经典公认的雌激素拮抗作用中所起作用的疑问,但这些位点可能会改变抗雌激素的表观分布容积,从而影响其生物学效能和药代动力学。

相似文献

1
Antiestrogen pharmacology and mechanism of action.抗雌激素药理学与作用机制。
J Steroid Biochem. 1983 Jul;19(1A):59-68.
2
Antiestrogen binding in antiestrogen growth-resistant estrogen-responsive clonal variants of MCF-7 human breast cancer cells.抗雌激素在MCF-7人乳腺癌细胞的抗雌激素生长抗性雌激素反应性克隆变体中的结合。
Cancer Res. 1984 Nov;44(11):5038-45.
3
Interactions of antiestrogens with human breast cancer in long-term tissue culture.抗雌激素与人类乳腺癌在长期组织培养中的相互作用。
Cancer Treat Rep. 1976 Oct;60(10):1421-9.
4
Antiestrogen interaction with estrogen receptors and additional antiestrogen binding sites in human breast cancer MCF-7 cells.
Arch Pharm Res. 1997 Dec;20(6):579-85. doi: 10.1007/BF02975215.
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Antiestrogenic potency and binding characteristics of the triphenylethylene H1285 in MCF-7 human breast cancer cells.三苯乙烯H1285在MCF-7人乳腺癌细胞中的抗雌激素活性及结合特性
Cancer Res. 1985 Sep;45(9):4192-9.
6
Resistance to tamoxifen with persisting sensitivity to estrogen: possible mediation by excessive antiestrogen binding site activity.
Cancer Res. 1992 Aug 1;52(15):4106-12.
7
Structure-activity relationships of nonisomerizable derivatives of tamoxifen: importance of hydroxyl group and side chain positioning for biological activity.他莫昔芬不可异构化衍生物的构效关系:羟基和侧链位置对生物活性的重要性。
Mol Pharmacol. 1991 Mar;39(3):421-8.
8
Biological activity and receptor binding of a strongly interacting estrogen in human breast cancer cells.一种在人乳腺癌细胞中具有强相互作用的雌激素的生物活性及受体结合情况
Cancer Res. 1984 Jun;44(6):2302-8.
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Antiestrogen action in breast cancer cells: modulation of proliferation and protein synthesis, and interaction with estrogen receptors and additional antiestrogen binding sites.抗雌激素在乳腺癌细胞中的作用:对增殖和蛋白质合成的调节,以及与雌激素受体和其他抗雌激素结合位点的相互作用。
Breast Cancer Res Treat. 1985;5(3):231-43. doi: 10.1007/BF01806018.
10
Characterization of estrogen and progesterone receptors and the dissociated regulation of growth and progesterone receptor stimulation by estrogen in MDA-MB-134 human breast cancer cells.雌激素和孕激素受体的特性以及雌激素对MDA-MB-134人乳腺癌细胞生长和孕激素受体刺激的解离调节
Cancer Res. 1986 Mar;46(3):1124-31.

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Binding sites of droloxifene in the cytosol of 7,12-dimethylbenz[a]anthracene-induced rat mammary tumor cells.屈洛昔芬在7,12-二甲基苯并[a]蒽诱导的大鼠乳腺肿瘤细胞胞质溶胶中的结合位点。
Jpn J Cancer Res. 1994 Jun;85(6):639-44. doi: 10.1111/j.1349-7006.1994.tb02407.x.
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Antiestrogen action in breast cancer cells: modulation of proliferation and protein synthesis, and interaction with estrogen receptors and additional antiestrogen binding sites.抗雌激素在乳腺癌细胞中的作用:对增殖和蛋白质合成的调节,以及与雌激素受体和其他抗雌激素结合位点的相互作用。
Breast Cancer Res Treat. 1985;5(3):231-43. doi: 10.1007/BF01806018.
6
Microsomal binding sites for antioestrogens in rat liver. Properties and detergent solubilization.大鼠肝脏中抗雌激素的微粒体结合位点。特性及去污剂增溶作用。
Biochem J. 1986 Jun 15;236(3):903-11. doi: 10.1042/bj2360903.
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A study on the effect of a single dose of tamoxifen on uterine hyperaemia and growth in the rat.单剂量他莫昔芬对大鼠子宫充血和生长影响的研究。
Br J Pharmacol. 1987 Oct;92(2):429-35. doi: 10.1111/j.1476-5381.1987.tb11339.x.
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Biochem J. 1988 Nov 15;256(1):229-36. doi: 10.1042/bj2560229.
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