Bioactivities, estrogen receptor interactions, and plasminogen activator-inducing activities of tamoxifen and hydroxy-tamoxifen isomers in MCF-7 human breast cancer cells.
Bioactivities, estrogen receptor interactions, and plasminogen activator-inducing activities of tamoxifen and hydroxy-tamoxifen isomers in MCF-7 human breast cancer cells.
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发表时间：
1984
期刊：
影响因子：
11.2
通讯作者：
B. Katzenellenbogen;M. Norman;R. L. Eckert;Stuart W. Peltz;Walter F. Mangel
中科院分区：
文献类型：
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作者：
B. Katzenellenbogen;M. Norman;R. L. Eckert;Stuart W. Peltz;Walter F. Mangel
他莫昔芬广泛用于治疗人类内分泌反应性乳腺癌。研究人员进行了研究，以检查 MCF-7 人乳腺癌细胞中他莫昔芬和羟基他莫昔芬的顺式和反式异构体的生物学特性（雌激素-抗雌激素特性）和雌激素受体（ER）相互作用。对于每种化合物，监测以下参数：对 ER 的亲和力以及对细胞 ER 水平的影响；刺激-抑制细胞生长、纤溶酶原激活剂活性和细胞孕酮受体水平；以及异构体相互转化和体外代谢。化合物顺式他莫昔芬、反式他莫昔芬、顺式羟基他莫昔芬和反式羟基他莫昔芬对细胞质ER的相对结合亲和力分别为0.3、2.5、1.8和310％，其中雌二醇的亲和力被认为是100％。顺式他莫昔芬在所有测定中均表现为弱雌激素激动剂，而反式他莫昔芬是有效的雌激素拮抗剂。顺式他莫昔芬在刺激MCF-7细胞生长和增加纤溶酶原激活剂活性和细胞孕酮受体含量方面表现得与雌二醇相似，尽管需要更高浓度的顺式他莫昔芬（10（-6）M）才能达到用10（-10）M雌二醇观察到的刺激水平。反式他莫昔芬和反式羟基他莫昔芬抑制细胞生长，抑制对照细胞的纤溶酶原激活剂活性，并抑制雌二醇对纤溶酶原激活剂活性的刺激，并且它们引起细胞孕酮受体水平的最小增加。反式羟基他莫昔芬对 ER 的亲和力增加了 100 倍，并且在抑制细胞生长和纤溶酶原激活剂活性方面比反式他莫昔芬更有效约 100 倍。顺式羟基他莫昔芬作为雌激素拮抗剂，抑制细胞生长和纤溶酶原激活剂活性，并引起黄体酮受体水平的次最大增加。顺式羟基他莫昔芬的这种明显矛盾的行为被证明是由于顺式和反式羟基他莫昔芬在暴露于我们的细胞培养条件下容易发生异构体相互转化，导致更高亲和力的反式羟基他莫昔芬在细胞核内质网部分中大量积累。与羟基他莫昔芬异构体容易相互转化相反，母体化合物顺式和反式他莫昔芬在体外没有代谢或相互转化。因此，根据我们使用的标准，反式他莫昔芬和反式羟基他莫昔芬的生物学特性相似，主要区别在于羟基化形式的效力增强了约100倍。相比之下，顺式-t
Tamoxifen is used widely in the treatment of endocrine-responsive breast cancers in humans. Studies were undertaken to examine the biological character (estrogenic-antiestrogenic properties) and estrogen receptor (ER) interaction of the cis- and trans-isomers of tamoxifen and hydroxytamoxifen in MCF-7 human breast cancer cells. For each compound, the following parameters were monitored: affinity for ER and effects on cellular ER levels; stimulation-inhibition of cell growth, plasminogen activator activity, and cellular progesterone receptor levels; and isomer interconversion and metabolism in vitro. The relative binding affinities of the compounds cis-tamoxifen, trans-tamoxifen, cis-hydroxytamoxifen, and trans-hydroxytamoxifen for cytosol ER were 0.3, 2.5, 1.8, and 310%, respectively, in which the affinity of estradiol is considered 100%. cis-Tamoxifen behaved as a weak estrogen agonist in all assays, while trans-tamoxifen was an effective estrogen antagonist. cis-Tamoxifen behaved like estradiol in stimulating MCF-7 cell growth and increasing plasminogen activator activity and cellular progesterone receptor content, although very much higher concentrations of cis-tamoxifen (10(-6) M) were needed to achieve the levels of stimulation observed with 10(-10) M estradiol. trans-Tamoxifen and trans-hydroxytamoxifen suppressed cell growth, inhibited plasminogen activator activity of control cells, and suppressed estradiol-stimulation of plasminogen activator activity, and they evoked minimal increases in cellular progesterone receptor levels. trans-Hydroxytamoxifen had a 100-fold increased affinity for ER and was approximately 100-times more potent than was trans-tamoxifen in suppressing cell growth and plasminogen activator activity. cis-Hydroxytamoxifen behaved as an estrogen antagonist, suppressing cell growth and plasminogen activator activity, and it elicited submaximal increases in progesterone receptor levels. This apparently paradoxical behavior of cis-hydroxytamoxifen was shown to be due to the fact that the cis- and trans-hydroxytamoxifens readily undergo isomeric interconversion upon exposure to our cell culture conditions, resulting in substantial accumulation of the higher-affinity trans-hydroxytamoxifen in the nuclear ER fraction of cells. In contrast to the facile interconversion of the hydroxytamoxifen isomers, there is no metabolism or interconversion of the parent compounds cis- and trans-tamoxifen in vitro. Hence, by the criteria we have used, the biological characters of trans-tamoxifen and trans-hydroxytamoxifen are similar, the major difference being the approximately 100-fold enhanced potency of the hydroxylated form. In contrast, cis-t