Antitumor activity of clomiphene analogs in vitro: relationship to affinity for the estrogen receptor and another high affinity antiestrogen-binding site.
Antitumor activity of clomiphene analogs in vitro: relationship to affinity for the estrogen receptor and another high affinity antiestrogen-binding site.
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克罗米芬类似物的体外抗肿瘤活性：与雌激素受体和另一个高亲和力抗雌激素结合位点的亲和力的关系。
DOI：
10.1210/jcem-57-2-373
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发表时间：
1983
期刊：
影响因子：
--
通讯作者：
R. Sutherland
中科院分区：
文献类型：
--
作者：
L. Murphy;R. Sutherland
本文研究了三种恩氯米芬（反式-1-（对-β-二乙氨基乙氧基苯基）-1，2-二苯基-2-氯乙烯）类似物及其顺式异构体扎氯米芬在培养的MCF 7人乳腺癌细胞中的抗肿瘤活性。相对抗肿瘤活性进行了比较，相对结合亲和力（RBAs）的核雌激素受体（RE;雌二醇= 100%）和微粒体抗雌激素结合位点（AEBS;他莫昔芬= 100%），在MCF 7细胞的无细胞提取物中测量。二乙基氨基乙氧基侧链的结构的修改影响RE和AEBS的亲和力。侧链（9599）的脱乙基化使对两个位点的亲和力降低65- 70%，而二乙基氨基丙氧基侧链（6866）使对RE的亲和力增加3倍（恩氯米芬= 2%; 6866 = 6%），但使对AEBS的RBA降低66%（恩氯米芬= 140%; 6866 = 45%）。醚键转化为胺（10222）增加了对RE的亲和力（10222 = 5%），但显著降低了对AEBS的亲和力（10222 = 15%）。所有五种化合物都能抑制培养的MCF 7细胞的生长，但效力明显不同。在低剂量（0.25-1.0 μ M），其中生长抑制作用被雌二醇逆转（祖氯米芬除外），相对抗肿瘤活性（6866大于10222大于恩氯米芬大于9599大于祖氯米芬）与RE的RBA相同。在较高剂量（大于2.5 μ M），其中生长抑制作用不受影响或部分逆转雌二醇，这些化合物作为抗肿瘤剂的相对效力发生变化。祖氯米芬的活性最强，而恩氯米芬的效力相对于6866和10222增加（祖氯米芬大于恩氯米芬大于6866大于10222大于9599）。在这些剂量下，雌激素不可逆的抗肿瘤活性与RE的亲和力无关，但与AEBS的亲和力有一定的相关性。它的结论是，这些化合物对乳腺癌生长在体外的主要影响是雌激素可逆的生长抑制作用，其幅度与RE的亲和力。然而，使用zuclomiphene和雌激素不可逆剂量的enclomiphene和6866的研究表明，这些抗雌激素也通过可能不涉及RE的机制影响体外细胞增殖。
The antitumor activity of three enclomiphene (trans-1- (p-beta-diethylaminoethoxyphenyl)1,2-diphenyl-2-chloroethylene) analogs and the cis isomer zuclomiphene was investigated in MCF 7 human mammary carcinoma cells in culture. Relative antitumor activity was compared with relative binding affinities (RBAs) for the nuclear estrogen receptor (RE; estradiol = 100%) and a microsomal antiestrogen-binding site (AEBS; tamoxifen = 100%) measured in cell-free extracts from MCF 7 cells. Modifications in the structure of the diethylaminoethoxy side chain influenced affinity of both RE and AEBS. Deethylation of the side chain (9599) reduced affinity for both sites by 65-70%, while a diethylaminoproproxy side chain (6866) resulted in a 3-fold increase in affinity for RE (enclomiphene = 2%; 6866 = 6%), but reduced the RBA for AEBS by 66% (enclomiphene = 140%; 6866 = 45%). Conversion of the ether linkage to an amine (10222) increased affinity for RE (10222 = 5%), but markedly reduced affinity for the AEBS (10222 = 15%). All five compounds inhibited the growth of MCF 7 cells in culture, but with markedly different potencies. At low doses (0.25-1.0 microM), where the growth-inhibitory effects were reversed by estradiol (except in the case of zuclomiphene), the relative antitumor activity (6866 greater than 10222 greater than enclomiphene greater than 9599 greater than zuclomiphene) was in the same order as RBA for RE. At higher doses (greater than 2.5 microM), where the growth-inhibitory effects were unaffected or partially reversed by estradiol, the relative potencies of these compounds as antitumor agents changed. Zuclomiphene became the most active, while the potency of enclomiphene increased relative to 6866 and 10222 (zuclomiphene greater than enclomiphene greater than 6866 greater than 10222 greater than 9599). At these doses, estrogen-irreversible antitumor activity was unrelated to affinity for RE, but showed some correlation with affinity for AEBS. It is concluded that the major effect of these compounds on mammary carcinoma growth in vitro is an estrogen-reversible growth-inhibitory effect, the magnitude of which is correlated with affinity for RE. However, studies with zuclomiphene and estrogen-irreversible doses of enclomiphene and 6866 indicate that these antiestrogens also influence cell proliferation in vitro by mechanisms that probably do not involve RE.
DOI：
10.1016/0022-4731(82)90137-6
发表时间：
1982-01-01
影响因子：
4.1
作者：
ROBERTSON, DW;KATZENELLENBOGEN, JA;KATZENELLENBOGEN, BS
通讯作者：
KATZENELLENBOGEN, BS
抗雌激素 CI628 和 U23,469 代谢物的生物效力和子宫雌激素受体相互作用。
影响因子：
4.8
作者：
Hayes,JR;Rorke,EA;Robertson,DW;Katzenellenbogen,BS;Katzenellenbogen,JA
通讯作者：
Katzenellenbogen,JA