Antitumor activity of clomiphene analogs in vitro: relationship to affinity for the estrogen receptor and another high affinity antiestrogen-binding site

The Journal of Clinical Endocrinology and Metabolism
L C Murphy, R L Sutherland

Abstract

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 zu...Continue Reading

Citations

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