Structural analogs of the nonsteroidal
antiestrogen tamoxifen, in which the basic dimethylaminoethoxy side chain was either absent or replaced with a variety of nonbasic side chains, were examined for their ability to inhibit the proliferation of a hormonally responsive cell line, MCF 7 human
breast cancer. The degree of inhibition was compared with relative binding affinities for the
estrogen receptor (RE) and a microsomal
antiestrogen binding site (AEBS). All modifications resulted in loss of detectable affinity for AEBS. Replacement of the basic side chain of
tamoxifen with a series of nonbasic side chains reduced affinity for RE by 78-93% except in the case of
1-(4-(1,2-diphenylbut-1-enyl)phenyl)-2,3-butanediol (ICI 145-680) where affinity was unchanged. When the basic side chain of
tamoxifen was replaced by a
hydroxyl group, to form the estrogenic analog ICI 141389 (Metabolite E), affinity for RE was reduced by 39%. ICI 141389 was a very weak inhibitor of MCF 7 cell growth, showing no significant growth inhibition at concentrations less than 10 microM. Despite the fact that
ICI 145680 and
tamoxifen had identical affinities for RE,
ICI 145680 was a significantly weaker
growth inhibitor than
tamoxifen over the concentration range studied, i.e. 0.1-20 microM. Differences in potency were greatest at concentrations greater than 7.5 microM where the effects were not reversed by
estradiol and where cytotoxicity played a major role in the decrease in cell numbers induced by
tamoxifen. Like
tamoxifen,
ICI 145680 demonstrated both
estrogen-reversible (at concentrations between 0.5-7.5 microM) and
estrogen-irreversible (10-20 microM) inhibition of MCF 7 cell proliferation which was associated with a concentration-dependent accumulation of cells in the G0/G1 phase of the cell cycle. In contrast to
tamoxifen, however,
ICI 145680 appeared not to possess cytotoxic activity. Whereas
ICI 145680 was without effect on proliferation of the RE negative human
breast cancer cell line, MDA-MB-330, at doses less than 20 microM,
tamoxifen inhibited growth at concentrations greater than 5 microM, but with changes in cell cycle kinetic parameters that were markedly different from those seen in RE positive cells.(ABSTRACT TRUNCATED AT 400 WORDS)