EFFECTS OF BIOLOGICALLY-ACTIVE METABOLITES OF TAMOXIFEN ON THE PROLIFERATION KINETICS OF MCF-7 HUMAN-BREAST CANCER-CELLS INVITRO

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  • 1 January 1983
    • journal article
    • research article
    • Vol. 43  (10) , 4618-4624
Abstract
The effects of 2 major metabolites of tamoxifen, N-demethyltamoxifen (DMT) and 4-hydroxytamoxifen (4OHT), on MCF-7 cell proliferation and cell cycle kinetic parameters were compared with those of the parent compound. All 3 compounds produced dose-dependent decreases in the rate of cell proliferation which were accompanied by decreases in the percentage of S- and G2-M-phase cells. 4OHT was 100- to 167-fold more potent than both tamoxifen and DMT in producing these effects, and this was correlated with their relative binding affinities (RBA) for the cytoplasmic estrogen receptor (ER) (17.beta.-estradiol = 100, 4OHT = 41, tamoxifen = DMT = 2). At doses .gtoreq. 2.5 .mu.M, these effects were completely reversed by 17.beta.-estradiol, but the required 17.beta.-estradiol:antiestrogen concentration ratios differend, i.e., 1:10 to 1:1 for 4OHT compared with 1:1000 to 1:100 for tamoxifen and DMT. Although the concentrations of 17.beta.-estradiol required for reversal were related to affinity of the metabolite for ER, they were 5- to 20-fold lower than predicted from the measured RBA. When the rate of cell proliferation was measured over a range of concentrations of antiestrogen, in the presence or absence of 17.beta.-estradiol, it was highly correlated (r2 = 0.96) with the percentage of S-phase cells. In addition to these 17.beta.-estradiol-reversible events, all 3 compounds caused 17.beta.-estradiol-irreversible cytotoxicity at higher concentrations (.gtoreq. 7.5 .mu.M DMT and 4OHT, 10 .mu.M tamoxifen). The order of potency in producing this effect was DMT > 4OHT > tamoxifen, which correlated with neither the RBA for ER nor the RBA for the high-affinity microsomal antiestrogen binding site. Estrogens and antiestrogens compete for a common event which regulates the rate of cell proliferation probably by controlling the proportion of cells entering S phase. Although it appears likely that ER is intimately involved in this regulatory process, 17.beta.-estradiol-irreversible mechanisms are also involved in antiestrogen action in vitro.