Although temporary benefits of tamoxifen therapy are observed in up to 40% of women with breast cancer, this compound, which is known to possess mixed estrogenic and antiestrogenic activities, has been associated with increased risk of endometrial carcinoma. This study compares the effects of the novel nonsteroidal pure antiestrogen EM-800 and related compounds with those of a series of antiestrogens on the estrogen-sensitive alkaline phosphatase (AP) activity in human endometrial adenocarcinoma Ishikawa cells. Exposure to increasing concentrations of up to 1000 nm EM-800 or its active metabolite EM-652 alone failed to affect basal AP activity. In contrast, incubation with 10 nm (Z)-4-OH-tamoxifen, (Z)-4-OH-toremifene, droloxifene, or raloxifene increased the value of this estrogen-sensitive parameter by 3.3-, 3.5-, 2.2-, and 1.6-fold, respectively, a stimulatory effect that was completely reversed by simultaneous exposure to 30 nm EM-800. Moreover, the stimulation of AP activity induced by 1 nm 17β-estradiol was completely reversed by EM-800, EM-652, or ICI-182780, at the IC50 value of 1.98 ± 0.23, 1.01 ± 0.16, and 5.64 ± 0.59 nm, respectively, whereas the partial blockade exerted by (Z)-4-OH-tamoxifen, (Z)-4-OH-toremifene, or raloxifene was observed at IC50 values of 13.5 ± 3.80, 41.0 ± 7.2, and 3.74 ± 0.43 nm, respectively. Thus, as assessed by their activity in the human Ishikawa endometrial carcinoma cells, EM-800 and EM-652 are the most potent known antiestrogens in Ishikawa cells, and, most importantly, they are devoid of the estrogenic activity observed in these human endometrial cancer cells with (Z)-4-OH-tamoxifen, (Z)-4-OH-toremifene, droloxifene, and raloxifene.


Supported by Endorecherche Inc.

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