BLOCKADE OF THE STIMULATORY EFFECT OF ESTROGENS, OH-TAMOXIFEN, OH-TOREMIFENE, DROLOXIFENE, AND RALOXIFENE ON ALKALINE-PHOSPHATASE ACTIVITY BY THE ANTIESTROGEN EM-800 IN HUMAN ENDOMETRIAL ADENOCARCINOMA ISHIKAWA CELLS

Although temporary benefits of tamoxifen therapy are observed in up to 40% of women with breast cancer, this compound, which is known to pos sess mixed estrogenic and antiestrogenic activities, has been associat ed with increased risk of endometrial carcinoma, This study compares t he effects of the novel nonsteroidal pure antiestrogen EM-800 and rela ted compounds with those of a series of antiestrogens on the estrogen- sensitive alkaline phosphatase (AP) activity in human endometrial aden ocarcinoma Ishikawa cells. Exposure to increasing concentrations of up to 1000 rut EM-800 or its active metabolite EM-652 alone failed to af fect basal AP activity. In contrast, incubation with 10 nM (Z)-4-OH-ta moxifen, (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 revers ed by simultaneous exposure to 30 nM EM-800. Moreover, the stimulation of AP activity induced by 1 nM l7 beta-estradiol was completely rever sed 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 par tial blockade exerted by (Z)-4-OH-tamoxifen, (Z)-4-OH-toremifene, or r aloxifene was observed at IC50 values of 13.5 +/- 3.8O, 41.0 +/- 7.2, and 3.74 +/- 0.43 nM, respectively. Thus, as assessed by their activit y 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 th ese human endometrial cancer cells with (Z)-4-OH-tamoxifen,(Z)-4-OH-to remifene, droloxifene, and raloxifene.