EFFECT OF TIBOLONE (ORG OD14) AND ITS METABOLITES ON ESTRONE SULFATASE ACTIVITY IN MCF-7 AND T-47D MAMMARY-CANCER CELLS

Tibolone (Org OD14) is a synthetic steroid with weak estrogenic, proge stagenic and androgenic properties which is used for the treatment of menopausal complaints. Since the compound possesses estrogenic activit y, it is important to assess its effects on pathways in breast cells i nvolved in the development of breast cancer. In the present study we c ompared the dose-response effect (range: 5x10(-8) to 5x10(-5)M) of Tib olone and its metabolites (Org OM38, Org 4094, Org 30,126) on the ''su lphatase'' pathway of two hormone-dependant human breast cancer cells: MCF-7 and T-47D; the results were compared with Norethisterone. After 24 hours incubation with physiological concentrations of estrone sulp hate (E(I) S: 5x10(-9) M) and high doses (5x10(-5) and 5x10(-6) M) of the different compounds, the conversion of E(I)S to estradiol (E(2)) w as strongly inhibited (85-98%) with all five substances tested. When l ow doses (5x10(-8) and 5x10(-7) M) were used, Tibolone and the metabol ites Org 4094 and Org 30,126 were still very efficient at blocking the conversion of E(I)S to E(2) (70-90%) in both cells. This inhibitory e ffect is less intense with the metabolite Org OM38 (45-70%). Norethist erone was the least potent antisulphatase agent (60-20%) tested. In co nclusion, this very significant inhibitory effect of Tibolone and of i ts metabolites Org 4094 and Org 30,126 on the enzymes involved in the biosynthesis of E(2) in human breast cancer cells, points to a potenti al beneficial effect of Tibolone which may be of relevance in its appl ication for the treatment of climacteric complaints.