Effects of Org OD14 (Livial) and its metabolites on 17 beta-hydroxysteroid dehydrogenase activity in hormone-dependent MCF-7 and T-47D breast cancer cells.

It is well recognized that estradiol (E2) is one of the most important hormones supporting the growth and evolution of breast cancer. Consequently, to block this hormone before it enters the cancer cell, or in the cell itself, has been one of the main targets in recent years. In the present study we explored the effect of Org OD14 (active substance in Livial) and its metabolites (Org 30126, Org 4094, Org OM38) on the 17 beta-hydroxysteroid dehydrogenase (17 beta HSD) activity of MCF-7 and T-47D human breast cancer cells. Using physiological doses of estrone ([3H]-E1: 5 x 10(-9) M) this estrogen is converted in a great proportion to E2 in both cell lines. After 24 hours, Org OD14 significantly inhibits this transformation in a dose-dependent manner, by 32 and 73% at 5 x 10(-7) M and 5 x 10(-5) M respectively, in T-47D cells; the effect is similar in MCF-7 cells. Among the three Org OD14 metabolites tested, Org 4094 and Org 30126 (3 alpha- and 3 beta-hydroxy metabolites) are more potent than their precursor, and Org OM-38 (4-ene isomer) is the weakest of the three steroids. The IC50 values were 0.79, 1.98, 7.12, and 22.84 microM in MCF-7 cells for Org 4094, Org 30126, Org OD14, and Org OM-38, respectively, and 4.83, 1.44, 2.03, and 35.25 microM, respectively, in T-47D cells. As Org OD14 and two of its metabolites, Org 30126 and Org 4094, also strongly decrease the conversion of estrone sulphate to estradiol in the hormone-dependent MCF-7 and T-47D breast cancer cells, it is concluded that the inhibition provoked by these steroids on the enzymes (estrone sulphatase and 17 beta-HSD) involved in the local biosynthesis of the biologically active estrogen estradiol, may reduce the risk of breast cancer in postmenopausal women during long-term hormone replacement treatment with Livial.