Effects of Org OD14 (Livial (R)) 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 (E-2) is one of the most important hor mones supporting the growth and evolution of breast cancer. Consequently, t o block this hormone before it enters the cancer cell, or in the cell itsel f, has been one of the main targets in recent years. In the present study w e explored the effect of Org OD14 (active substance in Livial (R)) and its metabolites (Org 30126, Org 4094, Org OM38) on the 17-beta-hydroxysteroid d ehydrogenase (17 beta HSD) activity of MCF-7 and T-47D human breast cancer cells. Using physiological doses of estrone [(H-3]-E-1: 5x10(-9)M) this est rogen is converted in a great proportion to E-2 in both cell lines. After 2 4 hours, Org OD14 significantly inhibits this transformation in a dose-depe ndent manner, by 32 and 73% at 5x10(-7) M and 5x10(-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 met abolites) 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 mu m 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 mu M, respectively, i n T-47D cells. As Org OD14 and two of its metabolites, Org 30126 and Org 40 94, also strongly decrease the conversion of estrone sulphate to estradiol in the hormone-dependent MCF-7 and T-47D breast cancer cells, it is conclud ed that the inhibition provoked by these steroids on the enzymes (estrone s ulphatase and 17 beta-HSD) involved in the local biosynthesis of the biolog ically active estrogen estradiol, may reduce the risk of breast cancer in p ostmenopausal women during long-term hormone replacement treatment with Liv ial (R).