INHIBITION BY NOMEGESTROL ACETATE AND OTHER SYNTHETIC PROGESTINS ON PROLIFERATION AND PROGESTERONE-RECEPTOR CONTENT OF T47-D HUMAN BREAST-CANCER CELLS

Progesterone receptors (PgR) of human breast cancer T47-D cells grown in an estrogenic environment (presence of phenol red, natural estrogens of foetal calf serum and insulin) were found to be present in considerable amounts (1-3 pmol/mg protein and 20 pmol/mg DNA), and to specifically bind progestins with a high affinity characterized by a K-d around 3 nM for ORG2058, and 4 nM for nomegestrol acetate (NOM; 17 alpha-acetoxy-6-methyl-19-nor-pregna-4,6-diene-3,20-dione), when measured under equilibrium conditions. Both compounds formed an highly stable ligand-receptor complex with a dissociation constant (k(-1)) around 1 x 10(-5) s(-1). At high pharmacological concentrations, NOM, ORG2058 and other synthetic progestins including promegestone (R5020), medroxyprogesterone acetate and norethindrone acetate (NOR), induced a dose-dependent inhibition of cell proliferation as measured by [H-3]thymidine incorporation. Dexamethasone, which did not bind to PgR, did not reproduce this inhibitory effect. NOM, R5020 and NOR treatments of T47-D cells at concentrations around K-d resulted in an 80% decrease in PgR content. Our data on NOM as compared to other progestins are consistent with their antiproliferative effects on human breast cancer cells grown in estrogenic conditions.