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 estrogen s of foetal calf serum and insulin) were found to be present in consid erable amounts (1-3 pmol/mg protein and 20 pmol/mg DNA), and to specif ically bind progestins with a high affinity characterized by a K-d aro und 3 nM for ORG2058, and 4 nM for nomegestrol acetate (NOM; 17 toxy-6 -methyl-19-nor-pregna-4,6-diene-3,20-dione), when measured under equil ibrium conditions. Both compounds formed an highly stable ligand-recep tor complex with a dissociation constant (k(-1)) around 1 x 10(-5) s(- 1). At high pharmacological concentrations, NOM, ORG2058 and other syn thetic progestins including promegestone (R5020), medroxyprogesterone acetate and norethindrone acetate (NOR), induced a dose-dependent inhi bition of cell proliferation as measured by [H-3]thymidine incorporati on. Dexamethasone, which did not bind to PgR, did not reproduce this i nhibitory effect. NOM, R5020 and NOR treatments of T47-D cells at conc entrations 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 estrog enic conditions.