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 Kd 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), medroxy-progesterone acetate and norethindrone acetate (NOR), induced a dose-dependent inhibition of cell proliferation as measured by [3H]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 Kd 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.
Botella
J
J
Laboratoire Théramex, Preclinical Research and Development Department, Monaco.
Duranti
E
E
Duc
I
I
Cognet
A M
AM
Delansorne
R
R
Paris
J
J
D001943:Breast Neoplasms / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D006801:Humans; D008535:Megestrol; D009649:Norpregnadienes / Q000378:metabolism / Q000494:pharmacology*; D011282:Pregnenediones / Q000494:pharmacology; D045167:Progesterone Congeners / Q000494:pharmacology*; D011397:Promegestone / Q000494:pharmacology; D011980:Receptors, Progesterone / Q000187:drug effects* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D009649:Norpregnadienes; D011282:Pregnenediones; D045167:Progesterone Congeners; D011980:Receptors, Progesterone; C020175:16 alpha-ethyl-21-hydroxy-19-nor-4-pregnene-3,20-dione; C038501:nomegestrol acetate; D011397:Promegestone; D008535:Megestrol