Nomegestrol acetate, a clinically useful 19-norprogesterone derivative which lacks estrogenic activity.
The estrogenic activity of various 19-norprogestin derivatives has been identified by several laboratories. We have previously hypothesized that the estrogenic activity of these compounds stems from the absence of a methyl group at the 19 position, as various progestins that have a methyl group at this position are not estrogens. To test this hypothesis more directly, we now compare the progestin megestrol acetate against its 19-nor analogue nomegestrol acetate. We also compare these compounds to known estrogens (estradiol, norgestrel, RU486) as well as compounds known to be devoid of estrogenic activity at concentrations as high as 10(-6) M (medroxyprogesterone acetate, R5020, ICI 182780). In growth assays using the MCF-7 and T47D:A18 human breast cancer cell lines, we find that only estradiol, norgestrel and RU486 stimulate proliferation, and this effect can be blocked by the pure antiestrogen ICI 182780. Furthermore, in transient transfection studies using a luciferase reporter construct containing three tandem copies of the Xenopus vitellogenin A2 estrogen response element, estradiol, norgestrel and RU486 can stimulate transcription, while none of the other compounds act as estrogens. Transcriptional stimulation by the estrogenic compounds can be blocked by ICI 182780. Our results demonstrate that the lack of a 19-methyl is not the major determinant for estrogenic activity in 19-norprogestins. We suggest that the 17-hydroxyl group more accurately defines estrogenic action.
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D001943:Breast Neoplasms; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D045166:Estradiol Congeners / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D008156:Luciferases / Q000096:biosynthesis; D008535:Megestrol; D008969:Molecular Sequence Data; D009649:Norpregnadienes / Q000494:pharmacology*; D009838:Oligodeoxyribonucleotides; D045167:Progesterone Congeners / Q000494:pharmacology; D011994:Recombinant Proteins / Q000096:biosynthesis; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection; D014407:Tumor Cells, Cultured; D014819:Vitellogenins / Q000096:biosynthesis; D014981:Xenopus
D045166:Estradiol Congeners; D004965:Estrogen Antagonists; D004967:Estrogens; D009649:Norpregnadienes; D009838:Oligodeoxyribonucleotides; D045167:Progesterone Congeners; D011994:Recombinant Proteins; D014819:Vitellogenins; D000077267:Fulvestrant; D004958:Estradiol; C038501:nomegestrol acetate; D008535:Megestrol; D008156:Luciferases