title: Is ICI 182,780 an antiprogestin in addition to being an antiestrogen?
abstract: The pure antiestrogen ICI 182,780 has been shown to have antiprogestin activity in reporter gene constructs. Cell lines, naturally devoid of progesterone receptors (PR) were transfected with either the A or B forms of the human PR and a luciferase construct driven by a progesterone-response element (PRE). Because this system is an artificial one, our purpose was to determine whether these observations could be made in a human breast cancer cell line, naturally containing PR. We further evaluated the dose-response of ICI 182,780 and RU-486 (mifepristone) on PR and estrogen receptors (ER) in the presence of either progesterone, norgestrel or estradiol. These effects were measured using immunoassays for prostate-specific antigen (PSA) and human glandular kallikrein (hK2) and pS2. We found that ICI 182,780 blocked progesterone-stimulated PSA and hK2 production 100% at 10(-5) M, which decreased significantly by 10-6 M. This inhibition did not occur when norgestrel was the progestin used. RU-486 showed 100% blockade for both progestins at all concentrations used. We concluded that the antiprogestin activity of ICI 182,780 exists for progesterone only. This weak antiprogestin activity may be unlikely to have significant clinical implications.
authors.affiliation: Department of Nutritional Sciences, University of Toronto, Mount Sinai Hospital, Ontario, Canada.
authors.forename: R S
authors.initials: RS
authors.lastname: Rosenberg Zand
authors.forename: L
authors.initials: L
authors.lastname: Grass
authors.forename: A
authors.initials: A
authors.lastname: Magklara
authors.forename: D J
authors.initials: DJ
authors.lastname: Jenkins
authors.forename: E P
authors.initials: EP
authors.lastname: Diamandis
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D015735:Mifepristone / Q000494:pharmacology; D011372:Progestins / Q000037:antagonists & inhibitors*; D017430:Prostate-Specific Antigen / Q000032:analysis; D011506:Proteins / Q000032:analysis; D011960:Receptors, Estrogen / Q000187:drug effects*; D011980:Receptors, Progesterone / Q000187:drug effects*; D020840:Tissue Kallikreins / Q000032:analysis; D000071163:Trefoil Factor-1; D014407:Tumor Cells, Cultured / Q000187:drug effects; D025521:Tumor Suppressor Proteins
chemical_list: D004965:Estrogen Antagonists; D011372:Progestins; D011506:Proteins; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C051838:TFF1 protein, human; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; D000077267:Fulvestrant; D015735:Mifepristone; D004958:Estradiol; D020840:Tissue Kallikreins; D017430:Prostate-Specific Antigen