Is ICI 182,780 an antiprogestin in addition to being an antiestrogen ?

The pure antiestrogen ICI 182,780 has been shown to have antiprogestin acti vity in reporter gene constructs. Cell lines, naturally devoid of progester one receptors (PR) were transfected with either the A or B forms of the hum an PR and a luciferase construct driven by a progesterone-response element (PRE). Because this system is an artificial one, our purpose was to determi ne whether these observations could be made in a human breast cancer cell l ine, 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 we re measured using immunoassays for prostate-specific antigen (PSA) and huma n glandular kallikrein (hK2) and pS2. We found that ICI 182,780 blocked pro gesterone-stimulated PSA and hK2 production 100% at 10(-5) M, which decreas ed 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 I CI 182,780 exists for progesterone only. This weak antiprogestin activity m ay be unlikely to have significant clinical implications.