The pure antiestrogen ICI 182,780 inhibits progestin-induced transcription

The pure antiestrogen ICI 182,780 binds to the estrogen receptor with high affinity and is currently in clinical trials for the treatment of human breast cancer. We now show for the first time that ICI 182,780 also exhibits potent antiprogestin activity at doses frequently used in laboratory investigations. The antiprogestin activity of ICI 182,780 was detected in HeLa, HepG2, and CV1 cells transiently transfected with either the A or B forms of the human progesterone receptor and a luciferase construct driven by a progesterone-response element. ICI 182,780 inhibited progesterone-induced gene transcription in a dose-dependent fashion with maximum inhibition obtained at 10^-6 m and an IC⁵⁰ of approximately 2 x 10^-7 M. The ICI compound produced the same degree of inhibition as thai obtained with the antiprogestin RU-486. The antiestrogen tamoxifen did not display antiprogestin activity in this test system, and ICI 182,780 did not inhibit the activity of transfected androgen or glucocorticoid receptors. These results clearly establish that ICI 182,780 has significant antiprogestin activity in addition to its well-documented antiestrogenic activity and raises the possibility that both antihormonal properties of this compound are exhibited in laboratory studies and in the course of treatment of human breast tumors.