Progesterone antagonists and progesterone receptor modulators in the treatment of breast cancer

Progesterone antagonists (PAs) (antiprogestins) or progesterone receptor mo dulators (PRMs) form an interesting category of new hormonal agents in the treatment of breast cancer. In vitro, antiproliferative effects of differen t PAs are mainly observed in estrogen-stimulated growth of PR-positive tumo r cell lines. Both progestin agonist/antagonist actions on mammary tumor ce lls are dependent on the type of cell line, culture medium and concentratio ns of the PAs used, and type of biologic response measured. In various expe rimental animal tumor models, different PAs showed a greater antitumor acti vity than tamoxifen or high-dose progestins. Most interestingly, combinatio n treatment of different PAs (mifepristone, ORG 31710, onapristone) or PRMs with different antiestrogens (tamoxifen, droloxifen, ICI 164384) or with a n aromatase inhibitor (atemestane) showed greater antitumor efficacy than t reatment with each single type of drug alone. These additive antiproliferat ive effects were demonstrated in various experimental in vitro and in vivo models. In some studies, these effects were accompanied by additive effects on several cell biologic parameters. In pretreated postmenopausal patients with metastatic breast cancer, objective responses have been observed in 1 0-12%, and stable disease in 42-46% of the patients; in previously untreate d patients objective response rates of Ii and 56% have been reported. The c linical development of onapristone was stopped because of liver toxicity. A t the present time, apart from development of new pure potent PAs, clinical investigation of combined therapy of PAs with antiestrogens are urgently n eeded. (C) 2000 Elsevier Science Inc. All rights reserved.