PRECLINICAL AND CLINICAL TREATMENT OF BREAST-CANCER WITH ANTIPROGESTINS

Antiprogestins form a new potential treatment modality for breast cancer and their mode of action has been assessed in vitro on several breast cancer cell lines, in vivo in rats with dimethylbenzanthracene (DMBA)-induced mammary tumours and in vivo in patients with metastatic breast cancer. In vitro in serum-free medium, the progestin Org 2058 and antiprogestins RU486 and Org 31710 caused a dose-dependently stimulated MCF7 cell growth. Both antiprogestins dose-dependently inhibited the oestrogen-stimulated proliferation of progesterone receptor (PgR)-rich T-47D cells in DCC medium. Inhibition by Org 31710 plateaued at 10(-8) M (74% inhibition), compared with RU486 at up to 10(-6) M (53% inhibition). No inhibition was observed at doses of 10(-12)-10(-6) M of both antiprogestins in the absence of oestradiol. The proliferation of the ZR-75.1 and MDA-MB-231 cell lines was not or only marginally affected by either antiprogestin. Rats with DMBA-induced mammary tumours given prophylactic treatment with RU486 displayed a doubled latency period. Antiprogestins were slightly more effective than tamoxifen or progestins in rats with existing tumours. Org 31710 sometimes showed a somewhat more pronounced inhibitory effect than the antiprogestins Org 31806 and RU486. Combined antiprogestational and anti-oestrogenic treatment showed striking additive growth inhibitory effects resulting in clear tumour remissions, in the presence of very strong suppression of oestrogen and PgRs. The growth inhibitory effect of luteinizing hormone-releasing hormone agonists was potentiated by antiprogestins. A preliminary clinical study on the efficacy of second-line treatment with RU486 in 11 post-menopausal patients with breast cancer yielded one objective response and six instances of short-term stable disease. Two clinical studies using RU486 as second or third-line treatment reported a partial response in 12% and stable disease in 46% among 33 patients, especially those with PgR-positive primary tumours. However, clear anti-glucocorticoid endocrine and clinical side-effects resulted in very high adrenocorticotrophic hormone, androstenedione and cortisol concentrations and peripheral aromatization of adrenal-derived androgens raised plasma oestradiol concentrations. Antiprogestins clearly cause growth inhibitory effects on oestradiol-stimulated PgR-rich tumour cell lines, rat mammary tumours and in patients with metastatic breast cancer.