PRECLINICAL AND CLINICAL TREATMENT OF BREAST-CANCER WITH ANTIPROGESTINS

Antiprogestins form a new potential treatment modality for breast canc er and their mode of action has been assessed in vitro on several brea st cancer cell lines, in vivo in rats with dimethylbenzanthracene (DMB A)-induced mammary tumours and in vivo in patients with metastatic bre ast cancer. In vitro in serum-free medium, the progestin Org 2058 and antiprogestins RU486 and Org 31710 caused a dose-dependently stimulate d MCF7 cell growth. Both antiprogestins dose-dependently inhibited the oestrogen-stimulated proliferation of progesterone receptor (PgR)-ric h 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% inhi bition). No inhibition was observed at doses of 10(-12)-10(-6) M of bo th antiprogestins in the absence of oestradiol. The proliferation of t he ZR-75.1 and MDA-MB-231 cell lines was not or only marginally affect ed by either antiprogestin. Rats with DMBA-induced mammary tumours giv en prophylactic treatment with RU486 displayed a doubled latency perio d. Antiprogestins were slightly more effective than tamoxifen or proge stins in rats with existing tumours. Org 31710 sometimes showed a some what more pronounced inhibitory effect than the antiprogestins Org 318 06 and RU486. Combined antiprogestational and anti-oestrogenic treatme nt showed striking additive growth inhibitory effects resulting in cle ar tumour remissions, in the presence of very strong suppression of oe strogen and PgRs. The growth inhibitory effect of luteinizing hormone- releasing hormone agonists was potentiated by antiprogestins. A prelim inary clinical study on the efficacy of second-line treatment with RU4 86 in 11 post-menopausal patients with breast cancer yielded one objec tive response and six instances of short-term stable disease. Two clin ical studies using RU486 as second or third-line treatment reported a partial response in 12% and stable disease in 46% among 33 patients, e specially those with PgR-positive primary tumours. However, clear anti -glucocorticoid endocrine and clinical side-effects resulted in very h igh adrenocorticotrophic hormone, androstenedione and cortisol concent rations and peripheral aromatization of adrenal-derived androgens rais ed plasma oestradiol concentrations. Antiprogestins clearly cause grow th inhibitory effects on oestradiol-stimulated PgR-rich tumour cell li nes, rat mammary tumours and in patients with metastatic breast cancer .