Comparison of the actions of the antiprogestin mifepristone (RU486), the progestin megestrol acetate, the LHRH analog buserelin, and ovariectomy in treatment of rat mammary tumors.

Abstract

The effects of the synthetic antiprogestin mifepristone (RU486) on growth of dimethylbenzanthracene (DMBA)-induced mammary tumors in female rats were investigated. Prophylactic treatment with mifepristone (10 mg/kg/day) for 3 weeks starting from the day of first DMBA injection resulted in a doubling of the average tumor latency period (81 +/- 16 days, n = 17 treated, versus 39 +/- 5 days, n = 75 controls; P less than 0.005) and was accompanied by a significant growth retardation as shown by lower body weight increments. A 3-week therapeutic treatment of rats bearing mammary tumors was performed by administration of different dosages of mifepristone (2.5, 10, or 40 mg/kg/day) or megestrol acetate (2.5 or 10 mg/kg/day), with the luteinizing hormone-releasing hormone agonist buserelin (40 micrograms/kg/day), buserelin plus mifepristone (10 mg/kg/day), or by ovariectomy. The effects of treatment on tumor load, pituitary, adrenal and reproductive organ weights, steroid receptor contents of mammary tumors, and blood plasma hormone concentrations were investigated. Mifepristone and megestrol acetate treatment gave rise to inhibition of mammary tumor growth with all dosages studied, in which mifepristone was more potent than megestrol acetate (80%-90% vs 40% inhibition, P less than 0.01). In contrast, buserelin treatment and ovariectomy resulted not only in inhibition, but in tumor remission by about 50%. Combined treatment with buserelin and mifepristone gave the same tumor remission as resulted from ovariectomy or single treatment with buserelin. Estradiol-stimulated growth of the human mammary cancer MCF-7 cells in culture was fully abolished by mifepristone (3.6 X 10(-8) M) or tamoxifen (4 X 10(-8) M), whereas growth of MCF-7 cells under control incubation was not affected by either agent. Therefore, a direct inhibition of the growth of rat mammary tumor cells by mifepristone appears likely. Based on the effects of mifepristone on plasma hormone levels (increased: luteinizing hormone, estradiol, progesterone; unchanged: follicle-stimulating hormone, adrenocorticotropic hormone, corticosterone), organ weights (increased: pituitary, ovaries, uterus; unchanged: adrenals) and steroid receptor contents of mammary tumors (decreased: estrogen receptor and progesterone receptor contents), the main mechanism of action is probably a direct antiprogestational effect at the level of the mammary tumor cells through occupancy of the progesterone receptor.