Endocrine and antitumor effects of combined treatment with an antiprogestin and antiestrogen or luteinizing hormone-releasing hormone agonist in female rats bearing mammary tumors.

Rats bearing mammary tumors induced with dimethylbenzanthracene were treated with the antiprogestin mifepristone (RU486; 10 mg/kg.day, sc), the antiestrogen tamoxifen (400 micrograms/kg.day, sc), LHRH agonists administered by either sc injections (buserelin; 40 micrograms/kg.day) or implant (buserelin or zoladex), or combinations of mifepristone and tamoxifen or LHRH agonists. Single treatment with mifepristone or tamoxifen caused a significant inhibition of tumor growth (90% and 75%, respectively), but no tumor remission. In contrast, single treatment with LHRH agonists caused remission of mammary tumor growth by 50% (injection) or 70% (implant), respectively. Combined treatment with mifepristone and tamoxifen caused additive tumor growth inhibitory effects resulting in the same extent of tumor remission as that observed after treatment with LHRH agonist injections alone. Combination of mifepristone with either manner of LHRH agonist administration resulted in the highest tumor remission (approximately 75%). Significant reductions in cytosolic steroid (estrogen and progesterone) receptor contents of mammary tumors were noted after various treatment modalities. The most pronounced decrements were observed after combined treatment with mifepristone and tamoxifen (residual estrogen receptor; 10%; residual progesterone receptor, 0%). On the other hand, suppression of pituitary-ovarian function was most pronounced after treatment with LHRH agonist implants alone or in combination with mifepristone. It is concluded that combination treatment with an antiprogestin and an antiestrogen or an LHRH agonist may be of great value in the endocrine therapy of breast cancer.