Endocrine and Antitumor Effects of Combined Treatment with an Antiprogestin and Antiestrogen or Luteinizing Hormone-Releasing Hormone Agonist in Female Rats Bearing Mammary Tumors*

Abstract

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.

Novel Endocrine Therapies in Breast Cancer

“…Using onapristone, Michna et al (35) demonstrated accumulation of cells into the GO-G1 phase of the cell cycle and induction of terminal differentiation accompanied by clear apoptosis of tumor cells. Most striking was our observation in a rat mammary tumor model that the addition of tamoxifen to antiprogestins showed additive antitumor effects (13) as was also demonstrated later on for a pure antiestrogen and an aromatase inhibitor (see 37).…”

“…In vitro and in rats with mammary tumor clear growth inhibitory effects were demonstrated by at least three different antiprogestins as mifepristone, onapristone, and Org 31710 (13,(34)(35)(36)(37)(38). Using onapristone, Michna et al (35) demonstrated accumulation of cells into the GO-G1 phase of the cell cycle and induction of terminal differentiation accompanied by clear apoptosis of tumor cells.…”

Novel Mechanisms of Antiprogestin Action

“…This hypothesis could be tested by the use of an antiestrogen having no agonist activity. Second, among the physiological effects seen in RU486-treated intact female rats are increased plasma levels of LH, prolactin, estradiol, and progesterone, as well as the persistence of numerous and actively secretory corpora lutea associated with hypertrophic pituitaries (30)(31)(32)(33)(34). It has therefore been proposed that the efficacy of simultaneous tamoxifen results from its ability to counteract the proliferative effects of the high estrogen levels induced by RU486.…”

CDB-4124, a Progesterone Receptor Modulator, Inhibits Mammary Carcinogenesis by Suppressing Cell Proliferation and Inducing Apoptosis

“…When the well-known antiprogestin, RU-486 (mifepristone), was used in DMBA-treated rats and in mice that spontaneously developed ER þ mammary tumors, a significant reduction in tumor incidence, multiplicity, and size was observed (14,15). In a separate study on the effects of RU-486 on DMBA-induced mammary tumors in rats, a reduction in tumor multiplicity was found in 90% of animals versus 75% of animals treated with tamoxifen (16). The combination of both agents further increased their antitumor potential.…”