Antitumor activity of the antiprogestins ZK 98.299 and RU 38.486 in hormone dependent rat and mouse mammary tumors: Mechanistic studies

Abstract

In the transplantable MXT mammary tumor model of the mouse and in the DMBA- and MNU-induced mammary tumor models of the rat, the progesterone antagonists ZK 98.299 and RU 38.468 were shown to have potent antitumor activity. The weight and/or morphology of the ovaries, uterus, and vagina, as well as the effects on serum hormone levels, indicate that the antitumor activity of both antiprogesterones in these models does not depend on a blockade of the ovarian and pituitary functions and does not depend on a non receptor-mediated cytotoxic effect. On the other hand, the morphology of the MXT and the DMBA-induced mammary tumors after treatment with the progesterone antagonists is completely different from that observed after ovariectomy. Treatment with the antiprogesterones seems to trigger differentiation of the mitotically active polygonal tumor cells towards glandular structures and acini with a massive sequestering of secretory products, as well as towards spindle-shaped necrobiotic subpopulations. By contrast, the induction of tumor cell degeneration and cytolysis is the predominant feature of the mammary tumors after ovariectomy. In conclusion, our results indicate that the main mechanism of the antitumor action of antiprogesterones in these models is a direct progesterone receptor-mediated antiproliferation effect at the level of the mammary tumor cells, most probably via the induction of terminal differentiation associated with terminal cell death. This antiproliferative effect seems to be dissociated from the antihormone (antiprogestational) activity of these progesterone antagonists.

The MPA mouse breast cancer model: evidence for a role of progesterone receptors in breast cancer

“…In this series, most side effects were related to the antiglucocorticoid activity of RU486, thus illustrating the need of pure Endocrine-Related Cancer (2009) 16 333-350 www.endocrinology-journals.org antiprogestins (Klijn et al 2000). Both RU486 and ZK 98299 were also shown to inhibit DMBA and MNUinduced mammary carcinomas in rats, as well as the MXT mouse tumors (Michna et al 1989a,b, Schneider et al 1989. Apoptosis and tumor differentiation were the mechanisms related with antiprogestin-induced tumor regression (Michna et al 1992a,b, Vollmer et al 1992.…”

Novel Mechanisms of Antiprogestin Action

“…In the hormone-dependent MXT-transplantable tumor model, treatment with ZK98299 or RU486 starting one day after transplantation led to an almost complete inhibition of tumor growth. Their effect on established tumors was equivalent to that of ovariectomy (32,34). In this model, the potent antiproliferative actions of the antiprogestins completely counteracted the growth stimulatory actions of estradiol, or of approximately equimolar doses of MPA, but at higher MPA doses, the agonist actions of the progestin prevailed (33).…”

“…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.…”

“…It appears that antiprogestins inhibit growth by direct antagonism of progesterone action at the tumor, probably mediated by PR. This conclusion is bolstered by the fact that the hormone-independent MXT tumor is antiprogestin-resistant (32).…”

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

“…Using progestin receptor knockout mice (PRKO) mice, the PR has been shown to be specifically important for DMBA carcinogenicity (13), indicating a sensitivity that would not seem to require the ER. 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).…”