A new approach for the treatment of
breast cancer could be the use of
progesterone antagonists. These compounds were originally developed for the inhibition of
progesterone-dependent processes and have been shown to be effective in inhibition of nidation and interruption of pregnancy. Although the roles of
progesterone and the
progesterone receptor in control of cell growth remain unclear, it was found in
progesterone receptor positive mammary
carcinoma cell lines that the antiprogestin,
Mifepristone, had an inhibitory effect on cell growth and a growth-inhibiting action on the DMBA-induced mammary
carcinoma of the rat. We have shown that the
progesterone antagonists,
Onapristone and
ZK 112993, which possess a reduced antiglucocorticoid activity compared to
Mifepristone, exert a strong
tumor-inhibiting effect in a panel of
hormone-dependent mammary
tumor models. The effects of these compounds were in some systems superior to those of
tamoxifen or high dose
progestins and comparable to
ovariectomy. Although prerequisites for their antiproliferative potency are an affinity to the
progesterone receptor as well as a sufficient number of available receptors in the
tumors, the strong
tumor inhibiting potential of the antiprogestins cannot be explained by a classical anti-hormonal mechanism. Surprisingly, the antitumor activity is evident in spite of elevated serum levels of ovarian and
pituitary hormones. It was established by morphometric procedures that treatment with
Onapristone triggers differentiation of the mitotically active polygonal
tumor epithelial cell towards secretory active glandular structures and acini. All our quantitative light and electron microscopic data indicate that the antitumor action of antiprogestins is accompanied by the initiation of terminal differentiation leading to (apoptotic) cell death. Finally, our flow cytometry studies revealed an accumulation of the
tumor cells in the G0G1 phase of the cell cycle, which may result from induction of differentiation since a differentiation-specific G1 arrest has already been proposed for other stem cell systems. It can be concluded from these data that the
progesterone receptor antagonists differ in their mode of action from compounds used in established endocrine treatment strategies for mammary
carcinoma. The ability of
progesterone antagonists like
Onapristone to reduce the number of cells in S-phase may offer a significant clinical advantage, since it is established that the S-phase fraction is a highly significant predictor of disease-free survival among axillary node-negative patients with diploid mammary
tumors.