of these naturally occurring progesterone receptors has not been fully elucidated but has obvious biologic and toxicity implications, and this represents an important area for future research.
The complex effects of PR-A and PR-B are further complicated by the fact that some PR-B effects may not appear to require DNA binding. In other studies of these receptors it appears that PR-A dominates PR-B; equimolar amounts of A abolish the agonist activity of B. The agonist activity of an antiprogestin bound to the PR-B represents a potential mechanism of clinical resistance to antiprogestin. The fact that PR-B agonist activity may be mediated by binding, not to DNA but to other regulatory proteins that might be distributed differently than the progesterone receptors, may also help explain tissue-specific differences in response to progesterone and antiprogestins.
Intriguing data by Michna et al. (1992) and Henderson at the IOM workshop have suggested a novel mechanism of action for the antiprogestins onapristone (ZK 98 299) and Schering's ZK 112 993. Specifically, morphologic and cell-cycle distribution data suggest that they induce terminal differentiation and produce cell death through apoptosis (programmed cell death)1 rather than necrosis. Data on down-regulation of tenascin, an extracellular matrix glycoprotein of tumor stroma, in rat mammary tumors provide additional support for the induction of terminal differentiation as an underlying mechanism of growth inhibition by onapristone. Interestingly, although ovariectomy and antiestrogen therapy were associated with growth inhibition in this model, neither was associated with decreased expression of tenascin (Volleyer et al., 1992). These observations may be important in attempting to define a unique clinical role for antiprogestins in the endocrine armamentarium and certainly deserve additional study.
Data from other studies that demonstrate enhanced antitumor activity with combination endocrine therapy may also have important implications for the future clinical development of antiprogestins (Baker et al., 1989). Improved antitumor activity was observed in rat mammary tumor models with combination endocrine therapies incorporating antiprogestins and antiestrogens or HL-releasing hormone (LHRH) agonists. Significant down-regulation of estrogen- and progesterone-receptor content was noted. Data on endocrine combinations are also presented by Horwitz (Appendix B9) in a rat dimethylbenzanthracene (DBA) (carcinogen-induced) breast cancer model with established tumors. These data demonstrated that the combination of an
In the normal course of events cells of the body die and are replaced by new cells; the programming and mode of this metabolic "suicide" have been given the name apoptosis to distinguish them from the type of death called necrosis. This latter implies that some harmful agent, foreign to the cell's own metabolic programs, has caused the cell to die.