The antitumor mechanism of progesterone antagonists is a receptor mediated antiproliferative effect by induction of terminal cell death.

The antiprogesterones Onapristone, ZK 112.993 (Schering AG), and Mifepristone (Roussel-Uclaf) proved to possess progesterone receptor-mediated antiproliferative effects in experimental mammary carcinomas. In this study, the potency and mechanism of the antitumor action of Onapristone and ZK 112.993 is characterized by ovariectomized, progestagen and/or estradiol substituted mice bearing hormone-dependent MXT(+) mammary tumours. Medroxyprogesterone acetate (MPA, 0.8 mg/mouse, 3 times weekly, s.c.) could only induce a poor stimulation of tumour growth (% T/C = 40; intact control % T/C = 100), which was only marginally inhibited (% T/C = 21) by Onapristone (0.2 mg/mouse, 6 times weekly, s.c.) during a 6-week therapy. Therefore, the antitumor mechanism of antiprogesterones cannot preferably depend on a classical progesterone antagonism. In contrary, the pronounced stimulation of tumor growth (% T/C = 152) by estradiol benzoate (EB, 0.33 microgram/mouse, 3 times weekly, s.c.) was completely inhibited (% T/C = 7) by the antiprogesterones. An even more stimulated tumour growth was achieved by a combination of EB and MPA (% T/C = 365 using 0.17 mg; % T/C = 225 using 0.8 mg MPA). Onapristone dramatically blocked tumor growth (% T/C = 7) at the lower dose of MPA; no inhibition (% T/C = 203), however, was detected at the higher dose of MPA. These data and a morphological analysis indicate that the potent antitumor activity of the progesterone antagonists depends on the binding to a number of available progesterone receptors high enough to trigger an antiproliferative effect via the induction of terminal differentiation associated with terminal cell death.
AuthorsH Michna, M R Schneider, Y Nishino, M F el Etreby
JournalJournal of steroid biochemistry (J Steroid Biochem) Vol. 34 Issue 1-6 Pg. 447-53 ( 1989) ISSN: 0022-4731 [Print] ENGLAND
PMID2626038 (Publication Type: Journal Article)
Chemical References
  • Antineoplastic Agents
  • Gonanes
  • ZK 112993
  • Mifepristone
  • Progesterone
  • Estradiol
  • onapristone
  • Animals
  • Antineoplastic Agents (therapeutic use)
  • Cell Division (drug effects)
  • Cell Line
  • Cell Survival (drug effects)
  • Estradiol (pharmacology)
  • Female
  • Gonanes (therapeutic use)
  • Mammary Neoplasms, Experimental (drug therapy, pathology)
  • Mice
  • Mice, Inbred Strains
  • Mifepristone (analogs & derivatives, therapeutic use)
  • Ovariectomy
  • Progesterone (antagonists & inhibitors)
  • Tumor Cells, Cultured (cytology, drug effects)

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