Tumor-inhibiting potential of ZK 112.993, a new progesterone antagonist, in hormone-sensitive, experimental rodent and human mammary tumors.
The progesterone antagonists Onapristone (ZK 98.299) and Mifepristone (RU 486) proved to be strong inhibitors of various rodent mammary tumors. Therefore, a further potent antiprogestin, ZK 112.993, and 11 beta-(4-acetyl-phenyl)-analog of Mifepristone, with a high progesterone receptor affinity was tested in experimental rodent and human breast cancer models. In the hormone-dependent MXT(+) mammary tumor of the mouse, treatment of tumors immediately after implantation with 5 mg/kg for 6 weeks led to an inhibition of growth by 95%, being significantly superior to that caused by tamoxifen, diethylstilbestrol and Onapristone. Treatment of established MXT(+) tumors by ZK 112.993 at doses of 0.5, 1.0 and 2.0 mg/kg led to a strong inhibition that equalled that of ovariectomy and surpassed that of Onapristone in the lower doses. In the human, receptor positive mammary carcinoma T61 implanted in male, castrated nude mice, ZK 112.993 (10 mg/kg) significantly retarded tumor growth. Its effect was again superior to Onapristone though weaker than that of tamoxifen. The NMU-induced mammary carcinoma of the rat (established tumors) was inhibited by ZK 112.993 (5 and 10 mg/kg) in a dose-dependent manner slightly superior to Onapristone but weaker than after ovariectomy. Due to its strong antitumor activity and because of the innovative mechanism of action of antiprogesterones in tumor treatment, ZK 112.993 could be of great value for the treatment of breast cancer.
Schneider
M R
MR
Research Laboratories of Schering AG, Berlin, F.R.G.
Michna
H
H
Nishino
Y
Y
Neef
G
G
el Etreby
M F
MF
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D002460:Cell Line; D004054:Diethylstilbestrol / Q000627:therapeutic use; D005260:Female; D006067:Gonanes / Q000627:therapeutic use; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D008770:Methylnitrosourea; D051379:Mice; D008819:Mice, Nude; D015735:Mifepristone / Q000031:analogs & derivatives* / Q000627:therapeutic use; D009368:Neoplasm Transplantation; D010052:Ovariectomy; D051381:Rats; D011919:Rats, Inbred Strains; D013629:Tamoxifen / Q000627:therapeutic use; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D006067:Gonanes; D013629:Tamoxifen; C064879:ZK 112993; D015735:Mifepristone; D008770:Methylnitrosourea; D004054:Diethylstilbestrol; C053238:onapristone