Pre-clinical and clinical treatment of breast cancer with antiprogestins.
Antiprogestins form a new potential treatment modality for breast cancer and their mode of action has been assessed in vitro on several breast cancer cell lines, in vivo in rats with dimethylbenzanthracene (DMBA)-induced mammary tumours and in vivo in patients with metastatic breast cancer. In vitro in serum-free medium, the progestin Org 2058 and antiprogestins RU486 and Org 31710 caused a dose-dependently stimulated MCF7 cell growth. Both antiprogestins dose-dependently inhibited the oestrogen-stimulated proliferation of progesterone receptor (PgR)-rich T-47D cells in DCC medium. Inhibition by Org 31710 plateaued at 10(-8) M (74% inhibition), compared with RU486 at up to 10(-6) M (53% inhibition). No inhibition was observed at doses of 10(-12)-10(-6) M of both antiprogestins in the absence of oestradiol. The proliferation of the ZR-75.1 and MDA-MB-231 cell lines was not or only marginally affected by either antiprogestin. Rats with DMBA-induced mammary tumours given prophylactic treatment with RU486 displayed a doubled latency period. Antiprogestins were slightly more effective than tamoxifen or progestins in rats with existing tumours. Org 31710 sometimes showed a somewhat more pronounced inhibitory effect than the antiprogestins Org 31806 and RU486. Combined antiprogestational and anti-oestrogenic treatment showed striking additive growth inhibitory effects resulting in clear tumour remissions, in the presence of very strong suppression of oestrogen and PgRs. The growth inhibitory effect of luteinizing hormone-releasing hormone agonists was potentiated by antiprogestins.(ABSTRACT TRUNCATED AT 250 WORDS)
Klijn
J G
JG
Department of Medical Oncology, Rotterdam Cancer Institute/Dr. Daniel den Hoed Cancer Center, The Netherlands.
Setyono-Han
B
B
Sander
H J
HJ
Lamberts
S W
SW
de Jong
F H
FH
Deckers
G H
GH
Foekens
J A
JA
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy*; D002455:Cell Division / Q000187:drug effects; D002986:Clinical Trials as Topic; D004354:Drug Screening Assays, Antitumor; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D005938:Glucocorticoids / Q000037:antagonists & inhibitors; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives; D006727:Hormone Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy; D010913:Pituitary-Adrenal System / Q000187:drug effects; D017698:Postmenopause; D011372:Progestins / Q000037:antagonists & inhibitors*; D051381:Rats; D016879:Salvage Therapy; D014407:Tumor Cells, Cultured
D005938:Glucocorticoids; D006727:Hormone Antagonists; D011372:Progestins; D007987:Gonadotropin-Releasing Hormone; D004958:Estradiol; D015127:9,10-Dimethyl-1,2-benzanthracene