Preclinical experience with two selective progesterone receptor modulators on breast and endometrium.
Org 31710 and Org 33628 are two highly selective progesterone receptor modulators (PRMs) with respect to their anti-progestational and anti-glucocorticoid activity. The compounds have been studied both in vitro and in vivo. Org 33628 has approximately four times stronger anti-progestational activity in vitro than does Org 31710, and in rats it is about 15 times more potent in the pregnancy interruption test. Two main indications for the use of PRMs are breast cancer and fertility regulation. The effects of both Org 31710 and Org 33628 were tested in relevant models for these indications. The effects of the two compounds on breast tumor development were assessed and in rats using the DMBA model. Their potency in menses induction was tested in monkeys on a 4-day regimen in the luteal phase, and after a single dose at day 21 of the normal cycle, and under a continuous progestin treatment using desogestrel. The compounds were also tested alone in a continuous low-dose regimen. The effects on follicular development and ovulation were determined by measuring estradiol and progesterone levels. Cycle control was monitored by daily vaginal swabs. In the DMBA model, Org 31710 at oral doses of 0.8, 2.0, and 5.0 mg/kg showed a clear dose-related reduction in tumor load. With the two highest doses, an even lower tumor load was seen after a 3-week treatment period compared to the tumor load at the start of treatment. Org 33628 showed a similar efficacy as Org 31710 at a dose of 2.0 mg/kg. RU 486 after oral treatment was two times less potent in this model than Org 31710 and Org 33628. The efficacy of menses induction using the 4-day regimen is dependent on the time of administration relative to the progesterone peak in the luteal phase. The highest efficacy is achieved in the descending part of the peak, at which a 100% success rate is found with a dose of 1 mg/kg of either Org 31710 or Org 33628. In Cynomolgus monkeys, at a single dose of 15 mg/kg of Org 31710 or Org 33628 in the luteal phase, menses induction was achieved only in 60% of the treatment cycles. Surprisingly menses induction can be achieved with a single dose that is about a ten-times lower when the monkeys are treated continuously with desogestrel. Cycle control is better at low than at high doses of antiprogestin in combination with daily dosing of 4 microg/kg desogestrel. Despite the difference in receptor affinity, no difference between Org 31710 and Org 33628 was found in menses induction. In the continuous low-dose (1 mg/kg) regimen with the PRMs, follicular development occurs normally while ovulation is inhibited. Ovulation is resumed shortly after stopping treatment, and a normal menses occurs after the first progesterone peak. Both compounds may be interesting options for the prevention and treatment of breast cancer and for fertility control.
Kloosterboer
H J
HJ
Research and Development N.V. Organon, Oss, The Netherlands. h.kloosterboer@organon.oss.azonobel.nl
Deckers
G H
GH
Schoonen
W G
WG
Hanssen
R G
RG
Rose
U M
UM
Verbost
P M
PM
Hsiu
J G
JG
Williams
R F
RF
Hodgen
G D
GD
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy; D002455:Cell Division / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D003271:Contraceptive Agents, Female / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004717:Endometrium / Q000166:cytology / Q000187:drug effects*; D004963:Estrenes / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D005663:Furans / Q000494:pharmacology* / Q000627:therapeutic use; D006727:Hormone Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008252:Macaca fascicularis; D008598:Menstruation / Q000187:drug effects; D008600:Menstruation-Inducing Agents / Q000494:pharmacology; D009374:Neoplasms, Experimental / Q000188:drug therapy; D051381:Rats; D011980:Receptors, Progesterone / Q000819:agonists / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D003271:Contraceptive Agents, Female; D004963:Estrenes; D005663:Furans; D006727:Hormone Antagonists; D008600:Menstruation-Inducing Agents; D011980:Receptors, Progesterone; C076196:Org 31710; C094798:Org 33628