Preclinical experience with two selective progesterone receptor modulators on breast and endometrium

Area of Science:

• Pharmacology
• Endocrinology
• Oncology

Background:

• Selective progesterone receptor modulators (PRMs) are investigated for therapeutic applications.
• Org 31710 and Org 33628 exhibit high selectivity with anti-progestational and anti-glucocorticoid activity.
• PRMs have potential indications in breast cancer and fertility regulation.

Purpose of the Study:

• To evaluate the efficacy of Org 31710 and Org 33628 in preclinical models for breast cancer and fertility control.
• To compare the anti-progestational potency of Org 31710 and Org 33628 in vitro and in vivo.
• To assess the effects of these PRMs on tumor development, menses induction, and ovulation.

Main Methods:

• In vitro and in vivo studies were conducted.
• Breast tumor development was assessed using the DMBA model in rats.
• Menses induction was tested in monkeys using various dosing regimens and in combination with desogestrel.

Main Results:

• Both Org 31710 and Org 33628 demonstrated dose-related reductions in breast tumor load in the DMBA model, outperforming RU 486.
• Menses induction efficacy in monkeys was dependent on the timing of administration relative to the progesterone peak.
• Continuous low-dose PRM treatment inhibited ovulation while allowing normal follicular development and subsequent menses upon cessation.

Conclusions:

• Org 31710 and Org 33628 are effective in reducing breast tumor burden and show potential for fertility regulation.
• The compounds exhibit significant anti-progestational activity, with Org 33628 being more potent.
• These PRMs represent promising candidates for breast cancer prevention/treatment and contraception.