Disease relevance of Onapristone

• In conclusion Onapristone can induce tumour responses in human breast cancer [1].
• The effect of Onapristone and concomitant oestrogen (E2) supplements on the growth of five human gastrointestinal cancer xenografts was examined [2].
• In contrast to the antiprogestin RU 486, onapristone showed no estrogenic activity (stimulation of growth and PR), which could be a decisive advantage in the therapy of breast cancer, taking into account, that many breast carcinomas grow estrogen dependent [3].
• (4) The characteristics of onapristone-induced preterm labor are generally similar to those of spontaneous term labor [4].
• These findings may be a further indication of the future potential of antiprogestins such as onapristone and ZK 136 799 in the treatment of endometriosis [5].

High impact information on Onapristone

• Using a transgenic rat model of CMT1A, we tested the hypothesis that long-term treatment with anti-progesterone (Onapristone) reduces Pmp22 overexpression and improves CMT disease phenotype of older animals, thereby extending a previous proof-of-concept observation in a more clinically relevant setting [6].
• The antiprogestin, onapristone, partially blocked the ability of progesterone to prevent stimulation of MMP-3 by IL-1alpha [7].
• Cells were treated with varying concentrations of cortisol, progesterone, the synthetic progestins R5020, and medroxyprogesterone acetate with or without RU486 or the specific progesterone receptor antagonist, onapristone, and the 3beta-hydroxysteroid dehydrogenase inhibitor, trilostane [8].
• We now present evidence that the effects of P on HB-EGF expression are blocked by treatment with ZK98299 (onapristone), indicating that they are receptor mediated [9].
• Three treatment protocols were investigated: Exp I, onapristone or lilopristone treatment only; Exp II, onapristone treatment after hysterectomy at day 1 p.hCG; Exp III, onapristone treatment together with 17 beta-estradiol, which represents the ultimate luteotropic hormone in the rabbit [10].

Chemical compound and disease context of Onapristone

• The tumour-inhibiting potential of the progesterone antagonist Onapristone in the human mammary carcinoma T61 in nude mice [11].
• (3) inhibition of nitric oxide by NG-nitro-L-arginine methyl ester also significantly increased the efficacy of high-dose onapristone (30 mg/kg) in preterm labor and delivery [12].
• This is the first report demonstrating an in vivo antitumor activity of antiprogestins (mifepristone, onapristone) alone and in combination with tamoxifen in the MCF-7 human breast cancer model [13].

Biological context of Onapristone

• Based on our previous experiences, a dose of 2.5 or 5 mg of onapristone was administered s.c. every third day during the menstrual cycle, because these dosages impair endometrial development without upsetting the normal gonadal endocrine profiles [14].
• Treatment with either of the two doses (2.5 or 5 mg) of onapristone caused a significant (P < 0.05) down-regulation in the expression of LIF in the peri-implantation endometria [14].
• CONCLUSIONS: This study demonstrates that low-dose onapristone treatment throughout the menstrual cycle prevents pregnancy without disturbing the menstrual cycle and ovulation in the majority of cycles [15].
• Onapristone inhibited apoptosis [16].
• The intrauterine pressure recording on day 43 after coitus revealed phasic, laborlike contractions in response to oxytocin in onapristone-treated animals, in contrast to tonic reactions in controls [17].

Anatomical context of Onapristone

• Immunocytochemical analysis of ER in uterine sections suggests that the increase in ER after onapristone treatment took place predominantly in the myometrium and surface epithelium [18].
• Effects of an antiprogestin onapristone on the endometrium of bonnet monkeys: morphometric and ultrastructural studies [19].
• A 2 x 2 factorial arrangement of estradiol and onapristone treatments was administered to groups of 5 ewes after destruction of ovarian follicles on Day 8 of the cycle [20].
• Onapristone (2 mg/kg) or its vehicle were administered on Day 13, immediately preceding the simultaneous collection of blood samples from the carotid artery, jugular vein, and vena cava at 7.5-min intervals for 7 h [20].
• To determine whether the anti-apoptotic effect of P(4) was regulated at the receptor level, luteal cells were cultured in the presence of PR antagonists, RU-486 and onapristone, for 48 h [21].

Associations of Onapristone with other chemical compounds

• In placentas delivered spontaneously, onapristone significantly increased production of interleukin 8 (P < .05), whereas in those from cesarean deliveries lilopristone caused a significant increase in production (P < .05) [22].
• Conversely, aminoguanidine plus onapristone treatment completely prevented pregnancy, whereas L-NAME plus onapristone reduced the pregnancy rate to approximately 50% [23].
• Early and delayed effects of hydrocortisone and onapristone on intestinal brush-border enzymes and their sialylation and on thymus growth in suckling rats [24].
• On the other hand, antiprogestins (2.3 nM) appeared to have some progesterone-like ("mimetic") activity with inhibition of C-4I cell growth; mifepristone (11%), onapristone (12%) and ZK-112993 (16%) [25].
• Both clomiphene citrate and onapristone suppressed connexin-43 expression, and concomitant addition of hCG did not counteract their effect [26].

Gene context of Onapristone

• Combined treatment with aminoguanidine and onapristone for 3 days led to a transient suppression of Erk1/2 and abolished Cox2 expression [27].
• Our objective was to investigate the influence of the antigestagen onapristone alone and in combination with other substances associated with cervical ripening on the expression of the inflammation-associated adhesion molecules ELAM-1, ICAM-1 and VCAM-1 [28].
• Onapristone stimulated preterm labor, increasing the iNOS and COX-2 mRNA (p<0.05) [29].
• Onapristone caused preterm delivery and a premature fall in RGS2 messenger RNA levels [30].
• Onapristone also affected the production of luteal phase endometrial proteins, as judged by the pronounced reduction in immunostaining of PGDH within the glands and the significant reduction in plasma concentrations of PP14 [31].

Analytical, diagnostic and therapeutic context of Onapristone

• Two compounds, 10 (LG120753) and 11 (LG120830) with potencies comparable or equal to the steroidal hPR antagonist onapristone (ZK98,299), were demonstrated to act as antiprogestins in vivo after oral administration to rodents [32].
• However, owing to the recognition in this and other clinical studies that some patients on Onapristone developed liver function test abnormalities, the development of this drug and recruitment to the study stopped in 1995 [1].
• Similarly, an infiltration of inflammatory cells occurs in pregnant guinea-pigs either spontaneously at term or at preterm after treatment with the antiprogestin onapristone [33].
• These findings suggest that onapristone could potentially be used as a method of postovulatory fertility control [31].
• The inhibitory effect of onapristone on the endometrium is dependent upon the strength of ovarian stimulation [34].

References