Studies on the mechanisms of action of progesterone antagonists

Elger, W.; Beier, S.; Chwalisż, Kristof; Fähnrich, M.; Hasan, S. H.; Henderson, David; Neef, Günter; Rohde, Richard D.

doi:10.1016/0022-4731(86)90314-6

Cited by 103 publications

(26 citation statements)

References 9 publications

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“…Since synthetic anti-progesterones are known to exert antiglucocorticoid activity, 12,23,24) it is not clear whether the acceleration of uterine cervical ripening by onapristone re- Onapristone (3 mg/kg of body weight) in 50% (v/v) ethanol was intravenously administered to pregnant rabbits at day 20 post coitum. Control rabbits were injected with the same volume of vehicle alone.…”

Section: Discussionmentioning

confidence: 99%

An Antiprogesterone, Onapristone, Enhances the Gene Expression of Promatrix Metalloproteinase 3/Prostromelysin-1 in the Uterine Cervix of Pregnant Rabbit.

Imada

Sato

Hashizume

et al. 2002

Biological & Pharmaceutical Bulletin

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Using a progesterone receptor antagonist, onapristone/ZK 98.299, we examined the in-vivo effects of progesterone on the function of uterine cervix during pregnancy. Onapristone was intravenously administered to pregnant rabbits on day 20 post coitum. After 24 h, the antiprogesterone increased the wet weight of the uterine cervix and decreased the DNA concentration in the cervix. In-situ hybridization also indicated that antiprogesterone augmented the expression of matrix metalloproteinase (MMP)-3/stromelysin-1 mRNA in the uterine cervix. These changes are very similar to those observed and reported thus far in ripened and dilated uterine cervix. These results suggest that during pregnancy, progesterone closely participates in the maintenance of the function of uterine cervix by preventing the production of MMPs and thereby destruction of extracellular matrix, and thus add support to the theory that antiprogesterone has the potential to accelerate for the uterine cervical ripening and dilatation.

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Section: Discussionmentioning

confidence: 99%

An Antiprogesterone, Onapristone, Enhances the Gene Expression of Promatrix Metalloproteinase 3/Prostromelysin-1 in the Uterine Cervix of Pregnant Rabbit.

Imada

Sato

Hashizume

et al. 2002

Biological & Pharmaceutical Bulletin

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“…1). The antigestagenic activity of ZK 98.299 is slightly stronger [2,10], the antiglucocorticoid activity is weaker [2,10], and there are some differences in its antitumor activity in comparison to RU 486 [6]. Moreover, in a preliminary clinical study some patients who had all been pretreated with various modalities showed favorable response to treatment with RU 486 [3].…”

Section: Introductionmentioning

confidence: 99%

“…Progesterone antagonists were originally created with regard to medicinal non-surgical termination of pregnancy [1,2]. Nevertheless a further medical indication has already emerged in which progesterone antagonists have gained great importance; it is the endocrine therapy of those breast cancers which possess receptors for progesterone [3].…”

Section: Introductionmentioning

confidence: 99%

Antitumor activity of the antiprogestins ZK 98.299 and RU 38.486 in hormone dependent rat and mouse mammary tumors: Mechanistic studies

Michna¹,

Schneider²,

Nishino³

et al. 1989

Breast Cancer Res Tr

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In the transplantable MXT mammary tumor model of the mouse and in the DMBA- and MNU-induced mammary tumor models of the rat, the progesterone antagonists ZK 98.299 and RU 38.468 were shown to have potent antitumor activity. The weight and/or morphology of the ovaries, uterus, and vagina, as well as the effects on serum hormone levels, indicate that the antitumor activity of both antiprogesterones in these models does not depend on a blockade of the ovarian and pituitary functions and does not depend on a non receptor-mediated cytotoxic effect. On the other hand, the morphology of the MXT and the DMBA-induced mammary tumors after treatment with the progesterone antagonists is completely different from that observed after ovariectomy. Treatment with the antiprogesterones seems to trigger differentiation of the mitotically active polygonal tumor cells towards glandular structures and acini with a massive sequestering of secretory products, as well as towards spindle-shaped necrobiotic subpopulations. By contrast, the induction of tumor cell degeneration and cytolysis is the predominant feature of the mammary tumors after ovariectomy. In conclusion, our results indicate that the main mechanism of the antitumor action of antiprogesterones in these models is a direct progesterone receptor-mediated antiproliferation effect at the level of the mammary tumor cells, most probably via the induction of terminal differentiation associated with terminal cell death. This antiproliferative effect seems to be dissociated from the antihormone (antiprogestational) activity of these progesterone antagonists.

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“…In contrast with the effect of hCG and OT, both clomiphene citrate, which has anti-estrogen properties (Clark & Markaverich 1982), and onapristone, a progesterone receptor antagonist (Elger et al 1986), decreased the expression of connexin-43 (phosphorylated and non-phosphorylated forms) in the baboon luteal cells. Co-treatment with hCG did not alter the effect.…”

Section: Connexin-43 In Baboon Corpus Luteum · F S Khan-dawood and Otmentioning

confidence: 83%

Hormonal regulation of connexin-43 in baboon corpora lutea

Khan-Dawood

Yang²,

Dawood³

1998

Journal of Endocrinology

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The synthesis and secretion of progesterone in the corpus luteum are regulated by both endocrine and paracrine/ autocrine factors which affect the steroidogenic cells. Evidence suggests that these cells communicate via cellcell junctional proteins, the connexins. Previously we have shown that connexin-43 is expressed in both human and baboon (Papio hamadryus anubis) corpora lutea, with differential expression throughout luteal development, but is not detectable in corpora albicantia. We have examined the effect of human chorionic gonadotropin (hCG), oxytocin, clomiphene citrate and the anti-progesterone onapristone on expression of connexin-43 protein in the early luteal phase 1-5 days after the mid-cycle luteinizing hormone (LH) surge (LH+1-5 days), the mid-luteal phase 6-10 days after the LH surge (LH+6-10 days), and the late luteal phase 11-15 days after the LH surge (LH+11-15 days) in corpora lutea obtained from normal adult cycling females. Connexin-43 was localized by immunohistochemistry in cultured cells from all the three stages. Western blot analysis of the treated cells indicated the presence of two bands at 43 and 45 kDa. The band at 45 kDa was found to be phosphorylated connexin-43, indicating the presence of functional gap junctions. hCG (10 IU/ml) stimulated the expression of connexin-43 throughout luteal development; however, maximum expression occurred in the early luteal phase with a significantly greater expression of the non-phosphorylated protein. In contrast, in the mid-luteal phase, the expression of the phosphorylated protein was predominant. Oxytocin (200 mU/ml) also stimulated connexin-43 expression throughout luteal development with similar effects on the phosphorylated and non-phosphorylated protein in the early and mid-luteal phase; however, compared with hCG, oxytocin had a greater effect on mid-luteal phase connexin-43 expression. In the presence of both hCG and oxytocin, the expression of connexin-43 was significantly higher than the control only in the late luteal phase. Both clomiphene citrate and onapristone suppressed connexin-43 expression, and concomitant addition of hCG did not counteract their effect. In the context of our previous studies, it is concluded that, together with LH/hCG and the steroid hormones, oxytocin is involved in cell-cell contact-dependent communication in the corpus luteum.

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Studies on the mechanisms of action of progesterone antagonists

Cited by 103 publications

References 9 publications

An Antiprogesterone, Onapristone, Enhances the Gene Expression of Promatrix Metalloproteinase 3/Prostromelysin-1 in the Uterine Cervix of Pregnant Rabbit.

An Antiprogesterone, Onapristone, Enhances the Gene Expression of Promatrix Metalloproteinase 3/Prostromelysin-1 in the Uterine Cervix of Pregnant Rabbit.

Antitumor activity of the antiprogestins ZK 98.299 and RU 38.486 in hormone dependent rat and mouse mammary tumors: Mechanistic studies

Hormonal regulation of connexin-43 in baboon corpora lutea

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