Pharmacological Profile of RU 486 in Animals

Philibert, D.; Moguilewsky, M.; Mary, Idicula Dr.Sumam; Lecaque, Dominique; Tournemine, C.; Secchi, Jean; Deraedt, R.

doi:10.1007/978-1-4684-1242-0_3

Cited by 100 publications

(50 citation statements)

References 25 publications

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“…This is in accord with our view that PSA production is mediated independently by the AR and the PR as mifepristone is known to block effectively the progesterone receptor and to a lesser but significant degree the androgen receptor (Philibert et al, 1985).…”

Section: Discussionsupporting

confidence: 89%

“…RU486 has been commercialized as an antiprogestin for first trimester pregnancy interruption. In our system, we found that Mifepristone has weak agonist activity, mediating PSA gene up-regulation at concentrations .10-8 M. This agonist activity was not observed by Philibert et al (1985), further suggesting that their biological tests are not as sensitive as our tissue culture system in detecting such an effect. In support of our data are reports by others showing weak agonist activity of RU486 in various systems (Gravanis et al, 1985;Gronemeyer et al, 1991;Wehle et al, 1995).…”

Section: Discussionmentioning

confidence: 65%

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Steroid hormone regulation of prostate-specific antigen gene expression in breast cancer

Zarghami

Grass²,

Diamandis³

1997

Br J Cancer

113

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Summary We have recently reported that about 30-40% of female breast tumours produce prostate-specific antigen (PSA) and that PSA production is associated with the presence of oestrogen (ER) and progesterone (PR) receptors. We have now developed a tissue culture system to study the regulation of the PSA gene in breast cancer. The breast carcinoma cell line T-47D produces PSA when stimulated by androgens, progestins and glucocorticoids/mineralocorticoids but not oestrogens. PSA mRNA appears approximately 2 h after stimulation; PSA protein appears after 4-8 h. Among 38 compounds tested, only androgens and progestins were able to stimulate PSA production at concentrations below 10-9 M. Evidence that the progesterone and androgen receptors can regulate the PSA gene independently was provided as follows: (a) the progestin norgestimate, which does not bind to the androgen receptor, up-regulates the PSA gene at concentrations as low as 10-10 M; (b) triamicinolone acetonide, which does not bind to the androgen receptor (AR) but binds to the PR, acts similarly to norgestimate; (c) the antiandrogen cyproterone acetate, which blocks the androgen receptor but has progestational activity, up-regulates the PSA gene at concentrations as low as 10-10 M; (d) the antiprogestin mifepristone completely blocks the stimulation of the specific progestin norgestimate. Our tissue culture system identified androgen -progestin agonist activities of 17a-ethinyloestradiol, the antioestrogen RU56, 187 and the antiprogestin mifepristone. Our data suggest that the expression of the PSA gene in the female breast is under the control of androgens and progestins. Our tissue culture system is a highly sensitive in vitro method for evaluating the biological activity of candidate compounds having agonist and antagonist steroid hormone activity.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 65%

Steroid hormone regulation of prostate-specific antigen gene expression in breast cancer

Zarghami

Grass²,

Diamandis³

1997

Br J Cancer

113

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“…Various studies have revealed that progesterone has an inhibitory control on prolactin release at the end of pregnancy (Vermouth & Deis 1972, 1974, Jahn et al 1986). In a previous paper (Soaje & Deis 1994) we showed that preventing the central inhibitory action of progesterone on prolactin release by the antiprogesterone mifepristone (Philibert 1985) at the end of pregnancy facilitated the release of prolactin and this effect was enhanced by the administration of the opioid antagonist naloxone. Our previous results demonstrated a dual neuromodulatory regulation of prolactin secretion by the opioid system during pregnancy.…”

Section: Introductionmentioning

confidence: 90%

Regulation by endogenous opioids of suckling-induced prolactin secretion in pregnant and lactating rats: role of ovarian steroids

Soaje¹,

Nasso²,

Deis³

2002

Journal of Endocrinology

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Evidence suggests that endogenous opioid peptides are implicated in the suckling-induced prolactin rise. We explored the role of the opioid system and the participation of ovarian hormones in the regulation of prolactin induced by the suckling stimulus at the end of pregnancy in rats with developed maternal behavior, and during lactation. Suckling for 24 h induced a significant increase in serum prolactin on day 19 of pregnancy, which was increased more than three times when naloxone (2 mg/kg s.c.) or mifepristone (2 mg/kg) was administered. The combination of naloxone and mifepristone did not increase serum prolactin more than either compound alone. Administration of tamoxifen (500 µg/kg orally) on days 14 and 15 of pregnancy completely abolished the effect of naloxone, indicating a role for estrogens in establishing this inhibitory role of opioids. To examine the participation of the opioid system during lactation, we used groups of rats on days 1, 3, 5, 12 and 19 postpartum either (i) isolated from the pups for 4 h, or (ii) isolated from the pups for 3·5 h and reunited with them and suckled for 30 min. Naloxone, given just before replacing the pups, prevented the increase in serum prolactin levels observed in the suckled group of rats but had no effect on the basal levels of the isolated rats. To examine whether the participation of the opioid system in the release of prolactin is dependent on the variation of progesterone levels, rats on day 20 of pregnancy were implanted with two cannulae containing progesterone (that blocked postpartum ovulation) or cholesterol, and cesarean surgery was performed on day 21. To maintain lactation, pups (1-3 days old) were replaced every 24 h, and 4 days after the cesarean eight pups were placed in the cage at 1800 h to maintain a strong suckling stimulus during the following 24 h. Naloxone administration significantly reduced serum prolactin levels in control (cholesterol) rats but progesterone implants prevented the inhibitory effect of naloxone and this effect was not modified by treatment with estrogen.These results indicate that the opioid system modulates suckling-induced prolactin secretion, passing from an inhibitory action before delivery to a stimulatory action during lactation. This regulatory shift seems to be dependent on the fall in progesterone concentration at the end of pregnancy and the subsequent increase after the postpartum ovulation and luteal phase.

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“…RU 486 is a synthetic steroid which acts as a progesterone antagonist [12][13][14]. In this study, RU 486 was given at a dose of 10 mg/kg for 3 consecutive days, since similar treatment has displayed both antinidatory and abortive activities, and even lower doses have blocked deciduomata formation in rats [14,23].…”

Section: Discussionmentioning

confidence: 99%

“…In this study, RU 486 was given at a dose of 10 mg/kg for 3 consecutive days, since similar treatment has displayed both antinidatory and abortive activities, and even lower doses have blocked deciduomata formation in rats [14,23]. In fact, as shown in Table 1, administration of RU 486 caused abortion in the intact uterine horn of sham-OVX rats, indicating that the drug had an antiprogesterone action even in the presence of plenty of progesterone secreted from the ovaries.…”

Section: Discussionmentioning

confidence: 99%

A Progesterone Antagonist Cannot Prevent Fetal Survival if the Uterine Horn is Incised.

1998

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Abstract. The fetuses released into the abdominal cavity by uterine incision escape from most physical influences of the uterus. This study examined whether these fetuses require progesterone actions for survival during late pregnancy in rats. A longitudinal incision in one uterine horn (with the other horn intact) together with bilateral ovariectomy (OVX), removal of the main progesterone-production sites, or sham OVX, were performed on day 18 of pregnancy. Thereafter the rats were given daily subcutaneous injections of anti-progesterone RU 486 (10 mg/kg), or vehicle alone, and the fetal survival rate in each uterine horn was examined on day 21. In those controls which received sham OVX plus injections of vehicle, fetal survival rates were more than 80% in both uterine horns. In the other groups, which received sham OVX plus injections of RU 486, or OVX plus injections of vehicle, or OVX plus injections of RU 486, the fetal survival rates in the intact uterine horns were 4%, 0% and 0%, respectively. In the incised uterine horns of these groups, however, the fetal survival rates were 59%, 67% and 56%, respectively. The results suggest that progesterone, which is required for maintaining pregnancy, may not be essential for survival of fetuses released into the abdominal cavity. Progesterone actions unrelated to uterine physical environment are likely to be dispensable for fetal survival during late pregnancy in rats.

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Pharmacological Profile of RU 486 in Animals

Cited by 100 publications

References 25 publications

Steroid hormone regulation of prostate-specific antigen gene expression in breast cancer

Steroid hormone regulation of prostate-specific antigen gene expression in breast cancer

Regulation by endogenous opioids of suckling-induced prolactin secretion in pregnant and lactating rats: role of ovarian steroids

A Progesterone Antagonist Cannot Prevent Fetal Survival if the Uterine Horn is Incised.

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