Non-steroidal antiandrogens: Synthesis and biological profile of high-affinity ligands for the androgen receptor

Teutsch, G.; Goubet, F.; Battmann, T.; Bonfils, A.; Bouchoux, F.; Cerede, E.; Gofflo, Dominique; Gaillard-Kelly, Martine; Philibert, D.

doi:10.1016/0960-0760(94)90257-7

Cited by 105 publications

(71 citation statements)

References 29 publications

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“…The newer antiandrogen RU56, 187 has affinity for the androgen receptor similar to testosterone but no detectable affinity for progesterone, glucocorticoid, mineralocorticoid or oestrogen receptors (Teutsch et al, 1994). In our system, we detected weak PSA gene up-regulation at RU56, 187 concentration .10-8 M. This up-regulation strongly suggests that RU56,187 has weak androgen agonist activity.…”

Section: Discussionmentioning

confidence: 56%

“…All these compounds bind to the androgen receptor leading to either inactive complexes (pure antiandrogens) or to complexes with some biological stimulatory activity (antiandrogens with weak agonist activity). In our system, hydroxyflutamide, casodex and nilutamide (anandron), which are known to bind to the androgen receptor with low affinity (<2% of testosterone affinity) (Teutsch et al, 1994), did not mediate any PSA production, suggesting formation of weak and inactive complexes with the androgen receptor. Cyproterone acetate, which binds to the androgen receptor with affinity approximately 10% of that of testosterone (Teutsch et al, 1994), was found to be a strong stimulator of PSA production, with activity even at concentrations of approximately 10-10 M. These data suggest that cyproterone acetate, a known antiandrogen that also interacts with the progesterone receptor (Teutsch et al, 1994;Levine, 1995) and has biological progestational activity (Levine, 1995), exerts its action on PSA regulation through binding to the progesterone receptor.…”

Section: Discussionmentioning

confidence: 72%

“…In our system, hydroxyflutamide, casodex and nilutamide (anandron), which are known to bind to the androgen receptor with low affinity (<2% of testosterone affinity) (Teutsch et al, 1994), did not mediate any PSA production, suggesting formation of weak and inactive complexes with the androgen receptor. Cyproterone acetate, which binds to the androgen receptor with affinity approximately 10% of that of testosterone (Teutsch et al, 1994), was found to be a strong stimulator of PSA production, with activity even at concentrations of approximately 10-10 M. These data suggest that cyproterone acetate, a known antiandrogen that also interacts with the progesterone receptor (Teutsch et al, 1994;Levine, 1995) and has biological progestational activity (Levine, 1995), exerts its action on PSA regulation through binding to the progesterone receptor. Our finding that cyproterone acetate can upregulate the PSA gene through the progesterone receptor in parallel to its expected down regulation of the PSA gene through androgen receptor blockade requires further investigation as monitoring PSA levels during cyproterone acetate treatment of prostate cancer may not be a reliable index of clinical response.…”

Section: Discussionmentioning

confidence: 72%

“…In our system, we detected weak PSA gene up-regulation at RU56, 187 concentration .10-8 M. This up-regulation strongly suggests that RU56,187 has weak androgen agonist activity. In this respect, our tissue culture system appears to be more sensitive than the in vitro systems used by Teutsch et al (1994) to evaluate RU56,187, concluding that this compound is totally devoid of binding to other steroid receptors and of any agonist effect. It remains to be determined if the weak agonist activity of RU56,187 has any biological significance.…”

Section: Discussionmentioning

confidence: 93%

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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: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 93%

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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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“…Разработка энзалутамида была начата с создания библиотеки мо-лекул с использованием нестероидного агониста RU59063 в качестве исходной химической матрицы на основании его относительно высокой аффинности к АР и селективности в отношении рецептора по срав-нению с другими ядерными гормональными рецепто-рами [13,[16][17]. Затем было проведено исследование соотношения структуры и активности на ряде анало-гов с использованием экспрессии простатического специфического антигена (ПСА) в качестве регистри-руемой величины на 2 различных линиях клеток РПЖ человека: нормальной (гормон-чувствительной) кле-точной линии LNCaP и кастрационно-резистентной клеточной линии LNCaR, которая создана для экс-прессии 3-и 5-кратных уровней АР дикого типа.…”

Section: диагностика и лечение опухолей мочеполовой системы рак предunclassified

Second-line hormonal therapy with the enzalutamid in patients with castrate-resistant prostate cancer

Алексеев¹,

Нюшко²,

Калпинский³

et al. 2016

Cancer Urology

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Bicalutamide dosages used in the treatment of prostate cancer

Kolvenbag

Nash

1999

Prostate

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BACKGROUND Androgen deprivation is often used for the treatment of patients with prostate cancer. Androgen deprivation can be achieved by surgical castration or medical castration, with or without using an antiandrogen. Each of these treatments may be used alone, or an antiandrogen may be used alongside castration to produce combined androgen blockade therapy. METHODS The nonsteroidal antiandrogen, bicalutamide (Casodex®), has been evaluated as a component in combined androgen blockade and as monotherapy. We review the arguments that indicate why a 50‐mg once‐daily dose of bicalutamide is appropriate in combined androgen blockade, while ongoing clinical trials evaluate 150‐mg once‐daily as monotherapy in the treatment of prostate cancer. RESULTS The choice of the 50‐mg dose of bicalutamide when used in combined androgen blockade is supported by four main arguments. First, bicalutamide 50 mg is at least equivalent to, if not better than, flutamide 750 mg in terms of receptor affinity, potency, and favorable plasma concentration profile. Second, the reduction in testosterone concentrations produced by medical or surgical castration decreases the potential competition between bicalutamide and testosterone for androgen receptors in prostate cells, allowing the use of a lower dose of antiandrogen in combined androgen blockade than is necessary in monotherapy. Third, bicalutamide 50 mg has an excellent tolerability profile. Fourth, at the 50‐mg dose, bicalutamide plus luteinizing hormone‐releasing hormone analogue was equivalent to flutamide plus luteinizing hormone‐releasing hormone analogue, although there was a trend towards longer survival with bicalutamide. Furthermore, investigations of higher doses of bicalutamide have justified evaluation of bicalutamide 150 mg as monotherapy. First, pharmacodynamic studies reveal an increasing prostate‐specific antigen response with increasing dose, which appears to plateau at a dose of around 150–200 mg. Second, in an analysis with 31% mortality, bicalutamide 150 mg appeared to have equivalent efficacy compared with castration in terms of survival in patients with nonmetastatic prostate cancer. CONCLUSIONS On the basis of available data, bicalutamide 50 mg is an appropriate dose to use in combined androgen blockade, while 150 mg is being evaluated in ongoing clinical trials as a suitable dose for monotherapy. Prostate 39:47–53, 1999. © 1999 Wiley‐Liss, Inc.

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Non-steroidal antiandrogens: Synthesis and biological profile of high-affinity ligands for the androgen receptor

Cited by 105 publications

References 29 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

Second-line hormonal therapy with the enzalutamid in patients with castrate-resistant prostate cancer

Bicalutamide dosages used in the treatment of prostate cancer

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