Effect of a New Topically Active Antiandrogen (RU38882) on the Rat Sebaceous Gland: Comparison with Cyproterone Acetate

Bouton, M.M.; Lecaque, Dominique; Secchi, Jean; Tournemine, C.

doi:10.1111/1523-1747.ep12284203

Cited by 20 publications

(7 citation statements)

References 18 publications

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“…Similar results were obtained when these compounds were tested locally on one hamster flank organ. Compound 77 reduced flank organ weight by 80% while under these conditions, compound 77 was more potent when compared to cyproterone acetate [102]. In another class of des-A-steroids, Ro 5-2537 showed weak antiandrogenic activity and no androgenic activity under the assay conditions used.…”

Section: Syntheticmentioning

confidence: 94%

Androgen Receptor Antagonists (Antiandrogens) Structure-Activity Relationships

Singh

Gauthier²,

Labrie

2000

CMC

214

162

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Prostate cancer, acne, seborrhea, hirsutism, and androgenic alopecia are well recognized to depend upon an excess or increased sensitivity to androgens or to be at least sensitive to androgens. It thus seems logical to use antiandrogens as therapeutic agents to prevent androgens from binding to the androgen receptor. The two predominant naturally occurring androgens are testosterone (T) and dihydrotestosterone (DHT). DHT is the more potent androgen in vivo and in vitro. All androgen-responsive genes are activated by androgen receptor (AR) bound to either T or DHT and it is believed that AR is more transcriptionally active when bound to DHT than T. The two classes of antiandrogens, presently available, are the steroidal derivatives, all of which possess mixed agonistic and antagonistic activities, and the pure non-steroidal antiandrogens of the class of flutamide and its derivatives. The intrinsic androgenic, estrogenic and glucocorticoid activities of steroidal derivatives have limited their use in the treatment of prostate cancer. The non-steroidal flutamide and its derivatives display pure antiandrogenic activity, without exerting agonistic or any other hormonal activity. Flutamide (89) and its derivatives, Casodex (108) and Anandron (114), are highly effective in the treatment of prostate cancer. The combination of flutamide and Anandron with castration has shown prolongation of life in prostate cancer. Furthermore, combined androgen blockade in association with radical prostatectomy or radiotherapy are very effective in the treatment of localized prostate cancer. Such an approach certainly raises the hope of a further improvement in prostate cancer therapy. However, all antiandrogens, developed so-far display moderate affinity for the androgen receptor, and thus moderate efficacy in vitro and in vivo. There is thus a need for next-generation antiandrogens, which could display an equal or even higher affinity for AR compared to the natural androgens, and at the same time maintain its pure antiandrogenic activity, and thus providing improved androgen blockade using possibly antiandrogens alone.

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Section: Syntheticmentioning

confidence: 94%

Androgen Receptor Antagonists (Antiandrogens) Structure-Activity Relationships

Singh

Gauthier²,

Labrie

2000

CMC

214

162

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“…In fact, CPA effects on sebum formation are not yet described at the molecular level. Early reports comparing CPA to other antiandrogens (32,33) have been followed by the study demonstrating CPA induced enzyme inhibition in the sebocyte line SZ95 (3).…”

Section: Introductionmentioning

confidence: 99%

Cyproterone Acetate Loading to Lipid Nanoparticles for Topical Acne Treatment: Particle Characterisation and Skin Uptake

et al. 2007

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“…In this study, CPA and spironolactone did not inhibit 5 -reductase activity or testosterone metabolism in SZ95 sebocytes or HaCaT keratinocytes in vitro . Similarly, studies by Bouton et al [33] and Battmann et al [34] on the non-steroidal anti-androgens inocoterone acetate or RU58841, respectively, did not show an effect on 5 -reductase and / or testosterone metabolism. We conclude, therefore, that any effect of these compounds on the biological activity of the investigated cells is not due to an interaction with enzymes of peripheral testosterone metabolism within the cells but due to binding to the androgen receptor [35] .…”

Section: Discussionmentioning

confidence: 71%

Inhibition of 5α-Reductase Activity in SZ95 Sebocytes and HaCaT Keratinocytes In Vitro

Seiffert¹,

Seltmann²,

Fritsch³

et al. 2007

Horm Metab Res

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Inhibition of 5alpha-reductase type 1 has been considered to be a promising target for treatment of androgen-dependent skin disorders, however, currently published clinical results on acne treatment are rather disappointing. In this study, the influence of selective inhibitors of 5alpha-reductase on testosterone metabolism within SZ95 sebocytes and HaCaT keratinocytes IN VITRO was investigated. In both cell types, the isotype 1 inhibitor MK386 completely inhibited the conversion of testosterone to 5alpha-dihydrotestosterone in concentrations higher than 10 (-9) M. Inhibitors of the isotype 2 such as finasteride, dihydrofinasteride, and turosteride, were >100-fold less active, while, as expected, androgen receptor inhibitors did not affect the 5alpha-reductase activity. MK386, but not finasteride, reduced testosterone-stimulated proliferation and slightly reduced the testosterone-induced increase in the amount of SZ95 sebocyte proteins. The androgen receptor inhibitor cyproterone acetate exhibited no effect on testosterone-induced proliferation, but inhibited the 5alpha-dihydrotestosterone-induced sebocyte proliferation. Our experimental findings and the existing clinical results indicate that the inhibition of 5alpha-reductase activity alone may be insufficient to reduce overall sebocyte activity and improve acne lesions.

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Effect of a New Topically Active Antiandrogen (RU38882) on the Rat Sebaceous Gland: Comparison with Cyproterone Acetate

Cited by 20 publications

References 18 publications

Androgen Receptor Antagonists (Antiandrogens) Structure-Activity Relationships

Androgen Receptor Antagonists (Antiandrogens) Structure-Activity Relationships

Cyproterone Acetate Loading to Lipid Nanoparticles for Topical Acne Treatment: Particle Characterisation and Skin Uptake

Inhibition of 5α-Reductase Activity in SZ95 Sebocytes and HaCaT Keratinocytes In Vitro

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