PubMed · 2948437
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C Jamin. 1986. [Hirsutism].. https://pubmed.ncbi.nlm.nih.gov/2948437/
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BACKGROUND: Endocrine therapy for prostate cancer aims to reduce the levels of circulating androgen or to inhibit androgen action by blocking the androgen receptor in the prostate, or both. Studies in various animal and human prostate cancer models suggested that there may be a downregulation of androgen receptor during prostate cancer progression. Recent work, however, showed androgen receptor expression in all stages of prostate cancer. The presence of mutant androgen receptors in a portion of prostate cancers and receptor activation in the absence of androgen or in the presence of low androgen concentrations is discussed within this context. METHODS: This review attempts to summarize the literature on androgen receptor expression in vitro and in vivo, as well as structural and functional alterations and communication between androgen signal transduction cascade and other signaling pathways. CONCLUSIONS: Prostate tumors adapt to an environment with low androgen supply by using a hyperactive androgen receptor. The mechanisms involved are mutations of the androgen receptor generating receptors with broadened activation spectrum, increased receptor expression, and activation by interaction with other signaling pathways.
The E. coli lacZ has been utilized as a reporter to evaluate ligand-mediated activation of the rat androgen receptor (AR) in Saccharomyces cerevisiae strain YCR1. beta-galactosidase activity was androgen-specific and was found to be inducible approximately 260-fold by dihydrotestosterone (DHT), testosterone and R1881. None of the antiandrogens tested was able to antagonize the DHT-dependent induction of beta-galactosidase activity. In the gel retardation assay, exposure of the receptor to DHT in vitro led to the formation of a protein-DNA complex that was not detected in yeast extracts unexposed to hormone. However, activation of AR by a steroidal (cyproterone acetate) and a non-steroidal antiandrogen (flutamide) either alone or in combination with DHT also results in a similar migration pattern. Additionally, LEM1, the ABC transporter that selectively modulates the biological potency of steroids in yeast, although operative in YCR1, was not responsible for antiandrogen resistance. These results thus indicate the involvement of other non-receptor factor(s) in mediating the effect of antiandrogens in yeast.
A new nonsteroidal antiandrogenic pharmacophore has been discovered using cell-based cotransfection assays with human androgen receptor (hAR). This series of AR antagonists is structurally characterized by a linear tricyclic 1,2-dihydropyridono[5,6-g]quinoline core. Analogues inhibit AR-mediated reporter gene expression and bind to AR as potently as or better than any known AR antagonists. Several analogues also showed excellent in vivo activity in classic rodent models of AR antagonism, inhibiting growth of rat ventral prostate and seminal vesicles, without accompanying increases in serum gonadotropin and testosterone levels, as is seen with other AR antagonists. Investigations of structure-activity relationships surrounding this pharmacophore resulted in molecules with complete specificity for AR, antagonist activity on an AR mutant commonly observed in prostate cancer patients, and improved in vivo efficacy. Molecules based on this series of compounds have the potential to provide unique and effective clinical opportunities for treatment of prostate cancer and other androgen-dependent diseases.