[Show abstract][Hide abstract] ABSTRACT: Benign prostatic hyperplasia is a common cause of urinary flow obstruction in aging men and may lead to lower urinary tract symptoms (LUTS). Benign prostatic hyperplasia has 2 physiological components: a static component related to increased prostate size and a dynamic component related to increased prostate smooth muscle tone. alpha1-Adrenoceptors (alpha1ARs) maintain prostate smooth muscle tone; hence, alpha1-antagonists (blockers) relax prostate smooth muscle and decrease urethral resistance, ultimately leading to relief of LUTS. This review focuses on alpha1AR subtypes and their location in lower urinary tract tissues involved in LUTS (prostate, bladder, spinal cord); it also summarizes major clinical trials published to date on the efficacy of alpha1AR blockers for LUTS. Benefits and adverse effects of clinically available alpha1AR antagonists are reviewed, followed by recent information on interactions between alpha1AR subtype antagonists and type 5 phosphodiesterase inhibitors used for impotence. alpha1-Adrenoceptor antagonists have become the mainstay of therapy for LUTS; knowledge about specific alpha1AR subtypes should facilitate rational choice of alpha1AR blocker therapy by clinicians.
Mayo Clinic Proceedings 12/2004; 79(11):1423-34. DOI:10.4065/79.11.1423 · 6.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The most effective therapy for metastatic prostate cancer is androgen deprivation. Genes activated directly or possibly even indirectly by this steroid hormone represent potential targets for anticancer therapy. One such gene may be hTERT, which encodes the catalytic subunit of telomerase. In prostate cancer cells telomerase is activated, permitting sustained proliferation. Therefore, we tested whether hTERT gene expression is modulated in prostate cancer cells in vitro and in vivo by androgens.
Transcriptional activation of hTERT during androgen stimulation was assayed by luciferase assays using the hTERT promoter fused to the luciferase gene and by reverse transcriptase-polymerase chain reaction to detect endogenous hTERT mRNA in LNCaP cells. hTERT mRNA levels and telomerase activity were also measured in CWR22 prostate cancer cells implanted in mice that were subsequently castrated and left untreated or administered androgen.
We report that the endogenous hTERT promoter is activated during the administration of androgen to androgen sensitive LNCaP prostate cancer cells. However, this effect was indirect since an hTERT promoter construct was not activated by androgens and transcription of the endogenous gene was not stimulated early enough in cultured cells to be considered a direct target of this steroid hormone. Importantly in an in vivo model of human prostate cancer androgen deprivation led to a decrease in hTERT expression, followed by a decrease in telomerase activity, which was reversed by a single administration of androgen.
The hTERT gene is regulated in human prostate cancer cells in vivo by androgens.
The Journal of Urology 09/2003; 170(2 Pt 1):615-8. DOI:10.1097/01.ju.0000074653.22766.c8 · 4.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: alpha(2)-Adrenergic receptor (alpha(2)AR) agonists have become important adjuncts as anesthetic agents. They act by binding to alpha(2)ARs on the surface of cell membranes and cause centrally mediated sedation and analgesia. alpha(2)ARs also contribute to other aspects of physiologic regulation. Three subtypes of alpha(2)ARs (alpha(2-C2), alpha(2-C4), and alpha(2-C10)) have been described using molecular and pharmacologic techniques. We recently demonstrated species heterogeneity in the distribution of alpha(1)-adrenergic receptor subtypes, therefore making it imperative to analyze the distribution of alpha(2)AR subtypes in human tissues. This information may have importance in the understanding of potential side effects of administration of alpha(2)AR subtype-selective agonists for anesthesia in humans. Methods: RNA extracted from human tissues was analyzed by using quantitative ribonuclease protection assays to determine alpha(2)AR subtype messenger RNA (mRNA) expression in cardiovascular, central nervous system, and peripheral tissues. Results: alpha(2),AR mRNA is present in greatest concentrations in human kidney, followed by aorta > spleen > heart = lung. alpha(2-C4) mRNA predominates in heart, lung, aorta, cerebral cortex, cerebellum, spleen, kidney, and adrenal gland; alpha(2-C2) mRNA in liver; and alpha(2-C10) mRNA in pancreas and small intestine. Hence alpha(2)AR subtype mRNA distribution is tissue-selective and differs from that reported for rat. Conclusions: (1) On comparison with previous research we find possible species heterogeneity in alpha(2)AR subtype mRNA distribution (rat vs. human) for all three alpha(2)AR subtypes. (2) We demonstrate the presence and subtype heterogeneity of alpha(2)AR subtype mRNA in both brain and peripheral tissues. (3) Significant concentrations of alpha(2)AR mRNA are present in adult human heart. These findings have important implications for our understanding of human adrenergic physiology, provide a possible explanation for the existence of pharmacologically similar yet distinct alpha(2)AR subtypes, and may be important for the rational development of (alpha(2)AR subtype-selective anesthetics and other therapeutic agents for use in treating human diseases.