finasteride, Propecia
Down-regulation of prostate-specific antigen expression by finasteride through inhibition of complex formation between androgen receptor and steroid receptor-binding consensus in the promoter of the PSA gene in LNCaP cells.

Wang LG, Liu XM, Kreis W, Budman DR.

Department of Medicine, New York University, Manhasset 11030, USA.

As a specific competitive inhibitor of 5alpha-reductase, an intracellular enzyme that converts testosterone to dihydrotestosterone, finasteride is being extensively used for the treatment of benign prostatic hyperplasia and in experimental settings for prostate cancer. In this study, we showed that finasteride markedly inhibited prostate-specific antigen (PSA) secretion and expression. The promoter of the PSA gene contains several well-known cis-regulatory elements. Among them, steroid receptor-binding consensus (SRBC) has been identified as a functional androgen-responsive element. Our previous study showed that PSA was not only present in conditioned medium of the PSA-positive LNCaP cells but was also detectable in small amounts in PSA-negative cell lines, PC-3 and DU-145 (L. G. Wang et al., Oncol. Rep., 3: 911-917, 1996). A strong correlation between binding of nuclear factors to SRBC and the level of PSA present in the conditioned medium and cell extracts was found in these three cell lines, whereas no such correlation with binding was obtained using Sp1 oligonucleotide as a probe. Binding of LNCaP cell nuclear proteins to SRBC was diminished when the cells were exposed to 25 microM finasteride, at which concentration 50% of both PSA mRNA and protein were inhibited. As a major component of DNA-protein complexes, the level of androgen receptor was dramatically decreased in the cells treated with finasteride. Our data indicate that inhibition of complex formation between SRBC and nuclear proteins due to the remarkable decrease in the level of androgen receptor plays a key role in the down-regulation of PSA gene expression by finasteride in LNCaP cells.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9044850&dopt=Abstract finasteride Propecia



finasteride, Propecia
Androgen metabolism in the prostate of the finasteride-treated, adult rat: a possible explanation for the differential action of testosterone and 5 alpha-dihydrotestosterone during development of the male urogenital tract.

George FW.

Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235-8857, USA. george02 utsw.swmed.edu

Previous work has clearly demonstrated that inhibition of 5 alpha-dihydrotestosterone (DHT) formation in vivo is not as effective as total androgen ablation (castration) in causing involution of the prostate. It is likely that this is due to the fact that testosterone is partially effective in maintaining androgen action. To provide insight into this observation, the androgenic metabolites of testosterone, androstenedione, and 5 alpha-DHT, were measured in prostate tissue and in blood of 5 alpha-reductase inhibitor (finasteride)-treated adult male rats. Finasteride treatment caused a significant decrease in prostatic DHT levels and a profound increase in prostatic testosterone and androstenedione levels. Similarly, circulating DHT levels were decreased in finasteride-treated rats (0.02 ng/ml compared with 0.05 ng/ml seen in control rats); and circulating androstenedione and testosterone levels were significantly elevated in finasteride-treated animals compared with controls. The in vitro effects of finasteride were assessed on the metabolism of [3H]testosterone in a tissue-slice assays. In the prostate, the inhibition of 5 alpha-reductase activity resulted not only in the decreased formation of 5 alpha-reduced metabolites (primarily DHT and 5 alpha-androstanedione), but also an increase in the 17-oxo metabolite androstenedione. In contrast, the tissues derived from the embryonic wolffian duct (seminal vesicle and epididymis) formed relatively low amounts of 17-keto steroids. Because DHT is a high affinity ligand for the androgen receptor and androstenedione shows very little, if any, affinity for the receptor, these studies suggest that 5 alpha-reduction of testosterone may be a mechanism to amplify androgen action in urogenital tissues such as the prostate by preventing catabolism of testosterone to the inactive androgen, androstenedione, at the site of hormone action.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9048585&dopt=Abstract finasteride Propecia



finasteride, Propecia
Clinical and biological characteristics of familial benign prostatic hyperplasia.

Sanda MG, Doehring CB, Binkowitz B, Beaty TH, Partin AW, Hale E, Stoner E, Walsh PC.

Urology Section, University of Michigan, Ann Arbor, USA.

PURPOSE: We attempted to determine the clinical and biological characteristics of familial benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: Urinary flow rate, prostate size, symptom score, serum prostate specific antigen, testosterone and dihydrotestosterone were measured in subjects who participated in the nationwide Merck phase III finasteride clinical trial. Findings in the 69 men with familial BPH (3 or more family members with BPH, including the proband) were compared to those in the 345 with no family history of BPH. Logistic regression was used to detect relationships between familial BPH, and these variables before and after 5 alpha-reductase inhibition with finasteride. RESULTS: Familial BPH was characterized by large prostate size. Mean prostate volume in men with familial and sporadic BPH was 82.7 and 55.5 ml., respectively (p < 0.001). Other clinical findings, including serum androgen levels and response to finasteride, were similar in familial and sporadic BPH. The frequency of familial BPH in patients with prostate size in the largest and smallest deciles was 46 and 13%, respectively. CONCLUSIONS: Familial BPH in this group of patients was associated with large prostate size, normal serum androgen levels and normal response to 5 alpha-reductase inhibition. A genetic factor responsible for familial BPH may exert its influence through androgen independent control of prostatic growth.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9072590&dopt=Abstract finasteride Propecia



finasteride, Propecia
Promoting effects and mechanisms of action of androgen in bladder carcinogenesis in male rats.

Imada S, Akaza H, Ami Y, Koiso K, Ideyama Y, Takenaka T.

Department of Urology, University of Tsukuba, Japan.

OBJECTIVE: It has been reported that blocking of testosterone production inhibits bladder carcinogenesis in various animal models. We investigated how testosterone acts on rat bladder carcinogenesis using an antiandrogen, flutamide, and a 5 alpha-reductase inhibitor, finasteride. METHODS: Experiment 1: we administered 0.05% BBN [N-butyl-N-(4-hydroxybutyl)nitrosamine] orally to 117 Wistar rats for 10 weeks, divided them into seven groups-control, surgical castration, finasteride (2 mg/kg), luteinizing hormone releasing hormone (LH-RH) agonist (1 mg/kg) flutamide (50 mg/kg), LH-RH agonist plus finasteride, and LH-RH agonist plus flutamide-, and then cystectomized them to investigate the incidence of bladder cancer on week 21; experiment 2: we administered 0.05% BBN to 154 Wistar rats for 7 weeks, divided them into seven groups-control, finasteride 2, 4, and 8 mg/kg, and flutamide 50, 100, and 200 mg/kg-, and then we cystectomized them to investigate the dose-dependent influence on bladder carcinogenesis of these drugs on week 20, and experiment 3: we investigated the presence of androgen receptors in rat and mouse normal bladder mucosa using a monoclonal antibody. RESULTS AND CONCLUSIONS: Experiment 1: Surgical castration and LH-RH agonist treatment significantly reduced the occurrence of carcinomas. There was no significant additive effect of coadministered finasteride or flutamide with LH-RH agonist. Finasteride or flutamide monotherapy showed no statistically significant effects on the results of experiment 1 at the doses used. Experiment 2: Flutamide showed a dose-dependent effect on reducing the number of rats with bladder cancer, and at a dosis of 200 mg/kg twice a week, the difference was statistically significant when compared with the control group, whereas finasteride had no statistically significant suppressing effect at any dose. Experiment 3: Mouse and rat bladder urothelium expressed the androgen receptor. Our results indicate that testosterone itself might have a more potent action on bladder carcinogenesis rather than its converting form, 5 alpha-dihydrotestosterone.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9129932&dopt=Abstract finasteride Propecia



finasteride, Propecia
Effects of finasteride, a type 2 5-alpha reductase inhibitor, on fetal development in the rhesus monkey (Macaca mulatta).

Prahalada S, Tarantal AF, Harris GS, Ellsworth KP, Clarke AP, Skiles GL, MacKenzie KI, Kruk LF, Ablin DS, Cukierski MA, Peter CP, vanZwieten MJ, Hendrickx AG.

Department of Safety Assessment, Merck Research Laboratory, West Point, Pennsylvania 19486, USA.

In genetic male fetuses, dihydrotestosterone (DHT) plays an important role in normal prostatic and external genital differentiation. The enzyme steroid 5-alpha reductase (5 alpha R) catalyzes the conversion of testosterone (T) to DHT. The importance of 5 alpha R in sexual differentiation is evident from the study of human genetic males who congenitally lack this enzyme and consequently develop ambiguous genitalia. These individuals are specifically deficient in the type 2 isozyme, whereas the normal type 1 isozyme activity has been found. The purpose of this study was to determine 1) the suitability of the rhesus monkey for testing the safety of 5 alpha R inhibitors when administered during pregnancy and 2) the potential risk of administering a known type 2 5 alpha R inhibitor, finasteride, during the critical period of internal and external genital differentiation in rhesus monkeys. In vitro studies were also performed on selected rhesus monkey tissues to determine the distribution of the 5 alpha R isozymes. Gravid monkeys were treated once daily from gestational days (GD) 20 to 100. Sonographic monitoring was performed during the course of gestation to monitor viability, growth, and organ system development. Detailed fetal evaluations for developmental abnormalities were performed at term (GD 152 +/- 2). A group of 13 pregnant monkeys ("positive control") were given a high oral dose (2 mg/kg/day) of finasteride to demonstrate that inhibiting type 2 5 alpha R results in specific external genital abnormalities in male fetuses. Thirty-two pregnant monkeys were administered an intravenous (i.v.) formulation of finasteride at doses of 8, 80, or 800 ng/day. The highest i.v. dose selected was at least 60-750 times the semen levels of finasteride in man given orally 5 or 1 mg/day, respectively. Seventeen vehicle-control pregnant monkeys were also included. Administration of a high oral dose (2 mg/kg/day) of finasteride resulted in external genital abnormalities characterized by hypospadias, preputial adhesions to the glans, a small underdeveloped scrotum, a small penis, and a prominent midline raphe in male fetuses; however, no developmental abnormalities were seen in female fetuses. Similarly, no abnormalities were observed in either male or female fetuses of mothers given iv doses (8, 80, or 800 ng/day) of finasteride during pregnancy. The in utero sonographic findings in fetuses correlated with the gross findings at term. These studies have shown that external genital abnormalities can be produced in male monkey fetuses when exposed to a high oral dose (2 mg/kg/day) of finasteride, whereas no abnormalities were observed in fetuses exposed to the i.v. formulation of finasteride. Detailed in vitro studies demonstrated that the rhesus monkey also has two 5 alpha R isozymes (types 1 and 2) with a tissue distribution similar to that seen in man and, furthermore, that finasteride is a potent, mechanism-based inhibitor with selectivity for both human and rhesus type 2 5 alpha R. These studies have demonstrated that the monkey is a suitable model for assessing the safety of 5 alpha R inhibitors administered during pregnancy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9143092&dopt=Abstract finasteride Propecia



finasteride, Propecia
Finasteride in biological fluids: extraction and separation by a graphitized carbon black cartridge and quantification by high-performance liquid chromatography.

Carlucci G, Mazzeo P.

Dipartimento di Chimica, Ingegneria Chimica e Materiali, Universita dell'Aquila, Coppito (L'Aquila), Italy.

A simple, specific and sensitive high-performance liquid chromatographic method has been developed and validated for the determination of finasteride in human plasma. A solid-phase extraction procedure was used to isolate finasteride from the biological matrix before quantitative analysis. The analyte was separated on a Symmetry reversed-phase column using acetonitrile-0.04 M orthophosphoric acid (pH 4.0) as mobile phase and quantified by measuring its UV absorbance at 215 nm. The limit of detection for the analyte was 0.005 microg/ml. 4-Androstene-3,17-dione was used as internal standard. The calibration graph of the method was linear from 0.01 to 3.0 microg/ml of finasteride in human plasma, and the coefficient of variation less than 4.5%. This HPLC procedure is simple, precise and accurate for the determination of finasteride in human plasma.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9200544&dopt=Abstract finasteride Propecia