finasteride, Propecia
Decreased gene expression of steroid 5 alpha-reductase 2 in human prostate cancer: implications for finasteride therapy of prostate carcinoma.

Luo J, Dunn TA, Ewing CM, Walsh PC, Isaacs WB.

Department of Urology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287, USA.

BACKGROUND: Steroid 5alpha-reductase 2 (SRD5A2) catalyzes the conversion of testosterone to the more potent androgen, DHT, in the prostate. The therapeutic influence of SRD5A2 inhibitor finasteride on prostate cancer is currently unknown. The direction and extent of changes in SRD5A2 expression in disease tissues is a relevant issue in this regard. METHODS: The expression differences of SRD5A2 in tissues representative of normal, benign, and malignant growth in the human prostate were examined in parallel by comparative analysis of relevant microarray gene expression data. Semiquantitative RT-PCR was used to further verify the gene expression differences of SRD5A2. RESULTS: Consistently decreased expression of SRD5A2 was observed in 25 prostate cancer samples when compared to 25 matched normal samples and nine BPH samples. Expression differences among these samples for six other genes were presented in parallel as indicators of the direction and extent of expression changes. These additional genes include SRD5A1, Hepsin (overexpressed in prostate cancer), AMACR (overexpressed in prostate cancer), Keratin 8 (epithelial marker), smooth muscle actin (stromal marker), Nell2 (overexpressed in BPH). Semiquantitative RT-PCR verified the expression differences for SRD5A2 in six normal, six BPH, and six prostate cancer samples. CONCLUSIONS: Results from this study, combined with those from previous studies, indicate an association of prostate cancer with reduced 5alpha-reductase enzymatic activity as a result of remarkably decreased expression of the SRD5A2 gene. The implications of this study for finasteride therapy of prostate cancer are discussed. Copyright 2003 Wiley-Liss, Inc.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12949937&dopt=Abstract finasteride Propecia



finasteride, Propecia
Finasteride inhibits the progesterone-induced spike-wave discharges in a genetic model of absence epilepsy.

van Luijtelaar G, Budziszewska B, Tetich M, Lason W.

NICI, Biological Psychology, University of Nijmegen, The Netherlands. luijtelaar nici.kun.nl

Previously, it was found that progesterone aggravates spike-wave discharges (SWD) in WAG/Rij rats in a nongenomic way. In order to elucidate whether the regulatory effect of progesterone depends on its conversion to allopregnanolone, the effect of finasteride, a 5alpha-reductase inhibitor, on progesterone-induced increase in SWD was studied in the same model for absence epilepsy. Progesterone (10 and 20 mg/kg ip) dose-dependently increased the number of SWD (by 54% and 97%, respectively) during the first hour postinjection. Pretreatment of rats with finasteride (50 mg/kg sc) blocked the progesterone-induced enhancement of SWD. Finasteride alone had no effect on the number of SWD, up to 24 h following its administration. It is concluded that finasteride blocked the progesterone-induced increase in SWD, which indicates that this action of progesterone is mediated by its neuroactive metabolite allopregnanolone.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12957232&dopt=Abstract finasteride Propecia



finasteride, Propecia
[Determination of finasteride in human plasma by HPLC-MS]

[Article in Chinese]

Li XY, Ding L, Li LM, Hao XY, Zhang ZX.

Department of Pharmacology, Qinghai Medical College, Xining 810001, China. qhmclxy 163.com

AIM: To develop an HPLC-MS assay for determination of finasteride in human plasma and to investigate the bioequivalence in healthy volunteers. METHODS: After alkalization with sodium hydroxide, plasma was extracted with ethyl acetate and separated using a C18 column with a mobile phase of methanol-water (85:15). LC-ESI-MS was performed in the selected ion monitoring (SIM) mode using target ions at m/z 395 for finasteride and m/z 407 for the IS. The fragmentor voltage was 120 V. A randomized crossover design was performed in 20 healthy volunteers. In the two study periods, a single 10 mg dose of each tablet was administered to each volunteer. RESULTS: Calibration curves were linear over the range 1-200 micrograms.L-1 (r = 0.9986). The limit of determination for finasteride in plasma was 0.05 microgram.L-1. The recovery of finasteride from plasma was in the range of 85.9%-98.7%. The results of variance analysis and two one-side t-test showed that there was no significant difference between the two formulations in the AUC and Cmax. CONCLUSION: The assay was proved to be sensitive, accurate and convenient. The two formulations were bioequivalent.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14513808&dopt=Abstract finasteride Propecia



finasteride, Propecia
Hormonal and morphologic evaluation of the effects of antiandrogens on the blood supply of the rat prostate.

Shibata Y, Ono Y, Kashiwagi B, Suzuki K, Fukabori Y, Honma S, Yamanaka H.

Department of Urology, Gunma University School of Medicine, Maebashi, Gunma, Japan.

OBJECTIVES: To clarify the basic aspects of the regulation of the prostatic blood supply by antiandrogens, their effect on the prostatic blood supply was studied for both androgen content and morphology of true capillaries in the rat ventral prostate. The effectiveness of antiandrogens on the control of hemorrhagic status in prostatic diseases has been previously reported. METHODS: Androgen concentrations in the prostate were quantified after administration of chlormadinone acetate (CMA), finasteride, or flutamide. The prostatic blood supplies were measured after administration of CMA, finasteride, flutamide, or bicalutamide. The alpha-blockers, terazosin and tamsulosin, were included in the study as negative controls. The histologic changes in the capillaries of the ventral prostate were observed, and the luminal area was measured. RESULTS: The prostate dihydrotestosterone concentrations were decreased by the administration of all antiandrogens. Treatment with CMA, finasteride, flutamide, or bicalutamide reduced the prostatic blood supply by 50% to 65%. The parallel reduction in luminal areas of the true capillaries was observed in rats treated with CMA. Treatment with alpha-blockers did not affect the prostate androgen content, prostatic blood supply, or capillary luminal area. CONCLUSIONS: The reduction of the prostatic blood supply was suggested to be the result of a decrease in dihydrotestosterone content and the reduction in the luminal area of capillaries. The early reductive effect of antiandrogens on the prostatic blood supply suggests an alternative use for antiandrogens independent of their typical use for prostate volume regression. The results support the basic aspects of the advantage of preoperative treatment with CMA, flutamide, and bicalutamide, similar to finasteride, in reducing perioperative hemorrhage.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14624931&dopt=Abstract finasteride Propecia



finasteride, Propecia
Dutasteride, the dual 5alpha-reductase inhibitor, inhibits androgen action and promotes cell death in the LNCaP prostate cancer cell line.

Lazier CB, Thomas LN, Douglas RC, Vessey JP, Rittmaster RS.

Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS, Canada. cblazier dal.ca

BACKGROUND: Reduction of T to DHT by 5alphaR in the prostate enhances androgenic activity for most targets. Inhibition of 5alphaR activity with finasteride attenuates androgen action in men and animal models. The objective of this study was to compare and contrast the effects of a potent new 5alphaR inhibitor, dutasteride, with finasteride in the LNCaP prostate cancer cell line. METHODS: LNCaP cells were incubated for varying times with T or DHT in steroid-free medium in the absence or presence of increasing doses of dutasteride or finasteride and the effects on 5alphaR activity, PSA accumulation in the medium, and on cell proliferation were determined. Drug effects on apoptosis were investigated using Annexin V staining and a cell death ELISA assay. Effects of the drugs on AR ligand-binding activity and on AR protein levels were determined. RESULTS: Dutasteride inhibited (3)H-T conversion to (3)H-DHT and, as anticipated, inhibited T-induced secretion of PSA and proliferation. However the drug also inhibited DHT-induced PSA secretion and cell proliferation (IC(50) approximately 1 microM). Finasteride also inhibited DHT action but was less potent than dutasteride. Dutasteride competed for binding the LNCaP cell AR with an IC(50) approximately 1.5 microM. High concentrations of dutasteride (10-50 microM), but not finasteride, in steroid-free medium, resulted in enhanced cell death, possibly by apoptosis. This was accompanied by loss of AR protein and decreased AR ligand-binding activity. Occupation of AR by R1881 partly protected against cell death and loss of AR protein. PC-3 prostate cancer cells, which do not contain AR, also were killed by high concentrations of dutasteride, as well as by 50 microM finasteride. CONCLUSIONS: Dutasteride exhibited some inhibitory actions in LNCaP cells possibly related to 5alphaR inhibition but also had antiandrogenic effects at relatively low concentrations and cell death-promoting effects at higher concentrations. Finasteride also was antiandrogenic, but less than dutasteride. The antiandrogenic effects may be mediated by the mutant LNCaP cell AR. Promotion of cell death by dutasteride can be blocked, but only in part, by androgens. Copyright 2003 Wiley-Liss, Inc.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14716738&dopt=Abstract finasteride Propecia



finasteride, Propecia
[Effects of finasteride on capillary in the ventral prostate of rat]

[Article in Chinese]

Liu XD, Li H, Bu H, Lu YP, Wei Q, Shi M, Chen ZF, Yang YR.

Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu 610041, China.

OBJECTIVE: To investigate the effects of finasteride on capillary in the ventral prostate of rat and study the mechanisms therein involved, METHODS: Male SD rats were given via gavage finasteride 40 mg/kg per day for 7 days (group B) and for 14 days (group C). The changes of capillary infused with Chinese ink were observed with the use of HE staining. Immunohistochemical (IHC) SP-method was adopted in measuring the protein expression of VEGF and eNOS in rat prostatic tissue. RESULTS: In comparison with the relevant values measured in the control group (group A), the microvessel density (MVD) values in group B and group C decreased by 35.2% and 56% respectively, the protein expression of VEGF in group B and group C decreased by 31.7% and 62.6% respectively, the protein expression of eNOS in group B and group C decreased by 15.7% and 52.5% respectively. CONCLUSION: Finasteride can inhibit the protein expression of VEGF and eNOS and thereby can suppress angiogenesis of capillary in the ventral prostate of rat.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15071924&dopt=Abstract finasteride Propecia