5α-Reductase Type 1 Immunostaining is Enhanced in Some Prostate Cancers Compared With Benign Prostatic Hyperplasia Epithelium

Thomas, Lynn N.; Douglas, Robert G.; Vessey, John P.; Gupta, R.; Fontaine, Dorrie K.; Norman, Richard W.; Thompson, Ian M.; Troyer, Dean A.; Rittmaster, Roger S.; Lazier, Catherine B.

doi:10.1097/01.ju.0000091804.20183.81

Cited by 75 publications

(40 citation statements)

References 18 publications

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“…Thigpen et al (24) showed that steroid 5a-reductase isozyme II is the predominant isoform in prostate tissue. Recent evidence supports increased isozyme I expression in prostate cancer (25) and recurrent prostate cancer (26). Catalytic activity at 50% maximal rate requires higher substrate concentration (testosterone) for steroid 5a-reductase isozyme I than isozyme II (27).…”

Section: Discussionmentioning

confidence: 99%

Testosterone and Dihydrotestosterone Tissue Levels in Recurrent Prostate Cancer

Titus

Schell

Lih

et al. 2005

Clinical Cancer Research

463

330

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Purpose: Prostate cancer eventually recurs during androgen deprivation therapy despite castrate levels of serum androgens. Expression of androgen receptor and androgen receptor^regulated proteins suggests androgen receptor activation in recurrent prostate cancer. Many groups have pursued mechanisms of ligand-independent androgen receptor activation but we found high levels of testicular androgens in recurrent prostate cancer tissue using RIA. Experimental Designs: Prostate specimens from 36 men were procured preserving blood flow to prevent ischemia and cyropreserved immediately. Recurrent prostate cancer specimens from18 men whose cancer recurred locally during androgen deprivation therapy and androgen-stimulated benign prostate specimens from 18 men receiving no hormonal treatments were studied. Tissue levels of testosterone and dihydrotestosterone were measured in each specimen using liquid chromatography/electrospray tandem mass spectrometry.Testosterone and dihydrotestosterone levels were compared with clinical variables and treatment received. Results: Testosterone levels were similar in recurrent prostate cancer (3.75 pmol/g tissue) and androgen-stimulated benign prostate (2.75 pmol/g tissue,Wilcoxon two-sided, P = 0.30). Dihydrotestosterone levels decreased 91% in recurrent prostate cancer (1.25 pmol/g tissue) compared with androgen-stimulated benign prostate (13.7 pmol/g tissue; Wilcoxon two-sided, P < 0.0001) although dihydrotestosterone levels in most specimens of recurrent prostate cancer were sufficient for androgen receptor activation.Testosterone or dihydrotestosterone levels were not related to metastatic status, antiandrogen treatment, or survival (Wilcoxon rank sum, all P > 0.2).Conclusions: Recurrent prostate cancer may develop the capacity to biosynthesize testicular androgens from adrenal androgens or cholesterol. This surprising finding suggests intracrine production of dihydrotestosterone and should be exploited for novel treatment of recurrent prostate cancer.Prostate cancer recurs in almost all men receiving androgen deprivation therapy (ADT) and is the main cause of death in prostate cancer. Recurrent prostate cancer retains androgen receptor protein expression, with androgen receptor remaining active in growth signaling despite castrate levels of circulating androgens (1). Androgen receptor protein and androgen receptor -regulated proteins are expressed in prostate cancer that recurs during ADT in both the primary (2 -5) and bone metastases (6, 7). Androgen receptor activation in recurrent prostate cancer may occur by a variety of mechanisms that alter the sensitivity (8 -10) or specificity (11) of androgen receptor (reviewed in refs. 12 -14). Recent studies using androgenindependent prostate cancer cell lines (8, 9) and xenografts (9) showed that androgen receptor overexpression allowed recurrent prostate cancer growth in the presence of castrate levels of circulating androgens. However, androgen receptor mutations that prevented ligand-binding prevented recurrent growth; ove...

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Section: Discussionmentioning

confidence: 99%

Testosterone and Dihydrotestosterone Tissue Levels in Recurrent Prostate Cancer

Titus

Schell

Lih

et al. 2005

Clinical Cancer Research

463

330

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“…Previously published reports 5,22 have demonstrated decreased expression of 5 ␣-reductase type II in prostate cancer specimens by microarray, reverse transcriptase-PCR analysis, 5 and immunostaining. 22 Thomas et al 23 demonstrated high immunoreactivity for 5 ␣-reductase Type I in 28% of prostate tumor epithelia specimens. Differences in the expression of 5 ␣-reductase isoenzymes in our samples also may reflect the primary nature of the model used.…”

Section: 12mentioning

confidence: 99%

Effects of the dual 5 α‐reductase inhibitor dutasteride on apoptosis in primary cultures of prostate cancer epithelial cells and cell lines

McCrohan

Morrissey

O’Keane

et al. 2006

Cancer

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BACKGROUNDThe profound reduction in serum dihydrotestosterone (DHT) observed with the dual 5 α‐reductase inhibitor (5ARI) dutasteride makes it an attractive agent for prostate cancer therapy. The objective of the current study was to determine whether dutasteride would induce apoptosis in a range of prostate epithelial cell lines and primary cultures.METHODSBoth human prostate androgen‐sensitive cell lines (PwR‐1E, PNT‐2, LNCaP, and PC3[AR2]) and an androgen‐independent cell line (PC‐3) were grown to confluence. Primary epithelial cells extracted from fresh prostate cancer radical prostatectomy specimens also were grown to confluence under optimal conditions. Total cellular protein was extracted to confirm cytokeratin 18 and antihuman α‐methylacyl‐CoA racemase (AMACR) expression of the primary cells. Apoptosis was assessed by propidium iodide DNA staining and flow cytometry after 24 hours of culture in from 0 μM to 10 μM of dutasteride.RESULTSDutasteride induced a dose‐dependent increase in apoptosis in the androgen‐sensitive prostate cell lines PwR‐1E, PNT‐2, and LNCaP and in the androgen receptor‐expressing PC3(AR2) cell line. However, there was no significant apoptosis noted in the parental PC‐3 cells. Of 16 primary epithelial cultures that were treated, 7 cultures were induced to undergo apoptosis, and 9 cultures were unresponsive. All primary cultures were positive for cytokeratin 18 expression, confirming their epithelial phenotype. Responder epithelial cells were positive for AMACR expression.CONCLUSIONSThe results of the current study confirmed that dutasteride differentially induced apoptosis in a subset of prostate cell lines and primary prostate epithelial cells. Understanding the cellular phenotype may indicate susceptible cells. Cancer 2006. © 2006 American Cancer Society.

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“…The cancer specimen showed 5a-R1 staining in the epithelium in 81% (high intensity in 28%) and in the stroma in 92% (high intensity in 21%). Thomas et al 8 suggested that 5a-R1 is of greater importance in promoting and maintaining prostate cancer as compared to 5a-R2. In an extension of this work, Thomas et al 9 found that 5a-R1 moderate plus high intensity immunostaining was augmented from 4.8% of total epithelial area in BPH to 17% in primary over 38% in recurrent, and 55.8% in metastases of prostate cancer, whereas 5a-R2 showed varying responses.…”

Section: Methodsmentioning

confidence: 99%

“…Both 5a-R isoforms are increased in 'androgen-independent' cancer which may reflect an adaptive or selective mechanism to amplify any remaining androgen signal. 8 The application of inhibitors of the 5a-R1 and 5a-R2 isoforms in cultures of primary prostate cancer decreased the cell proliferation dose-dependently through auto-or paracrine mechanisms. 53 When patients are treated with Dutasteride 6-10 weeks before radical prostatectomy the intraprostatic DHT 5a-Reductase inhibitor treatment J Dörsam and J Altwein was reduced by 97% and apoptosis was augmented possibly indicating tumor regression.…”

Section: Chemoprevention Of Prostate Cancermentioning

confidence: 99%

5α-Reductase inhibitor treatment of prostatic diseases: background and practical implications

Dörsam¹,

Altwein

2008

Prostate Cancer Prostatic Dis

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This literature review discusses the theoretical background of 5a-reductase inhibitor (5ARI) treatment and the resulting clinical implications. A Medline-based search for peer-reviewed articles addressing 5ARIs, benign prostatic hyperplasia and prostate cancer was performed. The 5ARIs Finasteride and Dutasteride, which specifically inhibit the production of dihydrotestosterone by acting as competitive inhibitors of 5a-reductase, are clinically well tolerated and represent an effective treatment option for benign prostatic obstruction. Finasteride is the first compound which has a proven efficacy in chemoprevention of prostate cancer. The aim of this review was to elucidate, if there are sufficient data available to point out clinically relevant differences between the drugs. Both compounds achieve a significant reduction of prostate volume, an improvement of symptoms and a lower risk of acute urinary retention. Whether the different pharmacokinetic and pharmacodynamic properties of Finasteride and Dutasteride are of clinical importance cannot be judged at this time.

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5α-Reductase Type 1 Immunostaining is Enhanced in Some Prostate Cancers Compared With Benign Prostatic Hyperplasia Epithelium

Abstract: The presence of increased 5alphaR1 in some prostatic malignancies suggests that it is worthwhile to investigate the use of a dual 5alphaR inhibitor to prevent or treat early stage prostate cancer.

Cited by 75 publications

References 18 publications

Testosterone and Dihydrotestosterone Tissue Levels in Recurrent Prostate Cancer

Testosterone and Dihydrotestosterone Tissue Levels in Recurrent Prostate Cancer

Effects of the dual 5 α‐reductase inhibitor dutasteride on apoptosis in primary cultures of prostate cancer epithelial cells and cell lines

5α-Reductase inhibitor treatment of prostatic diseases: background and practical implications

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