Systemic administration of a soluble betaglycan suppresses tumor growth, angiogenesis, and matrix metalloproteinase-9 expression in a human xenograft model of prostate cancer

BACKGROUND: Transforming growth factor beta (TGFbeta) over-expression in prostate cancer has been shown to promote tumor progression and neo-vascularization. In this study, we have investigated the efficacy and the potential mechanism of a TGFbeta antagonist, a recombinant soluble betaglycan (sBG), as a prostate cancer therapeutic agent after systemic administration in a xenograft model. METHODS: Recombinant sBG was delivered continuously via ALZET osmotic pumps or by daily bolus i.p. injection at 4.2 mg/kg/day for 14 days in human prostate cancer DU145 xenograft bearing nude mice. Tumors were analyzed for their size, blood volume by hemoglobin assay, microvessel density (MVD) by CD-31 immunostaining, and apoptosis by TUNEL assay. Matrix metalloproteinase-9 (MMP-9) activity and expression in the DU145 conditioned media were determined by gelatin zymography and Western blotting, respectively. Tissue sections were stained with a polyclonal antibody to MMP-9 using an immuno-fluorescence method. RESULTS: Continuous or bolus administration of sBG showed a similar significant inhibition of DU145 xenograft growth associated with a reduced tumor blood volume and MVD, and an enhanced intra-tumoral apoptosis. Treatment with sBG inhibited both endogenous and TGFbeta-induced MMP-9 activity and expression in a dose-dependent manner in vitro and reduced in vivo MMP-9 expression in DU145 xenografts. CONCLUSIONS: Our results for the first time indicate that TGFbeta blockade by systemic sBG administration can inhibit DU145 prostate xenograft growth and angiogenesis. The inhibition is likely in part mediated by the attenuation of TGFbeta-induced MMP-9 expression.     

基质金属蛋白酶在早期肺癌中的表达

目的 探讨早期肺癌中的基质金属蛋白酶(MMP)-9、MMP-2、MMP-7活性及与MMP抑制剂开发的关系.方法 采用明胶酶谱及酪素酶谱法测定60例Ⅰ期非小细胞肺癌(NSCLC)患者的肺肿瘤及对应正常肺组织中MMP-9、MMP-2、MMP-7的活性.结果 MMP-9活性均见于正常及癌组织中,但早期肺癌组织中的MMP-9的活性为(1189.3±537.0)灰度值,低于正常对照肺组织中(1557.7±422.5)灰度值(P<0.05).肿瘤的MMP-2的活性率(62 kDa/62 kDa+66 kDa)(45.5±8.4)%明显高于相对应的正常组织中的(25.9±10.5)%(P<0.01).阳性对照的人羊水标本在酪素酶谱凝胶上显示MMP-7约20 kDa的透明活性带,但同时肺癌及正常肺组织标本未显示出MMP-7的可检测的活性.结论 早期肺癌组织中MMP-9活性低及无明显MMP-7活性,MMP-2活性显著增高.     

Finasteride targets prostate vascularity by inducing apoptosis and inhibiting cell adhesion of benign and malignant prostate cells

BACKGROUND: This study investigated the effects of finasteride, a 5alpha-reductase inhibitor, clinically used for the treatment of benign prostatic hyperplasia (BPH) on prostate tumor vascularity, apoptosis, and cell adhesion in situ and in vitro. METHODS: Prostate specimens from BPH patients treated with finasteride for 1-12 months (n = 13), or without finasteride treatment (n = 14), were evaluated for apoptosis (TUNEL assay), microvessel density (Factor VIII), and prostate specific antigen (PSA) immunoreactivity. In vitro, the effect of finasteride was investigated in benign prostate cells, BPH-1, and its tumorigenic derivatives, CAFTD-01 and CAFTD-03, using Hoechst staining and cell adhesion assays. RESULTS: A significant increase in the apoptotic index, and reduced microvessel density and PSA expression were detected in prostates from finasteride-treated patients, compared to controls (P < 0.01). In vitro finasteride led to a significant decrease in prostate epithelial cell adhesion (P < 0.05). CONCLUSIONS: Finasteride can induce prostate apoptosis and reduce tissue vascularity by inhibiting epithelial cell adhesion. This evidence supports that finasteride has apoptotic and anti-angiogenic effects against benign and malignant prostate.     

多西环素对小鼠黑色素瘤基质金属蛋白酶-2、基质金属蛋白酶-9表达和活性的抑制作用

目的 观察多西环索对小鼠恶性黑色素瘤模型MMP-2、MMP-9表达和活性的作用.方法 C57/BL小鼠47只建立黑色素瘤模型,随机分为给药组和对照组.给药组每日腹腔注射盐酸多西环素,对照组给予等量生理盐水.7 d后处死给药组和对照组小鼠各10只.继续给药14 d后处死剩余小鼠,比较两个时间点多西环素对MMP-2、MMP-9、VEGF表达的影响.并用检测MMP.9、MMP-2酶原、活性MMP-2的活性变化.结果 多西环索给药7 d抑瘤率为52.36%,给药14 d抑瘤率为35.63%.给药组的MMP-2、MMP-9表达均低于对照组,而VEGF的表达高于对照组.给药组的MMP-9和活性MMP-2的条带酶解量以及活性MMP-2与MMP-2酶原比值均低于对照组,但两组间MMP-2酶原条带酶解量差异无统计学意义.结论 多西环素可以抑制恶性黑色素瘤小鼠移植瘤的生长,其作用机制可能和抑制MMP-2、MMP-9的表达和活性有关.     

NDRG2基因对前列腺癌细胞株PC-3M侵袭转移能力的影响

目的 观察NDRG2基因对人前列腺癌细胞株PC-3M侵袭转移能力的影响.方法 以携带人NDRG2基因的腺病毒感染体外培养的PC-3M细胞株,采用Western blot及明胶酶谱实验检测NDRG2、MMP-2、MMP-9蛋白表达情况及相关酶活性的变化.平板克隆实验、细胞生长实验检测NDRG2对PC-3M增殖能力的影响.Transwell实验检测NDRG2对PC-3M细胞体外侵袭能力的影响.结果 Ad-NDRG2感染后,PC-3M细胞中NDRG2表达明显增加,而MMP-2和MMP-9表达水平及活性均降低.噻唑蓝(MTT)比色法(抑制率24 h为16.2%、48 h为24.4%、72 h为43.7%)及平板克隆实验(3组分别为56.3%、55.2%和36.7%)显示NDRG2对PC-3M细胞的生长有明显抑制作用.Transwell显示对照组及Ad-LacZ组穿入下室面的细胞数明显多于Ad-NDRG2组(3组分别为93.0、94.8和50.4).结论 NDRG2对人前列腺癌PC-3M细胞株侵袭能力有明显抑制作用,提示NDRG2可能在前列腺癌的侵袭及转移中发挥重要作用.

Abstract：

Objective To investigate the effect of NDRG2 gene expression on the cell migration and invasion of human prostate cancer cell line PC-3M.Methods Recombinant adenovirus vectors carrying human NDRG2 gene (Ad-NDRG2) were infected into prostate cancer cell line PC-3M.The protein expression and enzymatic activities of NDRG2,MMP-2 and MMP-9 were determined by Western blotting and gelatin zymography respectively.Methylthiazol tetrazolium (MTT) assay and plate colony formation were used to determine the effect of proliferation of PC-3M cells.Invasion of PC-3M cells was measured by Transwell chamber assay.Results After infection by Ad-NDRG2,it had been verified that the protein expression of NDRG2 in PC-3M cells was obviously increased,and the expression and enzymatic activities of MMP-2 and MMP-9 were reduced.The MTT assay (inhibition ratio: 24 h,16.2%,48 h,24.4%,and 72 h,43.7% respectively) and plate colony formation (56.3%,55.2% and 36.7% in control group,Ad-LacZ group and Ad-NDGR2 group respectively) revealed that NDRG2 could significantly inhibit the growth and proliferation of PC-3M cells.The number of PC-3M cells that invaded the lower chamber in the Ad-NDRG2 group was significantly decreased as compared with the control group and the Ad-LacZ group (93.0,94.8 and 50.4 respectively).Conclusion NDRG2 gene can significantly inhibit invasion of the PC-3M cells,which may paly an important role in metastasis of prostate cancer.     

Multicenter, randomized, double-blind, placebo controlled study to investigate the effect of finasteride (MK-906) on stage D prostate cancer.

A total of 28 untreated patients with asymptomatic, stage D prostate cancer was randomized in a double-blinded fashion to receive finasteride (10 mg. per day), a 5 alpha-reductase inhibitor or placebo. Patients were evaluated at 3-week intervals by rectal examination, and serum prostate specific antigen (PSA) and prostatic acid phosphatase (PAP) levels, and at 6-week intervals by bone scan and transrectal ultrasound determinations of prostatic volume. Patients stopped the medication at week 6 at the discretion of the investigator when PSA levels increased from baseline. After 12 weeks all patients were reevaluated. Of the patients 13 received finasteride and 15 received placebo. The 2 groups did not differ statistically with respect to patient age, initial PSA and PAP level, or the extent of metastases on initial bone scan. A statistically significant decrease in the median percentage change from baseline in PSA at weeks 3 and 6 occurred in the finasteride group compared to the placebo group (-22.9% versus -2.9% and -15.1% versus +11.7%, respectively, p less than 0.05). Finasteride had no effect upon PAP, serum testosterone, prostatic volume or appearance of bone scans. A decrease in serum PSA in the finasteride treatment group suggests that finasteride exerts a minor effect in patients with prostate cancer. This effect does not approach that seen with medical or surgical castration yet because of the potency preserving feature and the lack of toxicity finasteride may warrant further study in the treatment of prostate cancer.     

Antagonistic effect of Lepidium meyenii (red maca) on prostatic hyperplasia in adult mice

The plants from the Lepidium gender have demonstrated to have effect on the size of the prostate. Lepidium meyenii (Maca) is a Peruvian plant that grows exclusively over 4000 m above sea level. The present study was designed to determine the effect of red maca (RM) in the prostate hyperplasia induced with testosterone enanthate (TE) in adult mice. Prostate hyperplasia was induced by administering TE, and then these animals ( n  = 6, each group) were treated with RM or Finasteride (positive control) for 21 days. There was an additional group without prostate hyperplasia (vehicle). Mice were killed on days 7, 14 and 21 after treatment with RM. Testosterone and oestradiol levels were measured on the last day of treatment. Prostatic stroma, epithelium and acini were measured histologically. RM reduced prostate weight at 21 days of treatment. Weights of seminal vesicles, testis and epididymis were not affected by RM treatment. The reduction in prostate size by RM was 1.59 times. Histological analysis showed that TE increased 2-fold the acinar area, effect prevented in the groups receiving TE + RM for 14 ( P  < 0.05) and 21 ( P  < 0.05) days and the group receiving TE + Finasteride for 21 days ( P  < 0.05). TE increased prostatic stroma area and this effect was prevented by treatment with RM since 7 days of treatment or Finasteride. The reduction in prostatic stroma area by RM was 1.42 times. RM has an anti-hyperplastic effect on the prostate of adult mice when hyperplasia was induced with TE acting first at prostatic stromal level.     

Expression of MMP-9 in mesangial cells and its changes in anti-GBM glomerulonephritis in WKY rats

Background Matrix metalloproteinase (MMP)-9, a member of the MMP family with specificity towards type IV collagen, is implicated in the turnover of the extracellular matrix in the kidney. To elucidate its physiological and pathophysiological significance, we examined the expression and localization of MMP-9 in the normal kidney and the changes in these features during the course of anti-glomerular basement membrane (GBM) glomerulonephritis induced in WKY rats, along with the changes in these features of tissue inhibitor of metalloproteinase 1 (TIMP-1) and MMP-2.Methods The expression of MMP-9, TIMP-1 and MMP-2 mRNA was quantified by ribonuclease protection assay, and the gelatinolytic activities of MMP-9 and MMP-2 were evaluated by gelatin zymography. The localization of MMP-9 was visualized by immunohistochemistry and immunofluorescence microscopy.Results The ribonuclease protection assay indicated the almost exclusive expression of MMP-9 mRNA in the glomerulus of normal kidneys. Immunohistochemistry and double-label immunofluorescence microscopy showed that MMP-9 was localized in the mesangial cells. During the course of anti-GBM glomerulonephritis, the expression of MMP-9 mRNA in glomeruli increased on day 1, peaked on days 3 to 7, and then decreased on day 14. The change in MMP-9 mRNA expression was accompanied by parallel changes in the gelatinolytic activity of the active form of MMP-9, TIMP-1 mRNA expression, and MMP-9 immunoreactivity in mesangial cells. In contrast, glomerular MMP-2 mRNA expression and its activity increased after the decline of MMP-9.Conclusions MMP-9 mRNA was predominantly expressed in the glomerulus in normal rat kidneys and MMP-9 was present in the mesangium. The MMP-9 mRNA expression increased in the glomerulus 3 to 7 days after the induction of anti-GBM glomerulonephritis in WKY rats, in parallel with the development of abnormal glomerular histology and injury, suggesting a role of MMP-9 in proteolysis of the GBM during glomerulonephritis. MMP-2 may participate in the later phase of the nephritis.     

Plasma matrix metalloproteinase 9 as biomarker of prostate cancer progression in Dunning (Copenhagen) rats

BACKGROUND: Matrix metalloproteinases (MMPs) play an important role in invasion and metastatic spread of cancer cells. The objective of this study was to assess MMPs in plasma of Dunning tumor rats as indicators of the progression of prostate cancer and follow-up parameters after treatment. METHODS: Prostate cancer was induced in male Copenhagen rats by either subcutaneous or orthotopic implantation of R3327-MatLyLu cells. During the development of the tumor, plasma MMP-2, and MMP-9 were measured by gelatin-substrate zymography and Western blot technique with densitometry in untreated animals, rats treated with laser-induced hyperthermia, or with the new synthetic MMP inhibitor RO 28-2653. RESULTS: Normal prostatic tissue of the Copenhagen rats predominantly expressed proMMP-2 but not proMMP-9 whereas MMP-9 was only found in cancerous tissue. Elevated plasma MMP-9 values were demonstrated in rats with subcutaneous or orthotopic tumors. Animals with tumors and treated with the MMP inhibitor RO 28-2653 had both a lower tumor volume and a lower plasma MMP-9 concentration compared with controls. CONCLUSIONS: The determination of plasma MMP-9 in Dunning tumor rats is a useful tool to monitor the progression of prostate cancer and to assess the efficacy of drugs like MMP inhibitors or other treatment protocols.     

Different mRNA and protein expression of matrix metalloproteinases 2 and 9 and tissue inhibitor of metalloproteinases 1 in benign and malignant prostate tissue

OBJECTIVE: The aim of this study was to assess the behavior of the matrix metalloproteinases (MMPs) 2 and 9 and the tissue inhibitor of metalloproteinases 1 (TIMP-1) in human prostate cancer. METHODS: mRNA and protein expression patterns of MMP-2, MMP-9, and TIMP-1 were studied in cancerous and noncancerous parts of 17 prostates removed by radical prostatectomy. Competitive RT-PCR, gelatin-substrate zymography, and ELISA techniques were used for quantification. RESULTS: On the mRNA level, MMP-2 expression was decreased and MMP-9, TIMP-1, the ratios of MMP-2 and MMP-9 to TIMP-1 were unchanged in cancerous tissue compared to the normal counterparts. On the protein level, expression of MMP-9 was significantly higher and TIMP-1 expression was significantly lower, MMP-2 was unchanged and the ratios of MMP-2 and MMP-9 to TIMP-1 were increased in tumor tissue. CONCLUSIONS: The higher concentration of MMP-9 as well as the increased ratios of MMP-2 and MMP-9 to TIMP-1 in malignant tissue prove the proteolytic dysbalance in prostate cancer, which does not seem to be associated with the stage and grade of the tumor. Comparison of mRNA and protein expression of MMP-2, MMP-9 and TIMP-1, respectively, did not show any significant relationships illustrating the necessity to study these components at both molecular levels.     

The effects of curcumin on the invasiveness of prostate cancer in vitro and in vivo

Curcumin has become a focus of interest with regard to its antitumor effects in prostate cancer; however, the effects of this agent on invasion and metastasis remain less well understood. Matrix metalloproteinases (MMPs) are important prerequisite for tumor invasion and metastasis. In this study, we evaluated the effects of curcumin on prostate cancer cells (DU-145) invasion in both in vitro and in vivo. We utilized zymography and ELISA in order to determine the MMP-2 and MMP-9 activity. Matrigel invasion assay was performed to assess cellular invasion. We developed a xenograft model to examine tumorigenicity. Curcumin treatment resulted not only in a significant reduction in the expression of MMP-2 and MMP-9, but also effected the inhibition of invasive ability in vitro. Curcumin was shown to induce a marked reduction of tumor volume, MMP-2, and MMP-9 activity in the tumor-bearing site. The metastatic nodules in vivo were significantly fewer in the curcumin-treated group than untreated group. Curcumin appears to constitute a potential agent for the prevention of cancer progression, or at least of the initial phase of metastasis, in prostate cancer.     

Noninvasive diagnosis of bladder cancer by detection of matrix metalloproteinases (MMP-2 and MMP-9) and their inhibitor (TIMP-2) in urine

OBJECTIVES: TIMPs control the activity of MMPs, one of the key molecules for tumor invasion and metastasis. The aim of this study was to assess the usefulness of MMP-2 and MMP-9 in relation to their inhibitor (TIMP2) as noninvasive diagnostic tests for bilharzial bladder cancer. MATERIAL AND METHODS: Voided urine samples were provided from 244 subjects (154 bladder cancer [136 bilharzial]; 60 benign urologic disorders; 30 healthy volunteers). Urine sediment was used for cytology, and the supernatant for estimation of MMPs and TIMP-2 by ELISA and gelatin zymography. RESULTS: The best cut-off values for the investigated markers were determined by ROC curve. Positivity rates and median levels for MMP-2, MMP-9, TIMP-2, MMP-2/TIMP-2, and MMP-9/TIMP-2 showed significant difference among the three investigated groups (p<0.001). MMP-9 and MMP-2/TIMP-2 were related to pathologic type, MMP-2/TIMP-2 was inversely related to the grade, and MMP-9/TIMP-2 was related to bilharziasis (p<0.05). MMP zymography results were comparable to those from ELISA. CONCLUSION: The sensitivity and specificity of MMP zymography, MMP-9/TIMP-2 ratio, and MMP-2/TIMP2 ratio were superior among all investigated parameters; furthermore, combined testing of cytology with them improves the sensitivity even in superficial and low-grade tumors.     

Terazosin modifies the content of glycosaminoglycans and the activity of matrix metalloproteinase 2 in the rat ventral prostate

OBJECTIVES: We have investigated the effects of terazosin on the content of glycosaminoglycans (GAGs), the activity of matrix metalloproteinase 2 (MMP-2) and MMP-9, and the content of tissue inhibitors of MMP (TIMP) in the ventral prostate of Wistar rats. METHODS: Rats were treated with terazosin (0.12, 1.2mg/kg orally every second day) for 120 d. GAGs were isolated and purified from ventral prostate homogenates by lipid extraction, ethanol precipitation, and extensive digestion with pronase and DNAse, separated by electrophoresis, and characterised using specific enzymes. The activity of MMP-2 and MMP-9 was estimated using gelatin zymography and TIMP-1 and TIMP-2 were measured by enzyme-linked immunosorbent assay. RESULTS: Terazosin treatment did not affect the weight of the ventral prostate gland. The prostate contains hyaluronic acid, chondroitin sulfate (CS), dermatan sulfate (DS), and heparan sulfate (HS), MMP-2, TIMP-1, and TIMP-2, but not MMP-9. Terazosin caused a significant increase in the relative content of DS and a significant decrease in the relative content of CS and to a lesser extent of HS. Terazosin evoked a significant increase in the activity of proMMP-2 and MMP-2 but did not affect TIMP. CONCLUSIONS: The differential effect of terazosin treatment in GAG molecules of the rat prostate may be beneficial because CS is known to induce and DS to inhibit cell proliferation. The effect of terazosin on GAGs and MMP-2 may contribute in the molecular mechanisms of terazosin-induced apoptosis because HS and CS have a proapoptotic effect, whereas DS and MMP-2 are antiapoptotic.     

Combined finasteride and flutamide therapy in men with advanced prostate cancer

Objectives

To evaluate the efficacy of combined finasteride and flutamide therapy in men with advanced prostate cancer by determining (1 ) the short-term tolerability of finasteride monotherapy and its effect on serum prostate-specific antigen (PSA) and hormone (testosterone, dihydrotestosterone) levels, and (2) the effects of the addition of flutamide on tolerability and on serum PSA and hormone levels.

Methods

Thirteen hormone-naive men with advanced prostate cancer (4 with Stage D2, 1 with Stage D1, 1 with Stage DO, 7 with rising PSA levels after radical prostatectomy [n = 2]or definitive radiation therapy [n = 5]) were initially treated with 5 mg finasteride daily. Flutamide (250 mg three times a day) was added after serum PSA levels stabilized.

Results

Finasteride alone (median 5 weeks) had no significant effect on serum PSA levels (P>0.05). Combined finasteride and flutamide resulted in a mean 91% reduction in serum PSA levels, with 85% of men achieving a nadir serum PSA level of less than 4.0 ng/mL and 46% achieving undetectable levels (0.2 ng/mL or less). Finasteride alone had no significant effect on serum testosterone levels (P>0.05) but did result in a mean 74% reduction in serum dihydrotestosterone levels. Combined finasteride and flutamide resulted in a mean 56% increase in serum testosterone levels but had no additional effect on serum dihydrotestosterone levels (P>0.05). Side effects occurred in 85% (gynecomastia or breast tenderness in 62% [8 of 13]and diarrhea in 23% [3 of 13]) of men on combined therapy. Potency was preserved in 66%. Combined finasteride and flutamide therapy was withdrawn from 15% (2 of 13) because of flutamide-induced diarrhea and from 23% (3 of 13) because of disease progression. All remaining patients (8 of 13) have serum PSA levels below 4.0 ng/mL and 4 of these 8 have undetectable levels. These men have received combined finasteride and flutamide for a median 11 months (range 6 to 19).

Conclusions

Finasteride monotherapy is inadequate therapy for advanced prostate cancer, but combined finasteride and flutamide may be a reasonable alternative for men with advanced prostate cancer who refuse conventional hormone therapy.     

Characterization of expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in prostate cancer cell lines

Stromal expression of some matrix metalloproteinases (MMPs) has been associated with increasing tumour burden in prostate cancer. We investigated the expression of mRNA (by RT-PCR) and protein (by zymography and western blotting) of MMPs and endogenous inhibitors (tissue inhibitors of metalloproteinases, TIMPs) in two parent epithelial prostate cancer cell lines and sublines of increasing invasive/metastatic potential. Expression of membrane type MMPs, MT1-MMP and MT3-MMP mRNA was higher in PC3-derived than in LNCaP-derived lines, whereas MT2-MMP mRNA expression was higher in the LNCaPderived than in PC3-derived cell lines. Active MT1, MT2 and MT3-MMP protein levels were similar in all lines, but processed MT-MMPs, indicative of latent MMP activation, were increased in more aggressive sublines. Expression of MMP-1, MMP-13 and TIMP-1 was higher in the more aggressive sublines and may be implicated in invasive/metastatic ability. Regulation of MMP-1 and MMP-13 expression may offer important therapeutic options for treating patients with prostate cancer.     

Prostate Tissue Composition and Response to Finasteride in Men With Symptomatic Benign Prostatic Hyperplasia

Purpose

We sought to quantify prostate tissue changes induced by finasteride and to identify a predictor of finasteride response in men with symptomatic benign prostatic hyperplasia (BPH) via a randomized, placebo controlled, double-blind clinical trial.

Materials and Methods

Men with symptomatic BPH (52 to 78 years old) were randomly assigned to 6 months of treatment with finasteride (26) or placebo (15). Outcome measures were clinical (urinary symptom score and flow rate), chemical (serum prostate specific antigen and dihydrotestosterone levels), volumetric (transrectal ultrasound, and magnetic resonance imaging for whole and zonal prostate volumes) and histological (morphometry of prostate sextant biopsies, separated into inner and outer gland segments, to measure the percent epithelium, stroma and glandular lumen).

Results

In the finasteride group we found a suggestion of decreasing symptom scores and increasing flow rates (not significant) with significant decreases (p <0.01) in prostate specific antigen (48%), dihydrotestosterone (74%) and prostate volume (21%). Finasteride treatment induced a 55% decrease in inner gland epithelium (p <0.01) with little effect on stroma or lumina. We also found a linear correlation between pretreatment inner gland epithelial content and prostate volume decrease induced by the drug (tau = 0.58, p = 0.01).

Conclusions

Finasteride treatment results in a major suppression of prostate epithelium, which is most pronounced in the inner gland. Moreover, a finasteride induced prostate volume decrease was predictable by quantification of epithelial tissues of the inner gland. These data lend additional support to the emerging concept of transition zone primacy in symptomatic BPH.     

Finasteride decreases the risk of prostatic intraepithelial neoplasia

PURPOSE: High grade prostatic intraepithelial neoplasia is likely a premalignant lesion of the prostate. Decreasing the frequency of high grade PIN may decrease the risk of prostate cancer. In the Prostate Cancer Prevention Trial we evaluated the impact of finasteride on the risk of a needle biopsy diagnosis of high grade prostatic intraepithelial neoplasia. MATERIALS AND METHODS: The Prostate Cancer Prevention Trial was a randomized, placebo controlled clinical trial that enrolled 18,882 men without evidence of prostate cancer, prostate specific antigen less than 3.0 ng/ml and normal digital rectal examination, and randomized them to 5 mg finasteride daily or placebo. Subjects were followed for 7 years with biopsy recommended for prostate specific antigen greater than 4.0 ng/ml, adjusted in the finasteride group to achieve an equal number of biopsy recommendations or for abnormal digital rectal examination. All cancer-free subjects were recommended to undergo biopsy after 7 years on study. We evaluated the diagnosis of high grade prostatic intraepithelial neoplasia with or without concomitant prostate cancer in these 2 study groups. RESULTS: The number of men evaluable for high grade prostatic intraepithelial neoplasia was 4,568 in the finasteride group and 4,886 in the placebo group. High grade prostatic intraepithelial neoplasia alone was diagnosed in 276 men (6.0%) in the finasteride group vs 347 (7.1%) in the placebo group (RR 0.85, 95% CI 0.73-0.99, p=0.04). High grade prostatic intraepithelial neoplasia accompanied by prostate cancer was diagnosed in 144 men (3.2%) in the finasteride group vs 223 (4.6%) in the placebo group (RR 0.69, 95% CI 0.56-0.85, p=0.0004). Finasteride significantly decreased the overall risk of high grade prostatic intraepithelial neoplasia (alone and with cancer) from 570 cases (11.7%) in the placebo group to 420 (9.2%) in the finasteride group (HR 0.79, 95% CI 0.70-0.89, p<0.001). CONCLUSIONS: Finasteride significantly decreased the risk of high grade PIN. This observation may explain how finasteride decreased prostate cancer in the Prostate Cancer Prevention Trial, supporting the notion that high grade prostatic intraepithelial neoplasia is a premalignant lesion of the prostate, and it provides new information relevant to the consideration of finasteride for prostate cancer prevention.     

前列腺增生治疗药物对前列腺癌发病率及病理分级的影响

目的 评估前列腺增生治疗药物对前列腺癌发病率及病理分级的影响.方法 回顾性调查1998年2月至2004年12月1029例前列腺增生症患者的药物治疗史,根据药物治疗史将患者分为非那雄胺组、α-受体阻滞剂组、非那雄胺加任一种α-受体阻滞剂联合用药组、对照组(未治疗组)4组.收集4组患者的穿刺病理资料,重新阅读病理片,进行Gleason评分.用Stata 7.0统计软件对4组患者前列腺癌发病率及前列腺癌病理分级差异进行分析.结果 前列腺癌总发病率为13.5%;非那雄胺组、α-受体阻滞剂组、联合治疗组、对照组发病率分别为9.8%、16.0%、10.3%、18.6%;4组间发病率比较应用非那雄胺的丙组与未应用非那雄胺的两组比较差异有统计学意义(P<0.05);前列腺癌患者中病理分级为中高级(Gleason≥7分)的占58.3%,中高分级前列腺癌在4组前列腺癌患者中分别占71.4%、59.6%、67.7%和40.0%.4组间中高分级前列腺癌构成比比较,应用非那雄胺组与未应用非那雄胺组差异有统计学意义(P<0.05).结论 非那雄胺治疗前列腺增生症能降低前列腺癌的发病风险,但同时能使发生的前列腺癌的病理级别增高;α-受体阻滞剂没有类似作用.