Finasteride treatment alters MMP-2 and -9 gene expression and activity in the rat ventral prostate

The safety of using finasteride as a prevention of prostate cancer is still under debate. In this study, we investigated the effects of finasteride on the location, gene expression and activities of matrix metalloproteinases -2 and -9, which are involved in the degradation of extracellular matrix components during tissue remodelling and prostate cancer progression, invasion and metastasis. Ventral prostates (VP) from Wistar rats treated with finasteride (25 mg/kg/day) for 7 and 30 days and age-matched controls were evaluated using histology, immunohistochemistry, semi-quantitative RT-PCR and gelatin zymography. Finasteride treatment reduced the epithelial immunostaining of MMP-2 but increased MMP-9 immunostaining in the epithelial cells and in the stroma. The mRNA expression of both MMP-2 and MMP-9 were significantly increased on day 7 of finasteride treatment, mainly for MMP-9 and returned to the control levels by day 30. However, gelatin zymography showed that MMP-9 activity was significantly increased on day 7 of finasteride treatment and remained elevated on day 30 ( p  < 0.05), while MMP-2 activity was reduced after 30 days of treatment. Finasteride increases MMP-9 and reduces MMP-2 activities in the prostate, which may affect negatively and positively both normal and tumoural prostatic cell behaviour during the treatment. Studies on expression of MMPs in the prostate during different androgen manipulation or cancer chemoprevention strategies can contribute to understand the tissue's overall response and clinical data.     

Castration rapidly results in a major reduction in epithelial cell numbers in the rat prostate,but not in the highly differentiated dunning R3327 prostatic adenocarcinoma

Rats with implanted highly differentiated Dunning R3327PAP prostatic tumors were castrated, and at 3, 7, and 14 days thereafter, the effects on tumor volume, epithelial cell numbers, and sizes were quantified using morphometrical methods. The castration response on these parameters was also examined in the normal prostate of the same rats. Castration resulted in a rapid decrease in organ volume, epithelial cell number, and size in the normal prostate, and morphological signs of epithelial cell death (apoptosis) were observed. Tumor growth and mitotic index were reduced, but there were no signs of increased apoptosis, and cell numbers remained fairly constant in the Dunning tumors during the study period. It is concluded that the castration-induced inhibition of tumor growth is caused by factors other than tumor cell death. © 1993 Wiley-Liss. Inc.     

Apoptosis related gene products in differentiated and tumorigenic rat Leydig cells and following regression induced by the cytotoxin ethane dimethanesulphonate

Androgen secreting Leydig cells in the adult are differentiated with a very low turnover, however, Leydig cell tumours can arise spontaneously or after treatment with toxins. This study in the rat investigated whether changes in components of programmed cell death could be involved. In contrast to their absence in differentiated Leydig cells, antiapoptotic Bcl-2 and proapoptotic Bax were expressed in tumours. Bak and Bcl-xl were found in both tumour and normal Leydig cells. Apoptosis was induced in subcutaneous implants of Leydig cell tumour by ethane dimethanesulphonate (EDS) which is known to kill differentiated Leydig cells. The marked regression of the tumour following EDS treatment was transient and re-growth occurred between 6 and 14 days later. Tumour regression and growth was associated with a similar weight pattern in the seminal vesicles caused by changes in serum testosterone. During tumour regression, clusterin and Bax proteins were elevated but Bak, Bcl-xl and Bcl-2 were unchanged. Fas-R, Fas-L and Bax were upregulated after tumour regression had taken place. These data show that Leydig cell tumours possess many of the apoptosis related gene products and can die by apoptosis, however, regulation is clearly different in differentiated and mitotic Leydig cells.     

Influence of diethylstilbestrol,leuprolelin (a luteinizing hormone-releasing hormone analog), finasteride (a 5α-reductase inhibitor), and castration on the lobar subdivisions of the rat prostate

The effects of various means of interfering with androgen action on rat coagulating gland, ventral prostate, lateral type 1 prostate, lateral type 2 prostate, and dorsal prostate were examined morphologically and quantitatively by assessing DNA content, wet weight, protein content, and zinc concentrations. Adult male Sprague-Dawley rats were subjected to 2 weeks of interfering with androgen action by treatment with Leuprolelin (a luteinizing hormone-releasing hormone analog), Finasteride (a 5α-reductase inhibitor), or diethylstilbestrol (DES), or by physical castration. For all prostatic lobes, inhibition of 5α-reductase elicited the smallest reduction in prostatic wet weight, DNA and protein contents, and zinc concentration. The most profound reductions in all parameters were elicited by castration. Treatments with DES and Leuprolelin gave intermediate effects with DES being the more effective in reducing all parameters in all prostatic lobes. Morphological changes elicited by all forms of androgen blockade were reduction of epithelial height, relative increase of connective tissue, reduction in ductal diameter, length, and number. The order of effectiveness of the various treatments on morphological features was as described above. While all forms of androgen blockade elicited similar effects throughout the prostate, differences in response to all forms of interference with androgen action were observed in different lobes of the prostate with regard to wet weight, DNA and protein contents, and zinc concentration as well as morphological effects. Regressive changes at the morphological level were particularly striking in the coagulating gland and ventral prostate, and indistinct in the lateral type 2 prostate. Prostatic zinc concentration in both normal and androgen-deprived rats was the highest in the lateral type 2 prostate and was reduced by interfering with androgen action to the greatest extent in the dorsolateral prostate (lateral type 1 and type 2, and dorsal prostate). The distribution of zinc correlated with the expression of metallothionein, which was detected by immunocytochemistry only in the lateral type 2 prostate of both normal and androgen-deprived rats. Intraprostatic heterogeneity of zinc and metallothionein expression emphasizes interlobar differences in biological function within the rat prostate. The mechanism of development of regional heterogeneity within the prostate may shed light on the pathogenesis of prostatic proliferative diseases (prostatic hyperplasia and prostatic cancer) that initially owe their development to focal changes within large cell populations. © 1996 Wiley-Liss, Inc.     

Differential expression of c-erb B2/neu, epidermal growth factor receptor, cytokeratin 8, and the prostatic steroid-binding protein gene in rat ventral prostate during postnatal development

BACKGROUND: The development and progression of prostate neoplasia may recapitulate the early developmental pattern of expression of genes in the prostate. The study of prostate development may, therefore, provide insights into the molecular mechanisms important in prostate neoplasia and reveal new markers. METHODS: We compared postnatal expression of four genes: neu and epidermal growth factor receptor genes (EGFR), androgen-upregulated in the ventral prostate of adult rats (C-3), and androgen-repressed (CK8) in Sprague-Dawley rats. In situ hybridization was performed on prostate frozen sections collected on postnatal days 1, 5, 10, 15, 20, 30, and 60 from five rats per day. Staining intensities for antisense probes specific for each gene were determined relative to day 1 intensity. RESULTS: Growth factor receptors including neu and EGFR may be coordinately regulated in the basal-cell population during prostate development. CK8 and C-3 show evidence of similar androgen regulation during development. CONCLUSIONS: CK8 and C-3 have distinct patterns of expression in the postnatal period of development and these genes may be good markers of differentiation. Both neu and EGFR may be involved in androgen-independent growth of basal cell population in prostate. Prostate 47:164-171, 2001.     

Similar rates of exponential decrease in serum concentrations of free prostate-specific antigen (PSA), PSA complexed to alpha-1-antichymotrypsin, and human glandular kallikrein 2 (hK2) in prostate cancer patients treated with GnRH-analogues

BACKGROUND: Our recently reported finding of rapid bi-exponential elimination of free prostate-specific antigen (PSA) after radical retropubic prostatectomy in patients with moderately elevated PSA levels, which contrasted a very slow, linear elimination of PSA complexed to alpha-1-antichymotrypsin (ACT), prompted us to study whether these elimination rates were applicable for patients selected for castration treatment with very high pretreatment concentrations of PSA in serum. In addition, serum concentrations of hK2, the activator of proPSA, were measured. METHODS: Pretreatment serum was obtained from 21 previously untreated prostate cancer patients due for hormonal treatment with a GnRH-analog. Samples were also collected during treatment up to a minimum of 24 weeks at 2-week intervals and analyzed with immunofluorometric assays for free PSA (PSA-F), PSA complexed to alpha-1-antichymotrypsin (PSA-ACT), total PSA (PSA-T), and human kallikrein 2 (hK2). For pharmaco-kinetic analysis the serum concentrations of hK2 and PSA forms for each patient were plotted against time both before and after logarithmic transformation and the half-lives were calculated as ln2/k. RESULTS: Median pretreatment serum concentrations were 322 ng/ml (range, 1.9-2210) for PSA-T, 27.8 ng/ml (range, 1.14-259) for PSA-F, and 207 ng/ml (range, 0.8-2080) for PSA-ACT. All patients had castrate levels of serum testosterone (< 2.5 nmol/l) in less than 21 days after initiation of GnRH-analog treatment. It was possible to evaluate data from 19/21 patients which showed an exponential decrease of all PSA concentrations in serum, with mean half-lives of 12.9 days (range, 7.3-30) for PSA-T, 15.5 days (range, 7.7-37.5) for PSA-F, and 12.3 days (range, 6.6-30) for PSA-ACT. Median pretreatment percent free PSA (PSA-F/PSA-T) was 12% compared to 18% at nadir. The median pretreatment level of hK2 was 3.5 ng/ml (range, 0.29-30.3). There was an exponential decrease in hK2 concentrations in serum after initiation of hormonal treatment with a mean half-life of 18.7 days (range, 7.5-37.5). CONCLUSIONS: For the majority of patients with hormonally treated prostate cancer the serum concentrations of PSA-T, PSA-F, PSA-ACT, and hK2 decreased slowly in parallel and mono-exponentially after initiation of treatment. Mean half-lives were between 12 and 19 days.