Biomedical subjects

Helmut Klocker

Publications and source records attributed to Helmut Klocker.

At least 37 records · Page 2Linked to original sources

PubMed2004

Genetic aberrations in prostate carcinoma detected by comparative genomic hybridization and microsatellite analysis: association with progression and angiogenesis.

BACKGROUND: In spite of increasing knowledge about the tumor biology of prostate cancer (PC), molecular events involved in tumor progression are not well characterized. There is evidence that a number of genetic alterations play a role in tumor progression and in addition, angiogenesis also contributes. In this study, comparative genomic hybridization (CGH), a sensitive method for detecting regional DNA copy number abnormalities, and microsatellite analysis was used to identify frequent genome changes in PC. Correlation of these data with microvessel density (MVD) and clinical follow-up data was performed to determine genetic alterations that are associated with angiogenesis and subsequent tumor progression. METHODS: Fifty-seven paraffin embedded radical prostatectomy (RP) specimens were microdissected. DNA from the microdissected PC tissue was amplified by degenerate oligonucleoitide primed (DOP)-polymerase chain reaction (PCR), and CGH was performed on the PCR product. Quantitative analyses of the CGH profiles were performed using a t-statistic. Additionally, a microsatellite analysis of chromosome 13q was performed on a subgroup of 31 of the tumors. Using a polyclonal antibody against factor VIII, MVD was determined for all RP specimens. The results of CGH and microsatellite analysis were correlated with the clinical data of the patients and with MVD. RESULTS: Forty-two of the tumors (75%) showed one or more gains while 39 (70%) showed one or more losses per tumor. The most frequent DNA copy number gains were on chromosome 3, 4, 7, 8, 10, 11, 12, 13, and X. The most frequent losses were on chromosomes 2, 5, 6, 8, 10, 13, 15, and 16. Cancer recurrence occurred in 15 patients. The total number of DNA copy number losses was significantly higher in patients with this progression (86%) than without (52%) (P < 0.001). There was no significant difference in the number of gains in patients with or without progression. Contingency table analysis showed a significant correlation between progression and losses in regions of chromosomes 6q and 13q and a gain of chromosome 7q. In multivariate analysis, only loss of chromosome 6 was independently prognostic. The gains that correlated most closely with MVD > 35 were on chromosomes 2q, 7q, and Xq, while the losses most closely associated with MVD > 35 were on chromosomes 8q, 10q, and 13q. However, only the association between loss of chromosome 13q and MVD > 35 was statistically significant. Microsatellite analysis revealed a statistically significant correlation between MVD and instability of locus 171. CONCLUSIONS: This study indicates that the frequency of genetic alterations in PC as detected by CGH correlates with clinical outcome, and that losses of DNA from chromosomes 6q and 13q are important events that correlate with tumor progression, with loss of 13q, especially instability of locus 171, also associated with angiogenesis.

Chromosome Aberrations↗

PubMed2004

Clinical and pathologic features of prostate cancer detected after repeat false-negative biopsy in a screening population.

BACKGROUND: The present study was designed to investigate whether the clinical or pathologic features of prostate cancer (PCa) are related to the number of repeat biopsies required to establish the diagnosis of PCa. METHODS: Between February 1993 and August 2000, 653 patients were evaluated in this retrospective study. All patients underwent transrectal ultrasound-guided biopsy of the prostate prior to radical retropubic prostatectomy. The pathologic findings of specimens obtained at radical prostatectomy and pelvic lymph node dissection as well as PSA levels, findings on DRE, prostate volumes, transition zone volumes, and age were analyzed separately for all PCa patients diagnosed at the first set of biopsies (group A) and compared with the data of those diagnosed at the 2nd-5th set of biopsies (group B). In a second step, we compared the results obtained from patients diagnosed at the 2nd set of biopsies (group B1) with those of patients diagnosed at the 3rd to 5th set of biopsies (group B2). RESULTS: Gleason scores, pathologic tumor stages, and tumor volumes in group B were found to be significantly decreased compared to group A. But from the 2nd to 5th serial biopsy no further decrease in pathologic stage, Gleason score, or tumor volume was observed. On the contrary, there was a tendency towards higher tumor stages and Gleason scores. Of the tumors detected after the second false-negative set of biopsies almost 70% were lesions with Gleason scores of 6 or higher. CONCLUSIONS: False-negative results at the first needle biopsy are predictive of a lower pathologic stage and grade as well as smaller tumor volumes of PCa diagnosed at repeat sets of biopsies. False-negative results on repeat biopsy, however, have no prognostic significance for the tumor stage of PCas detected at subsequent sets of biopsies.

Aged↗

PubMed2004

Long-term androgen-ablation causes increased resistance to PI3K/Akt pathway inhibition in prostate cancer cells.

BACKGROUND: In advanced stages of prostate cancer, the phosphatidylinositol-3' kinase (PI3K)/Akt signaling cascade, one of the major survival pathways in the cell, is frequently constitutively activated due to mutation or loss of the tumor suppressor protein phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Using cell culture models representing different tumor stages, we explored the effect of inhibition of this survival pathway on the induction of apoptosis. METHODS: Inhibition of the survival kinase Akt and induction of apoptosis was analyzed in androgen-insensitive DU145 and PC-3 cells, in androgen-responsive LNCaP, and in androgen-independent long-term androgen-ablated LNCaP-abl cells representing therapy-resistant prostate cancer cells. Activated Akt was determined by immunoblotting using a phospho-Akt specific antibody. Induction of apoptosis was analyzed employing annexing V and propidium iodide staining and flow cytometry and measurement of cleavage of the caspases substrate poly-ADP-ribose polymerase (PARP). RESULTS: IGF-1, EGF, and heregulin but not PDGF or activators of protein kinase A induced phosphorylation of Akt in DU145 cells and activation was completely blocked by the PI3K inhibitor LY294002. In the hormone-responsive prostate cancer cell line LNCaP that has a constitutively switched-on Akt kinase, LY294002 caused a dose- and time-dependent Akt inhibition, which was absent in long-term androgen-ablated LNCaP sublines. In agreement with the resistance to inhibition of the PI3K/Akt pathway, long-term androgen-ablated LNCaP sublines remained relatively resistant to induction of cell death by LY294002 or the cytotoxic drug etoposide. Inhibition of the PI3K/Akt pathway restored the sensitivity of long-term androgen-ablated cells to induction of apoptosis by a cytotoxic drug almost completely. CONCLUSION: These results suggest that long-term androgen ablation therapy for prostate cancer reinforces the PI3K/Akt pathway and impedes its inhibition thus contributing to increased resistance of tumor cells to induction of apoptosis. With regard to treatment of therapy-refractory prostate cancer, these findings suggest effectiveness of a combination of cytotoxic treatment and inhibition of the PI3K-Akt survival pathway in tumor cells after failure of androgen-ablation therapy.

Androgen Antagonists↗

PubMed2004

Screening for prostate cancer: updated experience from the Tyrol study.

The aim of the Tyrol study was to monitor the impact of screening in a natural experiment by comparing prostate cancer mortality in Tyrol, where prostate-specific antigen (PSA) testing was introduced at no charge, with the rest of Austria, where it was not strictly organized and not free of charge. In 1993, PSA testing was made freely available to men between the ages of 45 and 75 years in the Federal State of Tyrol, Austria. At least 70% of all of the men in this age range have been tested at least once during the first 10 years of the study. Initially, only total PSA was measured, but free PSA measurement was added in 1995. Since 2001, complexed PSA also has been measured. Digital rectal examination was not part of the screening examination. Significant migration to lower clinical and pathological stages has been observed since the introduction of this screening program. These findings are consistent with the hypothesis that the policy of making PSA testing freely available, and the wide acceptance by men in the population, is associated with a reduction in prostate cancer mortality in an area in which urology services and radiotherapy are available freely to all patients. It is our opinion that most of this decline is likely a result of aggressive downstaging and successful treatment and that any contribution from detecting and treating early cancers will become apparent in the years to come.

Aged↗

PubMed2004

Androgen receptor regulation by physiological concentrations of the isoflavonoid genistein in androgen-dependent LNCaP cells is mediated by estrogen receptor beta.

OBJECTIVES: Isoflavonoids are discussed for use in chemoprevention and treatment of prostate cancer. We investigated the potential of genistein to modulate androgen receptor (AR) expression and transcriptional activity in the human androgen-sensitive prostate cancer cell line LNCaP. MATERIALS AND METHODS: AR expression at mRNA and protein level was analyzed by real-time RT-PCR and immunoblot, respectively. In conditioned media PSA was measured by a microparticle enzyme immunoassay (MEIA). Binding of genistein to the AR was tested in a radioligand-binding assay and reporter gene co-transfection assay was employed to investigate AR activity. RESULTS: Using concentrations of genistein that have been detected in sera of Asian men on regular soy-diet we found down-regulation of androgen receptor at both mRNA and protein level. The relative binding affinity to the AR was below 4% when compared to methyltrienologe (R1881) and there was no modulation of AR transcriptional activity by genistein concentrations up to 1 microM. We also demonstrated inhibition of PSA secretion after genistein treatment. As the anti-estrogen ICI 164 384 abolished the inhibitory effect of genistein and ER-beta, but not ER-alpha is expressed in LNCaP cells we postulate that the mechanism of genistein action on androgen receptor is mediated through ER-beta. CONCLUSION: Using physiological concentrations of genistein we showed AR down-regulation by genistein in prostate cancer cells occurring via ER-beta. This likely results in a modified response to hormonal stimuli and may help to explain the low incidence of prostate cancer in the Asian population.

Antineoplastic Agents↗

PubMed2004

Identification of genes involved in estrogenic action in the human prostate using microarray analysis.

Estrogens have profound effects on the developing prostate and are suspected to contribute to the development of benign prostatic hyperplasia, but the mechanism by which this hormone elicits its regulatory function still remains largely unknown. Using complementary RNA microarrays comprising approximately 10,000 oligonucleotide gene targets we compared differences in mRNA expression of estradiol-treated and untreated prostatic stromal cells in vitro. Based on a threshold of greater than twofold change, 228, 241, and 464 of the expressed genes were found to be regulated by estradiol after 10, 24, and 48 h of treatment, respectively. The secondary analysis of one estradiol-activated transcript, namely lipopolysaccharide-binding protein, and four estradiol-repressed genes, namely ras homolog gene family member E (RhoE/Rnd3), ubiquitin thiolesterase, interleukin 6, and interleukin 8 (IL-8), by real-time quantitative PCR confirmed the results of the microarray analysis. Moreover, IL-8 and RhoE were found to be down-regulated by estradiol at the protein level as well. We identified a set of genes involved in a wide range of cellular functions that are potentially important for understanding the molecular basis of estradiol action in the prostate.

Acute-Phase Proteins↗

PubMed2004

Serum pro-prostate specific antigen preferentially detects aggressive prostate cancers in men with 2 to 4 ng/ml prostate specific antigen.

PURPOSE: Pro forms of prostate specific antigen (PSA) have been reported to be more cancer specific markers of prostate cancer than total PSA and they also may preferentially detect the more aggressive forms of the disease. MATERIALS AND METHODS: Research immunoassays with high specificity for pro-PSA forms were used to study 1091 retrospective serum specimens, including 555 with 2 to 4 and 536 with 4 to 10 ng/ml PSA, from men enrolled in prostate cancer screening studies who underwent prostate biopsy. RESULTS: In the 2 to 4 ng/ml PSA range the ratio of pro- to free-PSA (percent pro-PSA) using a cutoff of 1.8% for recommending prostate biopsy detected 90% of cancers, including 16 of 16 extracapsular tumors and 28 of 29 tumors with a pathology Gleason score of 7 or greater, while avoiding 19% of unnecessary biopsies. Serum percent pro-PSA was significantly increased for Gleason score 7 or greater vs less than 7 (p = 0.0018). In the PSA range of 4 to 10 ng/ml percent pro-PSA had the highest cancer specificity, avoiding 31% of unnecessary biopsies, while detecting 34 of 35 cancers with a pathology Gleason score of 7 or greater and 29 of 31 extracapsular tumors. Neither percent free PSA nor complexed PSA enhanced the detection of aggressive cancers in the 4 to 10 ng/ml PSA range. CONCLUSIONS: Percent pro-PSA was superior to percent free and calculated complexed PSA for the detection of prostate cancer in the PSA range of 2 to 10 ng/ml and it had selectivity for detecting more aggressive cancers, as indicated by Gleason score 7 or greater and/or extracapsular tumor extension.

Aged↗

PubMed2004

Phytoestrogens derived from Belamcanda chinensis have an antiproliferative effect on prostate cancer cells in vitro.

PURPOSE: Phytoestrogens are nonsteroidal plant derived compounds with estrogenic activity that have been implicated in protecting against prostate cancer progression. We hypothesized that these compounds would alter cell number and increase the ability of antiandrogens to induce cell death in prostate cancer cells. MATERIALS AND METHODS: RWPE-1, LNCaP and PC-3 cells were treated with or without an extract of Belamcanda chinensis, 2 purified phytoestrogens derived from this extract (irigenin and tectorigenin) and the antiandrogen bicalutamide. We assessed the effect on cell number, proliferation and apoptosis. RESULTS: Phytoestrogens (50 to 100 microM) and bicalutamide (10 to 50 microM) alone decreased the cell number in all 3 cell lines. Phytoestrogens (50 microM) combined with bicalutamide (10 microM) further decreased the number of RWPE-1 and PC-3 cells compared to these agents alone. Tectorigenin and irigenin inhibited the proliferation of RWPE-1, LNCaP and PC-3 cells, causing G1 arrest and the induction of p21WAF1 or p27 protein expression, whereas bicalutamide induced apoptosis in a dose dependent manner in all 3 cell lines. Phytoestrogens did not have antiandrogenic activity. CONCLUSIONS: These in vitro studies demonstrate a role for tectorigenin and irigenin in regulating prostate cancer cell number by inhibiting proliferation through cell cycle regulation.

Cell Division↗

PubMed2004

Measurement of intracellular versus extracellular prostate-specific antigen levels in peripheral macrophages: a new approach to noninvasive diagnosis of prostate cancer.

Although prostate-specific antigen (PSA) is a useful screening marker in prostate cancer, it has limited specificity. Previously it was shown that the amount of surface-bound PSA present on circulating macrophages was different between patients with localized prostate cancer and those with metastatic prostate cancer. It was recently demonstrated that intracellular PSA in macrophages can be measured by flow cytometry. In the context of searching for a noninvasive, highly reliable method for prostate cancer diagnosis, we assessed the extent to which extracellular (ie, surface-bound) and intracellular PSA-positive macrophages might differentiate patients with benign versus malignant prostatic disease. In a pilot study, the levels of complexed, surface-bound, and intracellular PSA were measured in 25 patients with elevated serum PSA values and histologically confirmed disease. In this group, no significant differences for serum PSA and complexed PSA levels, respectively, could be detected among patients with benign prostatic hyperplasia, prostatitis, and prostate cancer. Significant differences, however, were detected in intracellular PSA, although not in surface-bound PSA, among the 3 groups of patients. Intracellular PSA was measured prospectively in a second cohort of 189 patients who had a transrectal biopsy because of a serum PSA constellation suspicious for prostate cancer. In the expanded cohort, highly significant differences in intracellular PSA were observed between benign and malignant disease of the prostate, even in patients with serum PSA level<4 ng/mL. Screening of serum PSA alone or in combination with complexed PSA does not clearly distinguish patients with prostate cancer from those with prostatitis or benign prostatic hyperplasia. Macrophage intracellular PSA might represent a more.

Aged↗

PubMed2004

The importance of the CXCL12-CXCR4 chemokine ligand-receptor interaction in prostate cancer metastasis.

AIM: Chemokines or chemotactic cytokines are known to be important in the directional migration or chemotaxis of leucocytes in conditions of homeostasis and in inflammatory or immunological responses. However, the role of chemokines is extending beyond their involvement in mediating leucocyte trafficking with an increasing body of evidence suggesting these proteins are intimately involved in many stages of tumour development and progression. Our aim was to study the role of the CXCL12:CXCR4 chemokine ligand:receptor complex in determining the organ-specific metastasis of prostate cancer. MATERIALS AND METHODS: CXCR4 mRNA expression was determined by RT-PCR in 3 metastatic prostate cancer cell lines DU145, LNCaP and PC3, the primary prostate cancer cell line 1542 CPT3X and the normal prostate epithelial cell lines 1542 NPTX and Pre 2.8. This was followed by Taqman quantitative PCR analysis of CXCR4 mRNA in these cell lines. Flow cytometry analysis was then used to measure the expression of the CXCR4 receptor protein on the cell surface. The influence of the receptor on cell migration was studied using Transwell, Migration Assays. Finally, Taqman quantitative PCR was performed on RNA obtained from laser microdissected fresh primary prostate tumour and benign tissue samples from patients. RESULTS: In DU145, LNCaP and PC3 CXCR4 mRNA expression was approximately 1000, 400 and 21 times respectively that of 1542 NPTX, Pre 2.8 and 1542 CPT3X. In patient primary tumour samples and patient benign tissue specimens CXCR4 mRNA expression was similar to that of the metastatic cell line DU145. Flow cytometry analysis showed that significantly higher levels of the CXCR4 receptor were present on the cell surface of the 3 metastatic cell lines. Migration studies revealed that chemotaxis of the metastatic cell lines PC3 and DU145 was enhanced by CXCL12 ligand and inhibited by antibody to CXCR4. CXCL12 did not influence the migration of the normal prostate epithelial cell line 1542 NPTX. CONCLUSIONS: We have demonstrated that human prostate cell lines derived from metastases express functional CXCR4 receptor and that CXCL12 ligand enhances their migratory capabilities. Also, laser microdissected primary patient tumours and patient benign tissue specimens express CXCR4 mRNA at high levels (it is suggested that post-transcriptional modification of the CXCR4 receptor plays a major role in regulating protein expression). These results suggest prostate cancers may be influenced by the CXCL12:CXCR4 pathway during metastasis. This pathway would provide a novel target for therapeutic intervention.

Cell Line, Tumor↗

PubMed2003

Increased growth factor production in a human prostatic stromal cell culture model caused by hypoxia.

BACKGROUND: Local hypoxia may be one of the triggers of embryonic reawakening of the stroma and subsequent hyperplastic growth in the prostate. Using a cell culture model of human prostatic stromal cells, we investigated the effects of hypoxia on activation of hypoxia-inducible factor 1 (HIF 1) and on the production of growth factors. METHODS: Primary prostatic stromal cells were grown in normal and hypoxic (1% O(2)) atmosphere. Activation of HIF 1 was evaluated after different time intervals by Western blot. Induced secretion of growth factors VEGF, FGF-7, TGF-beta, IL 8, and FGF-2 were analyzed by ELISA. To confirm the in vitro findings we also performed immunohistochemistry of HIF 1alpha as well as pro-collagen I, collagens I, III, and IV in the benign tissue of radical prostatectomy specimens. RESULTS: HIF 1 is activated in a time-dependent manner, already starting 1 hr after exposure of stromal cells to hypoxic conditions. Secretion of VEGF, FGF-7, TGF-beta, FGF-2, and IL 8 is increased under hypoxic in vitro conditions in comparison to normoxia. Levels of TGF-beta, VEGF, and IL 8 were rapidly and statistically significantly increased in the supernatant of hypoxic cells. Consistent with the in vitro findings, immunohistochemistry of HIF 1alpha in (benign prostatic hyperplasia) BPH tissue revealed strong HIF 1alpha nuclear staining in hyperplastic areas. No difference was observed in the collagen pattern between hyperplastic and normal prostate tissue. CONCLUSIONS: Prostatic stromal cells respond to hypoxia by upregulation of secretion of several growth factors suggesting that hypoxia can trigger prostatic growth. Therefore, hypoxia might be a key factor contributing to the pathogenesis of BPH.

Cell Line↗

PubMed2003

Gene expression changes following androgen receptor elimination in LNCaP prostate cancer cells.

We have shown recently that inhibition of androgen receptor (AR) expression with an antisense AR oligonucleotide (ODN) inhibits LNCaP prostate tumor cells in vitro as well as in vivo. In this study, we investigated gene expression changes that occur after AR signaling blockade, either through AR elimination by antisense treatment or through complete androgen receptor inhibition by androgen deprivation combined with the antiandrogen bicalutamide, in order to search for genes that are directly or indirectly regulated through the AR. Gene expression changes were investigated with cDNA NIH 10K gene microarrays in response to treatment over 48 h. Expression of selected genes was further analyzed by real-time reverse transcriptase (RT)-polymerase chain reaction (PCR), Western blotting, and radioimmunoassay. A comparison of antisense-treated and androgen-deprived cells revealed several concordances such as significant downregulation of prostate-specific genes, cell-cycle regulatory genes, genes of the cholesterol biosynthesis pathway, and several cytoskeletal genes. However, there were also several genes that were differentially regulated. Among the genes that were exclusively changed by treatment with the antisense AR ODN were the insulin-like growth factor binding protein 2 (IGFBP2) and the phosphatidylinositol-4-phosphate 5-kinase type I alpha (PIP5KIA). On the other hand, complete androgen receptor blockade induced changes in the expression of the prostate overexpressed gene 1 and the S100 calcium binding protein P. In summary, we identified a cohort of interesting genes whose expression was highly affected by elimination of the AR in LNCaP prostate cancer cells. Further investigations are warranted to clarify their role in the AR signaling pathway and their susceptibility as a target for the treatment of prostate cancer.

Anilides↗

PubMed2003

The transcriptional co-activator cAMP response element-binding protein-binding protein is expressed in prostate cancer and enhances androgen- and anti-androgen-induced androgen receptor function.

Progression of human prostate cancer toward therapy resistance occurs in the presence of wild-type or mutated androgen receptors (ARs) that, in some cases, exhibit aberrant activation by various steroid hormones and anti-androgens. The AR associates with a number of co-activators that possess histone acetylase activity and act as bridging molecules to components of the transcription initiation complex. In previous reports, it was shown that the transcriptional co-activator CREB (cAMP response element-binding protein)-binding protein (CBP) enhances AR activity in a ligand-dependent manner. In the present study, we have investigated whether CBP modifies antagonist/agonist balance of the nonsteroidal anti-androgens hydroxyflutamide and bicalutamide. In prostate cancer DU-145 cells, which were transiently transfected with CBP cDNA, hydroxyflutamide enhanced AR activity to a greater extent than bicalutamide in the presence of either wild-type or the mutated AR 730 val-->met. In two sublines of LNCaP cells that contain the mutated AR 877 thr-->ala and overexpressed CBP, increase in AR activity was observed after treatment with hydroxyflutamide but not with bicalutamide. Anti-androgens did not influence AR expression in cells transfected with CBP cDNA, as judged by Western blot analysis. Endogenous CBP protein was detected by Western blot in nuclear extracts from the three prostate cancer cell lines, LNCaP, PC-3, and DU-145, all derived from therapy-resistant prostate cancer. In addition, CBP was expressed in both basal and secretory cells of benign prostate epithelium, high-grade prostate intraepithelial neoplasia, and prostate cancer clinical specimens, as evidenced by immunohistochemical staining. Taken together, our findings demonstrate the selective enhancement of agonistic action of the anti-androgen hydroxyflutamide by the transcriptional co-activator CBP, which is a new, potentially relevant mechanism contributing to the acquisition of therapy resistance in prostate cancer.

Androgen Antagonists↗

PubMed2003

Proenzyme psa for the early detection of prostate cancer in the 2.5-4.0 ng/ml total psa range: preliminary analysis.

OBJECTIVES: To determine the clinical utility of using proenzyme prostate-specific antigen (pPSA) for early detection of prostate cancer in the 2.5 to 4.0 ng/mL total PSA range. pPSA, the precursor form of PSA that contains a 7 amino acid leader peptide, and truncated forms such as [-2]pPSA and [-4]pPSA can be measured in serum by research immunoassay. METHODS: Archival serum from 119 men (noncancer, 88; cancer, 31), obtained before biopsy and in the total PSA range of 2.5 to 4.0 ng/mL, were assayed for total PSA, free PSA (fPSA), and pPSA. pPSA was defined as the sum of the [-2], [-4], and [-7] forms, and the percent pPSA (%pPSA) was defined as pPSA/fPSA. RESULTS: pPSA averaged 4.6% +/- 0.4% (SEM) of total PSA and 39.3% +/- 3.5% of fPSA. PSA and %fPSA values were similar between the noncancer and cancer groups, and %pPSA tended to be higher in the cancer group (50.1% +/- 4.4%) compared with the noncancer group (35.5% +/- 6.7%; P = 0.07). Using receiver operating characteristic analysis to assess clinical utility, the area under the curve for %pPSA was 0.688 compared with 0.567 for %fPSA. At a fixed sensitivity of 75%, the specificity was significantly greater for %pPSA at 59% compared with %fPSA at 33% (P <0.0001). CONCLUSIONS: In the 2.5 to 4.0 ng/mL total PSA range, 75% of cancers can potentially be detected with 59% of unnecessary biopsies being spared using %pPSA; use of %fPSA would result in sparing only 33% of unnecessary biopsies. A large prospective clinical trial is needed to confirm these preliminary findings.

Adult↗

PubMed2003

Impact of age on complexed PSA levels in men with total PSA levels of up to 20 ng/mL.

OBJECTIVES: To evaluate the relationship between age and complexed prostate-specific antigen (cPSA) in healthy white men with no evidence of prostatic disease and total PSA (tPSA) levels of 0 to 20 ng/mL. METHODS: A total of 10,530 tests for cPSA and tPSA in men between 40 and 79 years old were performed at Innsbruck University, Austria, between 2001 and 2002. After excluding 263 patients because of follow-up biopsy findings indicating prostatic disease, 10,267 PSA tests were available for study. All serum samples were analyzed using the Bayer Immuno 1 cPSA and tPSA assays. cPSA and tPSA values were determined in subjects with tPSA levels between 0 and 20 ng/mL. The concentrations were calculated for the 50th, 90th, and 95th percentiles of four age groups (40 to 49, 50 to 59, 60 to 69, and 70 to 79 years). For statistical analysis, the Kruskal-Wallis test was used. The 95th percentile was defined as the upper limit of normal. RESULTS: A total of 10,267 PSA tests were available for study. cPSA and tPSA levels correlated linearly and positively with age (P <0.001). Percent free PSA showed a significant increase with age (P <0.001), which may be attributed to the increase in prostate volume with advancing age. CONCLUSIONS: Both cPSA and tPSA levels were found to increase with age. The low tPSA and cPSA levels observed at the 95th percentile in men aged 40 to 59 years suggest that lower cutoff values should be used in place of the currently accepted tPSA level of 4 ng/mL. Lower cutoff values may help improve the detection of prostate cancer among otherwise healthy men.

Adult↗

PubMed2003

Androgen receptors in prostate cancer.

PURPOSE: Androgen receptor (AR) is expressed in the majority of human prostate cancers. For a better understanding of prostate carcinoma events it is necessary to present findings on the regulation of AR target genes, AR interaction with associated proteins, ligand independent activation and point mutations. MATERIALS AND METHODS: A comprehensive literature review of manuscripts published on AR in prostate cancer was performed using PubMed. RESULTS: AR regulates the expression of genes involved in the proliferation and differentiation of prostate cancer cells. Due to differential interactions with coactivators and corepressors AR activation results in the stimulation of a mitogenic response or in the expression of secretory proteins. AR is functional in advanced carcinoma of the prostate, as evidenced in studies of mutant receptors and ligand independent activation. AR point mutations appear in advanced prostate cancer more frequently than in organ confined disease. CONCLUSIONS: Current therapy options aimed to inhibit AR function in prostate cancer are limited. Antiandrogenic drugs frequently acquire agonistic properties in the presence of mutated ARs. In addition, androgen signaling pathway activity increases during long-term androgen ablation. AR coactivator complexes might be a target for novel therapies for prostate cancer.

Cell Division↗

PubMed2003

Serum pro prostate specific antigen improves cancer detection compared to free and complexed prostate specific antigen in men with prostate specific antigen 2 to 4 ng/ml.

PURPOSE: Pro prostate specific antigen (pPSA) is a precursor form of PSA enriched in tumor compared to benign prostate tissues that may be a more specific serum marker for prostate cancer. Serum pPSA was measured in the clinically relevant early detection PSA range of 2 to 10 ng/ml. MATERIALS AND METHODS: Research use immunoassays were used to measure native and truncated forms of pPSA. The subject cohort contained 1,091 serum specimens from men enrolled in prostate cancer screening studies at 2 sites who had undergone prostate biopsy and were divided into PSA ranges of 2 to 4 ng/ml (benign 320, cancer 235) and 4 to 10 ng/ml (benign 315, cancer 221). RESULTS: In PSA ranges 2 to 4, 2 to 6, 4 to 10 and 2 to 10 ng/ml, pPSA in a ratio with free PSA (%pPSA) gave the highest cancer specificity. At 2 to 4 ng/ml and 90% sensitivity, %pPSA spared 19% of unnecessary biopsies compared to 10% for free PSA and 11% for complexed PSA(p <0.001). Similar results were obtained at PSA 2 to 6 ng/ml. At 90% sensitivity in the PSA 4 to 10 ng/ml range, %pPSA spared 31% of unnecessary biopsies compared to 20% for % free PSA and 19% for complexed PSA (p <0.0001). In the combined 2 to 10 ng/ml range, %pPSA spared 21% of unnecessary biopsies compared to 13% for % free PSA and 9% for complexed PSA (p <0.0001). CONCLUSIONS: The %pPSA significantly improved specificity for cancer detection and decreased the number of unnecessary biopsies in the PSA 2 to 4 ng/ml range. This relative improvement of %pPSA compared to % free PSA and complexed PSA was maintained throughout the PSA range of 2 to 10 ng/ml.

Biopsy, Needle↗

PubMed2003

The cochaperone Bag-1L enhances androgen receptor action via interaction with the NH2-terminal region of the receptor.

Members of the Bag-1 family of cochaperones regulate diverse cellular processes including the action of steroid hormone receptors. The largest member of this family, Bag-1L, enhances the transactivation function of the androgen receptor. This occurs primarily through interaction with the NH(2) and COOH termini of the receptor. At the NH(2) terminus of the receptor, Bag-1L interacts with a region termed tau 5. Bag-1M, a naturally occurring variant of Bag-1L that binds to tau 5 but is defective in the COOH-terminal interaction, is less efficient in enhancing the transactivation function of the receptor. Surface plasmon resonance and transfection studies showed that the molecular chaperone Hsp70 contributes to the binding of Bag-1L to tau 5 and to the regulation of the transactivation function of the androgen receptor. Chromatin immunoprecipitation studies demonstrated that the androgen receptor, Hsp70, and Bag-1L are all targeted to the androgen response elements of the gene that encodes prostate-specific antigen. These studies demonstrate the regulation of transcriptional activity of androgen receptor by a molecular chaperone-cochaperone complex.

Carrier Proteins↗