[Androgens stimulate the expression of SOCS-3 and inhibits their effect on proliferation and secretion]. / C. E. Alken Preis 2007: Androgene stimulieren die Expression von SOCS-3 und bewirken die Inhibition der Proliferation und Sekretion.

PURPOSE: Suppressors of cytokine signalling (SOCS) are induced by interleukins and peptide hormones. These molecules prevent the activation of diverse signalling pathways in benign and malignant cells. In previous studies, we showed that SOCS-3 is expressed in most prostate cancer cell lines and tissue specimens. In the present study we investigated the effects of androgen on the regulation of SOCS-3 in prostate cancer cell lines. MATERIALS AND METHODS: SOCS-3 expression was determined with PCR and Western blot techniques. The activity of the SOCS-3 promoter was measured with the luciferase test. We measured proliferation with (3)H-thymidine assay. RESULTS: We show that androgen induces the expression of SOCS-3 in two prostate cancer cell lines. The non-steroidal anti-androgen bicalutamide is able to block the induction of SOCS-3 -expression. Androgenic hormones did not induce the expression of SOCS-3 mRNA or its promoter activity. In LNCaP-IL-6- cells transfected with the inducible Tet-On construct SOCS-3 expression was induced. The effects of androgenic hormones on the proliferation and induction of PSA were -diminished in the presence of SOCS-3. CONCLUSIONS: Our results show that androgenic -regulation of SOCS-3 leads to inhibition of prolif-eration and secretion in human prostate cancer.

The antiapoptotic effect of IL-6 autocrine loop in a cellular model of advanced prostate cancer is mediated by Mcl-1.

Levels of the proinflammatory cytokine interleukin-6 (IL-6) are increased in therapy-resistant prostate cancer. IL-6 has been considered a positive growth factor in late-stage prostate cancer cells and a potential target for therapeutic interference. Effects of inhibition of IL-6 on cell survival were studied in LNCaP-IL6+ cells, a model system for advanced prostate cancer, which produce IL-6. We show that the autocrine IL-6 loop is responsible for resistance to apoptosis and increased cellular levels of myeloid cell leukemia-1 (Mcl-1) protein, an antiapoptotic member of the Bcl-2 family. Treatment of cells with a chimeric anti-IL-6 antibody (CNTO 328) led to the induction of apoptosis and downregulation of Mcl-1 protein levels. Specific knockdown of Mcl-1 gene expression by small interfering RNA also yielded an increase in apoptosis of LNCaP-IL-6+ cells. Vice versa, inactivation of IL-6 autocrine loop had no influence on apoptosis levels in the absence of Mcl-1, thus suggesting this molecule as a mediator of the survival action of IL-6. Mcl-1 protein regulation by the endogenous cytokine directly involved the extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase pathway. Our data support the concept of anti-IL-6 targeted therapy in therapy-resistant prostate cancer.

Mechanisms of endocrine therapy-responsive and -unresponsive prostate tumours.

Several options for the endocrine treatment of non-organ-confined prostate cancer are available. They include surgical or medical removal of androgenic hormones or administration of non-steroidal anti-androgens. However, tumour progression after a period of remission of the disease inevitably occurs in virtually all patients. The androgen receptor (AR) is, in various tumour models, implicated in the development of therapy resistance but molecular mechanisms that by-pass the receptor have also been described. Adaptation mechanisms relevant to tumour recurrence include up-regulation of AR mRNA and protein, overexpression of AR coactivators, increased activation of mutated receptors by steroids and anti-androgens, and ligand-independent activation. For research studies, sublines that respond to but do not depend on androgen for their proliferation were generated. Coactivators SRC-1, TIF-2, RAC3, p300, CBP, Tip60, and gelsolin are highly expressed in endocrine therapy-resistant prostate cancer. AR point mutations are increasingly detected in relapsed cancers and contribute to the failure of endocrine therapy in a subgroup of patients. Ligand-independent activation of the AR by HER-2/neu and interleukin-6 is associated with activation of the signalling pathway of mitogen-activated protein kinase. Increased activity of intracellular kinases may affect cellular events in both an AR-dependent and -independent manner. Mitogen-activated protein kinases are strongly phosphorylated in endocrine therapy-resistant prostate tumours. Similarly, activation of the AR by phosphorylated protein kinase B, Akt, has also been reported in prostate cancer. Activation of the Akt pathway contributes to increased survival of prostate tumour cells.

Antiandrogens in prostate cancer endocrine therapy.

Prostate cancer is the most frequently diagnosed tumor in industrialized countries. Endocrine therapy, which is based on interference with androgen signaling is only palliative. Drugs used in prostate cancer therapy are luteinizing hormone releasing hormone (LHRH) agonists and antiandrogens. Application of LHRH agonists leads to suppression of the levels of circulating androgens, and antiandrogens block the function of the androgen receptor (AR). The steroidal antiandrogen cyproterone acetate and nonsteroidal compounds hydroxyflutamide and bicalutamide are used most frequently. They prevent acquisition of a transcriptionally active conformation of the AR. It became clear that tumors progress to therapy resistance in the presence of the AR which might be structurally altered. These mutations generate receptors that respond to other steroids and antiandrogens by increased activation. In addition, AR expression increases during endocrine treatment. AR is also activated by nonsteroidal compounds such as growth factors, interleukin-6, and neuropeptides. Therefore, new experimental approaches are needed to antagonize AR expression and function more efficiently. The AR associates with a number of proteins, coactivators and corepressors. There are indications that expression of some of these proteins is altered in prostate cancer, a fact which might be important for improvement of endocrine therapy.

An autocrine loop for vascular endothelial growth factor is established in prostate cancer cells generated after prolonged treatment with interleukin 6.

Concentrations of interleukin 6 (IL-6) and its receptor are increased in human prostate cancer. Prostate cancer LNCaP-IL-6+ cells, established after prolonged treatment with IL-6, have been found to acquire a growth advantage. Vascular endothelial growth factor (VEGF) may accelerate the growth of various tumours by stimulation of VEGF receptor 2 (VEGFR-2). To understand better the regulation of proliferation of LNCaP-IL-6+ cells, the expression of VEGF and VEGFR-2 was here investigated in the LNCaP-IL-6+ subline. VEGF was measured in cellular supernatants by enzyme-linked immunoassay. The expression of VEGFR-2 was assessed by Western blot. LNCaP-IL-6+ and control LNCaP-IL-6- cells were treated with a neutralising antibody against VEGFR-2. VEGF concentrations were 20-fold higher in LNCaP-IL-6+ than in LNCaP-IL-6- cells. The stimulatory effect of IL-6 on VEGF production was abolished by an inhibitor of the signalling pathway for phosphoinositol 3 kinase in LNCaP-IL-6+ and LNCaP-IL-6- cells. Exogenous VEGF did not stimulate proliferation in either LNCaP-IL-6+ cells or controls. VEGFR-2 was detected only in LNCaP-IL-6+ cells, in which the neutralising antibody caused a partial inhibition of cell proliferation. It was concluded that a VEGF autocrine loop is established in prostate cancer cells generated after chronic treatment with IL-6. Because of the upregulation of IL-6 in patients with prostate cancer, these findings might be clinically relevant.

Androgen receptors in prostate cancer.

The androgen receptor (AR), a transcription factor that mediates the action of androgens in target tissues, is expressed in nearly all prostate cancers. Carcinoma of the prostate is the most frequently diagnosed neoplasm in men in industrialized countries. Palliative treatment for non-organ-confined prostate cancer aims to down-regulate the concentration of circulating androgen or to block the transcription activation function of the AR. AR function during endocrine therapy was studied in tumor cells LNCaP subjected to long-term steroid depletion; newly generated sublines could be stimulated by lower concentrations of androgen than parental cells and showed up-regulation of AR expression and activity as well as resistance to apoptosis. Androgenic hormones regulate the expression of key cell cycle regulators, cyclin-dependent kinase 2 and 4, and that of the cell cycle inhibitor p27. Inhibition of AR expression could be achieved by potential chemopreventive agents flufenamic acid, resveratrol, quercetin, polyunsaturated fatty acids and interleukin-1beta, and by the application of AR antisense oligonucleotides. In the clinical situation, AR gene amplification and point mutations were reported in patients with metastatic disease. These mutations generate receptors which could be activated by other steroid hormones and non-steroidal antiandrogens. In the absence of androgen, the AR could be activated by various growth-promoting (growth factors, epidermal growth factor receptor-related oncogene HER-2/neu) and pleiotropic (protein kinase A activators, interleukin-6) compounds as well as by inducers of differentiation (phenylbutyrate). AR function is modulated by a number of coactivators and corepressors. The three coactivators, TIF-2, SRC-1 and RAC3, are up-regulated in relapsed prostate cancer. New experimental therapies for prostate cancer are aimed to down-regulate AR expression and to overcome difficulties which occur because of the acquisition of agonistic properties of commonly used antiandrogens.

Primary lymphatic metastatic spread in testicular cancer occurs ventral to the lumbar vessels.

OBJECTIVES: To analyze whether primary metastatic spread occurs behind the lumbar vessels and whether removal is necessary for accurate staging in diagnostic retroperitoneal lymph node dissection, because dissection of lymphatic tissue behind the lumbar vessels is a challenging maneuver. METHODS: One hundred thirty-nine patients were included in our study. Twenty-nine patients with clinical Stage I tumor underwent laparoscopic staging lymph node dissection, including removal of the lymph nodes behind the lumbar vessels. Sixty-four patients with Stage II testicular cancer were retrospectively examined by computed tomography to determine the localization of the enlarged lymph nodes in relation to the lumbar vessels. On the basis of these results, 49 patients with clinical Stage I underwent laparoscopic lymph node dissection within the same template but without dissection of the lymphatic tissue behind the lumbar vessels. RESULTS: In the first group, 10 of 29 patients had pathologic Stage IIA tumors, with positive nodes exclusively ventral to the lumbar vessels. In group 2, 39 patients with solitary metastatic lesions had enlarged lymph nodes, which were always ventral to the lumbar vessels. Only in 3 of 25 patients with multiple metastases was one enlarged node found behind the lumbar vessels. In group 3, no tumor recurrence either before or behind the lumbar vessels could be found in 46 patients after a mean follow-up of 27.8 months. CONCLUSIONS: On the basis of these data, we believe that primary lymphatic metastatic spread in testicular cancer always occurs ventral to the lumbar vessels. Therefore, the removal of lymphatic tissue behind the lumbar vessels for diagnostic procedures is not necessary.

Combined study of prostatic carcinoma by classical cytogenetic analysis and comparative genomic hybridization.

Conventional cytogenetic analysis of prostatic carcinoma (PC) is characterized by inefficient growth of tumor cells during in vitro culture, leading to a lack of aberrant karyotypes in many of investigated tumors. In this study we have combined a modified short-term tissue culture method for conventional banding analysis and comparative genomic hybridization (CGH) to examine genetic changes in PC, and to evaluate the effect of the in vitro culture on chromosomal changes by comparing results of the two methods. Cytogenetic analysis was performed on 34 PCs using both, conventional and molecular methods. Tumor tissues were obtained predominantly from untreated primary tumors from 48 patients. For karyotyping all tumor samples were short-term cultured using a feeder layer technique. Additionally DNA from uncultured tumor material from 17 of those patients was isolated and screened for copy number changes using CGH. Conventional banding analysis: clonal aberrations were detected in 65% of the tumor samples. Most of the chromosomal findings were numerical changes, including loss of chromosomes Y (32%), 18, 19 and 21 (each 12%). Less frequent, trisomy of chromosome 7 and monosomy of chromosomes 9, 12 and 22 (each 9%) was found. Additionally an inversion of chromosome 9p and a deletion at chromosome 7q was found in two cases. In 35% no clonal aberrations could be detected. CGH: DNA copy number changes were detected in 65% of the analyzed tumors. Predominantly losses of DNA sequences were found. The most common losses were found at chromosome regions 13q21q33 (29%), 6q11q23 (24%), 16q, and 18 (each 18%), and the most common gains at 19 (18%). In six tumors no copy number changes were found. Both methods showed a similar aneuploidy rate, suggesting that the feeder layer technique is quite a suitable method for in vitro culture of PC cells. However, the two techniques produced substantially differing results for most of the tumor samples, and in some cases the discrepancies are quite striking. Therefore eventual culture effects need to be taken into account when comparing results from conventional cytogenetics and CGH. Some contrary findings from the two methods are discussed.

Prostate cancer cells (LNCaP) generated after long-term interleukin 6 (IL-6) treatment express IL-6 and acquire an IL-6 partially resistant phenotype.

PURPOSE: The levels of interleukin-6 (IL-6) are frequently elevated in sera from patients with advanced prostate carcinoma. Our main objective was to investigate changes in responsiveness to IL-6 and/or androgen that occur in LNCaP cells after long-term treatment with IL-6. This in vitro model could be of clinical relevance because of its similarity with late-stage prostate carcinoma. EXPERIMENTAL DESIGN: LNCaP human prostate cancer cells were treated with IL-6 at a concentration of 5 ng/ml. After 20 passages, the new subline LNCaP-IL-6+ has been established. Passages 20-40 are referred to as low passages (LP) and passages 41-73 as high passages (HP). LNCaP cells passaged at the same time in the absence of IL-6 were used as controls (LNCaP-IL-6-). Cells were counted after treatment with either IL-6 or the synthetic androgen methyltrienolone (R1881), and cell cycle analysis was performed. Binding of IL-6 or R1881 was assessed by radioligand binding assays. Reporter gene activity was measured by chloramphenicol acetyltransferase assay. Prostate-specific antigen in LNCaP-IL-6+ supernatants was measured by an enzyme immunoassay. Expression of IL-6 mRNA and protein was assessed by reverse transcription-PCR and ELISA, respectively. RESULTS: The basal proliferation rate in HP LNCaP-IL-6+ cells was higher than that in LNCaP-IL-6- cells. IL-6 inhibited proliferation of LNCaP-IL-6- cells but not that of either LP or HP of LNCaP-IL-6+ cells. This inability to elicit a growth-inhibitory response was associated with lack of effect on cell cycle distribution in the LNCaP-IL-6+ subline. In parallel, IL-6 binding decreased gradually during long-term IL-6 treatment and, in HP, reached only 33% of the levels measured in controls. Binding of radiolabeled androgen increased 2-fold in HP LNCaP-IL-6+ cells. Reporter gene assays revealed that R1881, at nanomolar concentrations, was a more potent androgen receptor activator in LNCaP-IL-6+ than in LNCaP-IL-6- cells. However, androgen- and IL-6-induced prostate-specific antigen secretion decreased in long-term IL-6-treated cells. IL-6 cDNA fragments were detected by reverse transcription-PCR in HP LNCaP-IL-6+ cells but not in controls or LP. IL-6 protein was first detected in passage 36 of LNCaP-IL-6+ cells, and it increased in HP. CONCLUSIONS: Long-term treatment of LNCaP human prostate cancer cells with IL-6 leads to abolishment of inhibitory growth response. In contrast to control cells, the LNCaP-IL-6+ subline expresses IL-6 mRNA and protein.

Ureteroileal anastomosis in orthotopic urinary diversion: how much or how little is necessary?

PURPOSE: An increasing number of patients with an orthotopic neobladder and their expanding life expectancy necessitate an effective antireflux protection of the upper urinary tract. During the evolution of urinary diversion in the 20th century, several techniques to perform an ureteroileal anastomosis have been introduced. Those techniques most commonly used for orthotopic neobladders are discussed. MATERIALS AND METHODS: Vascularization of both the ureteral ends and the recipient bowel as well as a meticulous surgical technique are necessary to reduce the reported postoperative stricture rate, which ranges between 3% and 30%. Variations such as preservation of additional periureteral adventitial tissue and its use for coverage of the ureterointestinal suture line are described. High-pressure urinary reflux may lead to mechanical damage of the renal parenchyma, whereas low-pressure occasional reflux in conjunction with chronic bacteriuria will lead to pyelonephritic changes and eventually deterioration of renal function. An intraluminal valve mechanism with increasing efficiency during pouch filling is clearly the most physiological form of antireflux mechanism. Interposition of an afferent ileal limb in addition to the antireflux valve seems advantageous due to the favorable vascularization in the dissected midureter. CONCLUSIONS: Increased life expectancy in patients with orthotopic neobladders will increase the number of cases where access to the upper urinary tract becomes necessary due to a benign or malignant disease. Any technique that simultaneously provides an efficient antireflux mechanism and facilitates retrograde manipulation of the ureters (via the pouch) will be greatly appreciated by both patients and treating physicians.

Laparoscopic retroperitoneal lymph node dissection.

PURPOSE: Retroperitoneal lymph node dissection is the most sensitive and specific diagnostic modality for detecting occult lymph node metastases in clinical stage I testicular tumor. In stage II disease, residual tumors after chemotherapy have to be removed surgically. To reduce the morbidity of these procedures we have replaced open surgery by laparoscopy. PATIENTS AND METHODS: Between August 1992 and December 1999 125 patients underwent laparoscopic RPLND (stage I: 76 pts., stage II: 49 pts.) RESULTS: Laparoscopic RPLND could be completed as planned in all but two patients in whom bleeding required conversion to open surgery. Once the learning curve had been overcome, mean operative time decreased significantly from 476 to 219 min for stage I and averaged 226 min in stage IIB disease. Only minor postoperative complications occurred such as asymptomatic lymphoceles (7 pts.) and chylous ascites (6 pts.). Mean post-op hospital stay was 3.3 and 3.5 days, respectively (stages I and II). Mean followup is currently 46 months for stage I and 35 months for stage II tumors. Over this period a single retroperitoneal recurrence was observed (stage I), which, however, was not due to surgical failure, but to false negative histologic findings. All other patients have remained free of relapse. CONCLUSIONS: Laparoscopic RPLND is a demanding procedure with a long and steep learning curve. It has proved feasible also after chemotherapy. The diagnostic accuracy of laparoscopic RPLND was as good as that of the open procedure, while the morbidity is significantly lower. Tumor control was not compromised by the laparoscopic approach.

Interleukin-6 and prostate cancer progression.

Prostate cancer, while initially dependent on androgens for proliferation, progresses to an androgen-independent state. Evidence has been accumulating that interleukin-6 (IL-6) may contribute to prostate cancer progression. Serum levels of IL-6 correlate with prostate tumor burden and patient morbidity. The prostate tissue itself appears to be a source of IL-6 and its receptor. Furthermore, experimental data suggest that IL-6 is an autocrine and paracrine growth factor for androgen-independent prostate cancer cell lines. For example, inhibition of IL-6, with anti-IL-6 antibody, sensitizes androgen-independent prostate cancer cells to chemotherapeutic agents in vitro. Finally, IL-6 activates a variety of signal transduction cascades, some which stimulate androgen receptor activity, in prostate cancer cells. These data suggest that targeting IL-6 may have multiple benefits in prostate cancer patients.

Predictive value of total and percent free prostate specific antigen in high grade prostatic intraepithelial neoplasia lesions: results of the Tyrol Prostate Specific Antigen Screening Project.

PURPOSE: We evaluate the predictive values of total and percent free prostate specific antigen (PSA) in regard to high grade intraepithelial lesions in volunteers who participated in the Tyrol PSA Screening Project. MATERIALS AND METHODS: Between June 1995 and December 1998, 1,474 patients undergoing transrectal biopsy of the prostate were evaluated. The primary detection rates of prostate cancer and high grade intraepithelial lesions were evaluated. In addition, the rate of prostate cancer detected on biopsy in patients diagnosed with high grade prostatic intraepithelial neoplasia on the previous biopsy was assessed. Mean total PSA values and mean percent free PSA levels were determined for each study group and compared using the Mann-Whitney U test. RESULTS: A total of 1,077 (73.1%) volunteers had benign prostatic hyperplasia or prostatitis, and 327 (22.2%) had prostate cancer. The primary detection rate for high grade intraepithelial lesions was 4.7% (70 patients) and on repeat biopsy was 38.6% (27). Mean total PSA for the benign prostatic hyperplasia, prostate cancer, high grade and intraepithelial cancer groups were 6.0, 8.7, 5.9 and 5.2 ng./ml., respectively. Mean percent free PSA values for the various groups were 21.9, 12.1, 15.0 and 12.0, respectively. In regard to total PSA there was a statistically significant difference between the prostate cancer and high grade prostatic intraepithelial neoplasia groups (p = 0.016), as well as the prostate cancer and intraepithelial cancer groups (p = 0.028). However, the high grade and intraepithelial cancer groups did not differ significantly. In regard to percent free PSA there were statistically significant differences between the prostate cancer and high grade prostatic intraepithelial neoplasia groups (p = 0.0001), and the high grade and intraepithelial cancer groups (p = 0.013). CONCLUSIONS: In regard to percent free PSA our data indicate a significant difference between high grade intraepithelial lesion and intraepithelial cancer. Due to a substantial overlap in percent free prostate specific antigen between the 2 groups, a clinically useful cutoff point could not be established. Therefore, we recommend repeat biopsy in all patients with high grade intraepithelial lesions regardless of the percent free PSA.

Life after cystectomy and orthotopic neobladder versus ileal conduit urinary diversion.

Patients frequently complain about changes in their everyday life after radical cystectomy and urinary diversion. The aim of this study was to compare subjective morbidity of ileal neobladder to the urethra versus ileal conduit urinary diversion and to elucidate its influence on quality of life. A total of 102 patients who underwent radical cystectomy due to a bladder malignancy were included in the study: 69 patients (67.6%) with an orthotopic neobladder and 33 patients (32.4%) with an ileal conduit. The compliance was 99% and mean follow-up was 37 months. All patients completed two retrospective quality-of-life questionnaires, namely the QLQ-C30 and a questionnaire developed at our institution to elucidate specific items regarding urinary diversion. The questioning was performed by a nonurologist. The results obtained from the validated (QLQ-C30) and our self-designed questionnaire clearly demonstrate that patients with an orthotopic neobladder better adapt to the new situation than patients with an ileal conduit. In addition, neobladder to the urethra improves quality of life due to a better self-confidence, better rehabilitation as well as restoration of leisure, professional, traveling, and social activities, and reduced risk of inadvertent loss of urine. For example, 74.6% of neobladder patients felt absolutely safe with the urinary diversion in contrast to 33.3% in the ileal conduit group. Only 1.5% of neobladder patients had wet clothes caused by urine leakage during day versus 48.5% of ileal conduit patients; 92.8% of neobladder patients felt not handicapped at all; and 87% felt not sickly or ill in contrast to 51.5% and 66.7% of ileal conduit patients, respectively. Moreover, 97% of our neobladder patients would recommend the same urinary diversion to a friend suffering from the same disease in contrast to only 36% of ileal conduit patients. The results obtained by this study demonstrate that quality of life is preserved in a higher degree after orthotopic neobladder than after ileal conduit urinary diversion.

VI--choosing the right reconstruction for your female patients.

Like in male patients, selection of female patients for an orthotopic neobladder is important from an oncological and functional standpoint. The anatomy and the behavior of the isolated urethra in women had to be restudied because of the shorter urethra, the absence of the prostate, an undefined level of urethral dissection, and the different anatomy of the urethral sphincter-system. Retrospective long-term observations of female patients with primary bladder cancer revealed a 2% incidence of secondary urethral tumors in women. The only significant risk factor for urethral tumor involvement was primary bladder cancer at the bladder neck. Any type of gastrointestinal segment may be used for creating a pouch in women. As a result of an approximately 15% possibility of urinary retention or larger post-void residuals, the use of an efficient antireflux valve mechanism seems prudent. Clinical experience in an increasing number of women confirms the preliminary favorable results. Despite the selection criteria outlined in this article, most women can safely and rewardingly be offered an orthotopic neobladder.

Photodynamic diagnosis with 5-aminolevulinic acid in the treatment of secondary urethral tumors: first in vitro and in vivo results.

OBJECTIVES: Photodynamic diagnosis (PDD) is able to detect dysplasia and transitional cell cancer of the bladder. We report our first experiences using PDD in the urethra. MATERIALS AND METHODS: Three patients with secondary transitional cell cancer of the urethra were treated by using PDD. 5-Aminolevulinic acid (ALA) was applied in a mixture with lubricant to achieve long enough contact with the urothelium. Negative effects were tested in vitro on three bladder cell lines. RESULTS: In vitro assays showed no enhanced negative effects on the viability of bladder cells using the combination of ALA/lubricant and medium in comparison to lubricant/medium alone. All patients showed markedly fluorescent areas, which were resected. The treatment was well tolerated without side effects attributable to the photosensitizer containing lubricant. CONCLUSION: Lubricant with ALA forms a viscous solution, which can successfully be used for PDD in the urethra. Thus marking tumors by fluorescence may improve transurethral resection and thus preserve the urethra.

Androgen receptor mutations in carcinoma of the prostate: significance for endocrine therapy.

Endocrine therapy for advanced prostate cancer involves androgen ablation (orchiectomy or application of luteinizing hormone releasing hormone analogs) and/or blockade of the androgen receptor (AR) with either steroidal (cyproterone acetate) or nonsteroidal (hydroxyflutamide, bicalutamide and nilutamide) antiandrogens. These antagonists prevent androgen-induced conformational change and activation of the AR. During long term androgen ablation, the AR adapts to an environment with low androgen concentrations and becomes hypersensitive to low concentrations of androgens, either alone or in combination with various cellular regulators. Bicalutamide can switch from antagonist to agonist during long-term androgen withdrawal, as shown in prostate cancer LNCaP cells. AR point mutations were detected in metastatic lesions from human prostate cancer more frequently than in primary tumors. Although functional characterization of only some mutant AR detected in prostate cancer tissue has been performed, data available suggest that they are activated by dihydrotestosterone, its precursors and metabolites, synthetic androgens, estrogenic and progestagenic steroids and hydroxyflutamide. A direct association between AR mutations and endocrine withdrawal syndrome has been investigated in only one study thus far. There is no evidence at present that activation of any of the mutant AR genes detected in prostate cancer is enhanced in the presence of a nonsteroidal AR stimulator. Coactivators of the AR are proteins that associate with the receptor, possess histone acetylase activity and facilitate AR activation. The coregulatory proteins ARA70 and ARA160 differentially affected the activity of the mutated AR Glu(231)-->Gly, which was discovered in a mouse authochthonous prostate tumor. ARA70 enhanced receptor activation by both androgen and estradiol, whereas ARA160 augmented only androgen-induced AR activity. Novel experimental therapies that down-regulate AR expression have been developed; they include the application of ribozymes and antisense oligonucleotides.

Quality of life after cystectomy and orthotopic neobladder versus ileal conduit urinary diversion.

The impact of bladder removal and urinary diversion for patients' everyday life is largely unknown. The aims of this study were to compare subjective morbidity of ileal neobladder to the urethra versus ileal conduit urinary diversion and to elucidate its influence on quality of life. A total of 102 patients who underwent cystectomy due to a bladder malignancy were included in the study. In 69 patients (67.6%) an orthotopic neobladder and in 33 patients (32.4%) an ileal conduit was performed as urinary diversion. The compliance was 99% and mean follow-up was 37 months. All patients completed two retrospective quality of life questionnaires, namely the QLQ-C30 and a questionnaire developed at our institution to ask for urinary diversion specific items. The questioning and assessment was performed by non-urologists. The results obtained from the validated (QLQ-C30) and our own specially compiled questionnaire clearly demonstrate that patients with an orthotopic neobladder are more able to adapt to the new situation than patients with an ileal conduit. In addition, neobladder to the urethra improves the quality of life because it improves self-confidence, causes better rehabilitation as well as the restoration of leisure, professional, travelling, and social activities, and reduced risk of inadvertent loss of urine. For example, 92.8% of neobladder patients did not feel handicapped at all, and 87% did not feel sick or ill, in contrast to 51.5% and 66.7% of ileal conduit patients, respectively. Of the neobladder patients, 74.6% felt absolutely safe with the urinary diversion in contrast to 33.3% in the ileal conduit group. Only 1.5% of neobladder patients had wet clothes caused by urine leakage during the day, versus 48.5% of ileal conduit patients. Moreover, 97% of our neobladder patients would recommend the same urinary diversion to a friend suffering from the same disease, but only 36% of ileal conduit patients would do so. These results demonstrate that the quality of life is preserved to a higher degree after orthotopic neobladder than after ileal conduit urinary diversion.

Expression and function of androgen receptor in carcinoma of the prostate.

This article reviews recent findings on androgen receptor expression, structure, and function in carcinoma of the prostate. In this decade, it became clear that androgen-resistant prostate cancers contain androgen receptors and, therefore, regulation of androgen receptor expression and function receives considerable attention. The article summarizes findings on regulation of androgen receptor expression by androgens, growth factors, and protein kinase A activators. In addition, modulation of function of the wild-type and mutant AR is discussed. Androgen receptor functional activity is up-regulated by androgens and nonsteroidal activators, which influence transcription of androgen receptor-regulated genes in a cell type-dependent manner. This study also contains a chapter on androgen receptor-associated proteins, coactivators, and coreppressors and their possible role in pathological situations.