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M Burchardt

Publications and source records attributed to M Burchardt.

At least 19 recordsLinked to original sources
PubMed2006

Nitric oxide-mediated inhibition of androgen receptor activity: possible implications for prostate cancer progression.

Chronic inflammation increases the risk of cancer and many cancers, including prostate cancer, arise at sites of chronic inflammation. Inducible nitric oxide synthase (iNOS) is an enzyme dominantly expressed during inflammatory reactions. Although synthesis of high amounts of nitric oxide (NO) by iNOS has been demonstrated in pathophysiological processes, such as acute or chronic inflammation, autoimmune diseases or tumorigenesis, the role of iNOS activity in most of these diseases is poorly understood. Analysing prostate cancer biopsies by immunohistochemistry we found iNOS protein expression in tumor cells strongly paralleled by nitrotyrosine suggesting that iNOS is fully active. In vitro, NO inhibits androgen receptor-dependent promoter activity and prostate specific antigen production as well as DNA-binding activity of the androgen receptor (AR) in a concentration-dependent manner. Inhibition of the activity of androgen receptor-dependent reporter constructs is neither owing to diminished AR protein levels nor owing to an inhibition of its nuclear import. In addition, NO inhibits the proliferation of androgen receptor-positive prostate cancer cells significantly more efficiently than proliferation of androgen receptor-negative prostate cancer cells. In summary, our findings suggest that intratumoral iNOS activity favors development of prostate cancer cells that are able to proliferate androgen receptor-independently, thereby promoting prostate tumor progression.

Androgen Receptor Antagonists↗
PubMed2006

Transurethral microwave thermotherapy for the treatment of BPH: still a challenger?

Minimally invasive therapies for treatment of benign prostatic hyperplasia (BPH) compete with the gold standard transurethral resection of the prostate (TURP). Comparisons of efficacy and safety have broadened the knowledge of different treatment modalities. Concerns of quality of life such as unaltered sexual function as well as cost considerations drive the market to develop techniques of lower level invasiveness. Among the competitors the office based transurethral microwave thermotherapy (TUMT) provides the broadest scale of scientific data. Numerous manufacturers sell various modifications of this technology. According to different clinical studies TUMT proved to be an effective, safe, and durable therapy for the treatment of lower urinary tract symptoms (LUTS) secondary to BPH. However, TURP still holds the steadier long-term results and is more effective to reduce obstruction as well as other LUTS.

Humans↗
PubMed2005

Effects of WNT/beta-catenin pathway activation on signaling through T-cell factor and androgen receptor in prostate cancer cell lines.

Dysregulation of the WNT/beta-catenin pathway is thought to contribute to prostate cancer progression. Mutations of beta-catenin occurring in 5-7% of advanced prostate cancers may act by stimulating TCF-dependent and/or androgen receptor (AR)-dependent transcription. Using a reporter gene approach we found overexpressed mutated beta-catenin to enhance AR-regulated probasin-promoter activity in the AR-positive prostate cancer cell line 22Rv1, particularly at low androgen levels. In 22Rv1 cells mutated beta-catenin was able to stimulate TCF-dependent transcription but was unable to do so in LNCaP cells where it activates the AR. Since beta-catenin mutations are rare in vivo, we studied further possible routes of WNT-pathway modulation. Higher concentrations of LiCl, a GSK3beta-inhibitor, were required to activate TCF-dependent rather than AR-dependent reporter constructs. In 22Rv1 overexpression of E-cadherin repressed androgen-dependent transcription, but did not inhibit transcription of TCF-dependent reporter genes as in bladder cancer cell lines. Interestingly, Wnt-3a stimulated proliferation selectively in the AR-positive prostate cancer cell lines 22Rv1 and LNCaP, even though TCF-dependent reporter gene transcription was not induced in LNCaP cells. In summary, the data from our study support the idea that activation of WNT/beta-catenin signaling in AR-positive prostate cancer cells may predominantly act through AR-dependent mechanisms rather than classical TCF-dependent mechanisms.

Cell Proliferation↗
PubMed2003

[Perspectives for molecular diagnostics exemplified by urothelial bladder carcinoma].

The rapidly growing knowledge of molecular mechanisms will change the daily routine of clinicians in the near future. Regarding urothelial bladder carcinoma, one may expect that molecular diagnostics will identify patients susceptible to disease development by screening their genotype. Furthermore, in addition to histopathologic findings, prognostic markers will be used for disease management. In an ongoing multicenter trial, the decision on whether or not to treat patients with adjuvant chemotherapy after cystectomy is based on their p53 status. In the near future, cytostatic medications are expected to be chosen according to genetic profiles of the tumor or patient. New medications, which target tumor-specific alterations of cell-signaling cascades in bladder or other cancers, prominently inhibitors of the ERBB membrane receptor family, are currently under clinical investigation and will undoubtedly form an important part of therapeutic oncologic regimens. In conclusion, evaluation of gene profiles of tumors and patients will gain importance for clinicians.

Cell Transformation, Neoplastic↗
PubMed2003

Fibroblast growth factors and their receptors in urological cancers: basic research and clinical implications.

Because therapeutical options for advanced urological cancers are limited, the understanding of key elements responsible for invasion and metastasis is very important. It has been hypothesized that progression to malignant growth is associated with a dysregulation of growth factors and/or their receptors. In the last few years, signaling pathways of the fibroblast growth factor (FGF) family have been subject to intense investigation. Fibroblast growth factors constitute one of the largest families of growth and differentiation factors for cells of mesodermal and neuroectodermal origin. The family comprises two prototypic members, acidic FGF (aFGF) and the basic FGF (bFGF), as well as 21 additionally related polypeptide growth factors that have been identified to date. FGFs are involved in many biological processes during embryonic development, wound healing, hematopoesis, and angiogenesis. In prostate, bladder, and renal cancers, FGFs regulate the induction of metalloproteinases (MMP) that degrade extracellular matrix proteins, thus facilitating tumor metastasis. Probably due to their potent angiogenic properties, aFGF and bFGF have received the most attention. However, there is increasing evidence that other FGFs also play crucial roles in tumors of the prostate, bladder, kidney, and testis. This review will discuss the different elements involved in FGF signaling and summarize the present knowledge of their biological and clinical relevance in urological cancers.

Animals↗
PubMed2003

Cavernous nerve graft reconstruction during radical prostatectomy or radical cystectomy: safe and technically feasible.

High local stage prostate and bladder cancers frequently require wide local resection and sacrifice of one or both cavernous nerves to achieve a negative surgical margin, thus resulting in erectile dysfunction. This is a report on preliminary experience with cavernous nerve graft reconstruction using sural nerve grafts with radical prostatectomy or radical cystectomy.Pre-operative evaluation was performed and consent was obtained in 14 potent men with prostate (11) or bladder (three) cancer. Sural nerve grafts of resected cavernous nerves were performed using a microsurgical technique. Post-operative treatment (Sildenafil or Alprostadil) was pursued until return of spontaneous function, documented by interview and adequate scores (>20) in the erectile function (EF) domain of the International Index of Erectile Function (IIEF).Twelve unilateral nerve grafts were performed, 10 during radical prostatectomy and two during radical cystoprostatectomy. Two procedures were technically not possible because of locally advanced disease. Mean age was 57.5 y (36-68 y). Mean follow up was 16.1 months (7-28 months). Pathological stage of prostate cancer was pT2 in 2, pT3 in 7 and pT4 in one. Surgical margins were positive in five out of 10 (50%), and two (20%%) had positive lymph nodes. Four patients (three post prostatectomy and one post cystectomy) were fully potent. Additionally, one patient post prostatectomy had improving partial erections. Six patients post prostatectomy and one patient post cystectomy had no erections. The only complication was one superficial wound infection in the sural nerve donor site. Preliminary experience shows that sural nerve grafts are feasible and safe after radical prostatectomy and cystectomy. However, candidates usually present with high stage disease, high risk for recurrence and frequent requirement for adjuvant therapy that further compromises erectile function. Randomized studies with more patients and long follow-up periods are necessary in order to define the ideal candidate for nerve graft procedures.

Adult↗
PubMed2003

Molecular biology of prostate cancer.

In spite of progress in diagnosis and treatment, prostate cancer has become one of the most frequent lethal cancers in males in many Western industrialized countries. Research on the molecular biology of prostate cancer is expected to reveal those aspects of Western lifestyle contributing to its high incidence with the aims of improving prevention, distinguishing slow-growing from aggressive clinically relevant cancers, and providing targets for treatment, particularly of locally advanced and of metastatic disease. Traditionally, prostate cancer research focused on androgens. More recently, tumour suppressors and proto-oncogenes important in other human cancers have been intensely investigated. Current approaches include the search for genes mutated in familial cases, identification of recurrent chromosomal alterations and their associated potential tumour suppressor genes, determination of gene expression profiles characterizing tumour stages and subclasses, and elucidation of the importance of epigenetic alterations. Results from such studies have begun to be translated into the clinic. Further successful transfer of results from molecular biology to the clinic will, however, require integration of the amassed molecular data into a biological framework model of prostate carcinoma.

Aged↗
PubMed2003

The androgen receptor in hormone-refractory prostate cancer: relevance of different mechanisms of androgen receptor signaling (Review).

The last decade has brought increased awareness to prostate cancer as a significant health problem. Prostate cancer is very heterogeneous in its etiology and progression, but androgen signaling appears to be a common key element in its development and progression. Blocking of androgen signaling results in a decrease in tumor volume as well as a decline in serum PSA in the majority of patients with prostate cancer. Today, endocrine therapy involves androgen depletion by orchiectomy or by treatment with LHRH-analoga as well as blockade of the androgen receptor (AR) with anti-androgens. However, during these treatments almost all tumors relapse to a hormone-insensitive state. The mechanisms that lead from initially androgen-sensitive to androgen-unresponsive tumor cell growth have been partly elucidated by new insights into the molecular mechanisms of androgen receptor signaling over the past several years. In addition to androgen receptor mutations that broaden the ligand-specificity of the AR, androgen-independent transactivation of the AR by peptide growth factors such as epidermal growth factor and insulin-like growth factor-I has been discovered. Furthermore, analysis of proteins that interact with the AR led to the isolation of coactivator proteins that mediate transcriptional activation by the AR. The following review will discuss the elements involved in androgen receptor signaling and summarize the present knowledge of their biological and clinical relevance in advanced prostate cancer.

Cell Division↗
PubMed2002

[Results of comprehensive data collection concerning urologic laparoscopy].

To evaluate the current status of laparoscopy, the "Working Group Laparoscopy" of the German Urological Association performed a questionnaire among urologists in Germany. Of 300 questionnaires 183 were returned and analyzed (61%): 54% of the departments already performed laparoscopy and another 50% are planning to introduce this technique. The major concerns are economical (70%), long learning curve (92%), investment (53%), and lack of scientific data (76%). Simple nephrectomy, cryptorchism, and varicoceles are treated by 66, 59, and 58 of the 96 departments laparoscopically (of 183 resp.). Laparoscopic surgery for radical prostatectomy and tumor nephrectomy is done by 32 and 34 of 96 departments. Only a minority of the centers performs more than 40 laparoscopies per year and indication. Compared to a survey conducted in 1995, the acceptance level of this technique has increased (100% vs 48%). Only a minority of the departments performs more than 40 laparoscopic interventions per year for one indication.

Attitude of Health Personnel↗
PubMed2001

Reduction of wild type p53 function confers a hormone resistant phenotype on LNCaP prostate cancer cells.

BACKGROUND: The protein encoded by the p53 gene is required for some forms of apoptosis and loss or mutations in this gene are found with increased frequency in advanced and hormone resistant human prostate cancers. In order to better appreciate whether reduction of wildtype p53 function in prostate cancer cells might contribute to the development of therapeutic-resistance by these cells, we created stable variants of the androgen-responsive, wild type p53-expressing human prostate cancer cell line, LNCaP, by transfection with expression vectors designed to reduce expression or function of wildtype p53 in them. These cells were then tested for their ability to form tumors in castrated male nude mice. METHODS: A conditional eukaryotic expression vector (under tetracycline regulation) expressing antisense p53 cDNA was constructed and either directly transfected into LNCaP cells or tranduced into these cells using recombinant retroviruses containing the vector. Stably transfected/transduced cells (LNCaP/Asp53) were evaluated by Western blot analysis for the ability of doxycycline to reduce p53 protein expression and for their ability to form tumors in castrated male nude mice treated or untreated with doxycycline. Additionally, we derived an LNCaP subline (LNCaP/DD) stably expressing a dominant-negative form of p53 and tested these cells for their ability to form tumors in castrated male nude mice. RESULTS: LNCaP/Asp53 cells showed reduced expression of p53 protein when cultured in a medium containing doxycycline and tested sublines were able to efficiently form tumors in castrated male nude mice only when the mice were treated with doxycycline. LNCaP/DD cells were readily able to form tumors in castrated male nude mice whereas parental LNCaP cells or control-transfected LNCaP cells were not. CONCLUSION: Loss of wildtype p53 function can contribute to the phenotype of hormone resistance of prostate cancer cells.

Animals↗
PubMed2001

Erectile dysfunction is a marker for cardiovascular complications and psychological functioning in men with hypertension.

The aim of this study was to investigate the incidence of cardiovascular complications in hypertensive patients with erectile dysfunction (ED). An anonymous questionnaire was mailed to 467 and received from 104 hypertensive male patients. Despite the low response rate of 22%, the following interesting findings could be observed: 70.6% of the patients who responded suffered from ED. The hypertensive patients with ED had significantly higher prevalence of cardiovascular complications (P < 0.05). The correlation between depression and low quality of life as well as between ED and low sexual satisfaction was also statistically significant (P = 0.05). ED in hypertensive patients can be considered as a marker for cardiovascular complications in this patient group.

Adult↗
PubMed2001

Long-term outcomes of inflatable penile implants: reliability, patient satisfaction and complication management.

Despite the revolutionary introduction of oral erectogenic agents for the treatment of erectile dysfunction, there will always be patients who do not respond to conservative therapy. Penile prosthetic surgery remains an important option for these patients. Mechanical reliability and patient satisfaction have improved significantly throughout the years. This review focuses on the most recent and important updates regarding product enhancements, patient satisfaction studies, and management of intra- and postoperative problems.

Erectile Dysfunction↗
PubMed2001

Biomarker analysis demonstrates a hypoxic environment in the castrated rat ventral prostate gland.

Within the first 24 h after castration of an adult male rat, the vascular system of the ventral prostate gland undergoes a degenerative process that drastically reduces blood flow to the tissue. Since the vascular degeneration precedes the loss of the prostatic epithelium (by apoptosis), we have proposed that the onset of epithelial cell apoptosis in this tissue is caused by an ischemic/hypoxic environment resulting from the loss of blood flow. In order to further evaluate the extent to which ischemia/hypoxia might be a factor in apoptosis of the prostate epithelium after castration, we analyzed for biomarkers of cellular hypoxia in rat ventral prostates during the first 3 days following castration. Ventral prostate tissues removed from hypoxyprobe-1-treated adult male rats (uncastrated controls; surgically castrated for 24, 48 or 72 h, or sham-castrated for equivalent times) were directly analyzed for evidence of hypoxia by in situ immunohistochemical evaluation of hypoxyprobe-1 adduct formation in the prostate cells. Protein extracts from these tissues were also tested for expression of the 120 kDa hypoxia-inducible factor-1-alpha (HIF-1-alpha) protein as well as for expression of mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) proteins using a Western blot assay. The tyrosine phosphorylation status of the latter signaling molecules was also evaluated by Western blotting using anti-tyrosine phosphate antibodies. Our results showed that epithelial cells of the rat ventral prostate stained positively for hypoxyprobe-1 adducts at all times after castration, whereas cells in control tissues were unstained by this procedure. In addition, the prostatic expression of HIF-1-alpha protein was increased approximately 20-fold at 48 h after castration compared to control tissues. Finally, although prostatic MAPK and JNK protein expression was unaltered during the early period after castration, phosphorylation of the JUN kinase protein was significantly elevated, indicating that this stress-activated cellular signaling pathway becomes more active subsequent to castration. These results support our proposal that early castration-induced degeneration and constriction of the vascular system of the rat ventral prostate gland leads to reduced oxygenation of prostatic epithelial cells and the activation of hypoxic cellular signaling in these cells through upregulation of HIF-1-alpha expression and stimulation of the JUN kinase signaling pathway.

Animals↗
PubMed2000

Blood-based RT-PCR assays of MN/CA9 or PSMA: clinical application in renal cancer patients.

OBJECTIVES: To report a survey of blood-based RNAs obtained from common groups of control and renal cancer patients for expression of both MN/CA9 and prostate-specific membrane antigen (PSMA) messenger RNAs. METHODS: Reverse transcription polymerase chain reaction (RT-PCR) assays for MN/CA9 and PSMA were performed on RNAs extracted from 81 blood samples (59 patients with renal cancer, 7 with benign tumors, and 15 control volunteers). The results of these assays were statistically analyzed to determine whether a positive result (individually or combined) correlates with any tumor characteristics. RESULTS: Neither MN/CA9 nor PSMA amplification products were detected in the RNAs from peripheral blood samples of the 15 control volunteers and from the 7 patients with benign renal tumor (sensitivity 100%). MN/CA9 alone was detected in 11 (19%) of 59 samples and PSMA alone in 12 (20%) of 59 samples from patients with renal cancer. PSMA positivity was significantly correlated with vascular invasion of the primary tumor. Expression of one or both of these molecular tumor markers was detected in 21 (36%) of 59 renal cancer patients. When combined, the results of the MN/CA9 and PSMA RT-PCR tests were found to be highly associated with vascular invasion in nephrectomy specimens (sensitivity 67%, specificity 77%, odds ratio = 6.89, P = 0.002). CONCLUSIONS: Combination of RT-PCR assays for MN/CA9 and PSMA provides a sensitive blood test for molecular detection of clear cell carcinoma of the kidney and its potential for vascular invasion. Further testing of this assay will be required to evaluate its efficacy in the diagnosis, screening, and follow-up of patients with kidney cancer.

Adult↗
PubMed2000

Biomarkers of renal cell carcinoma. Past and future considerations.

Renal cancer includes several distinct entities with a range of biologic and clinical behaviors from relatively indolent to extremely aggressive tumors. Although conventional prognostic factors such as stage and grade are quite useful, other clinical, laboratory, and pathologic findings are now believed to have additional predictive values. This article reviews the literature on the potential utility of biomarkers in renal cell carcinoma. To date, only a few biomarkers, such as Ki-67, appeared to be potentially useful for monitoring renal cancer patients. New biomarkers including MN/CA9 and circulating cell detection require further and extensive studies to assess their potential clinical utility.

Journal Article↗
PubMed2000

Vascular endothelial growth factor-A expression in the rat ventral prostate gland and the early effects of castration.

BACKGROUND: Blood flow to the rat ventral prostate gland is drastically reduced during the very early period after castration, and this reduction coincides with the appearance of striking degenerative changes within the prostatic vascular system. These early effects on the prostate vascular system are likely to be important for the subsequent regression of the ventral prostate that occurs in response to castration. Since the endothelial cells of the ventral prostate do not express androgen receptor protein (AR), we proposed that these early effects might be indirectly mediated by changes in the local expression of vascular regulatory factors. In order to evaluate whether vascular endothelial growth factor-A (VEGF-A) might be among the primary mediators of these effects, we measured expression of VEGF-A mRNA and protein in the rat ventral prostate gland prior to and within the first 3 days after castration. METHODS: Ventral prostate tissues were obtained from control (unoperated) rats, sham-operated rats, or rats at sequential daily intervals (1-3 days) after castration. A quantitative RNase protection assay and a comparative RT-PCR assay were used to evaluate the extent to which the expression of VEGF-A mRNA in the ventral prostate was affected by castration. In situ immunohistochemistry, using an anti-VEGF-A antibody, was performed to localize VEGF-A protein in the various cells of the tissue. Western blot analysis and a quantitative ELISA assay using anti-VEGF-A antibodies were performed to determine how VEGF-A protein expression in the rat ventral prostate was affected by castration. RESULTS: Results of VEGF-A mRNA analysis in the rat ventral prostate gland during the first 3 days after castration showed a biphasic change characterized by a transient reduction of VEGF-A mRNA expression (by approximately 50%) on the second day after castration that was restored to higher than control levels by the third day after castration. Immunohistochemical analysis for VEGF-A in control and castrated ventral prostates showed that the prostatic epithelial and smooth muscle cells were the major source of VEGF-A expression in this tissue. Quantitative analysis of VEGF-A protein expression by Western blot and ELISA methods confirmed a biphasic change in the expression of the polypeptide that correlated well with the results of the mRNA analyses. CONCLUSIONS: VEGF-A expression in the ventral prostate gland of the Sprague-Dawley rat is downregulated on the second day after castration but returns to control levels by the third day after castration. Since critical changes in the ventral prostate vascular system are already evident by 1 day after castration, we believe that these findings indicate that VEGF-A is not likely to be the critical or sole mediator of the early effects of castration on the vascular system of the rat ventral prostate gland.

Androgens↗
PubMed2000

Acute increase in blood flow to the rat bladder subsequent to partial bladder outlet obstruction.

Partial obstruction of the rat bladder outlet initiates a multi-step process during which the bladder progressively loses its functional ability. The first step in this progression is bladder hypertrophy; the organ dramatically increases in size and weight to compensate for the effects of obstruction. Unoperated female rats, age-matched, sham-obstructed rats, and rats that received a partial bladder outlet obstruction were studied. During the first 24 hours after partial bladder outlet obstruction, relative bladder blood flow was measured using a fluorescent microsphere infusion technique and laser Doppler imaging. Nitric oxide synthase (NOS) activities of control and obstructed rat bladder tissues were determined using an enzymatic assay that measures the conversion of (3)H-L-arginine to (3)H-L-citrulline. Using the microsphere infusion technique, a significant increase in blood flow to the obstructed rat bladder was observed during the first 24 hours after partial bladder outlet obstruction. Relative bladder blood flow increased approximately sixfold at 4 and 6 hours post-obstruction and remained elevated through 24 hours of obstruction. Sham operations (evaluated after 6 hours after surgery) resulted in a minor increase in blood flow that did not reach statistical significance. Relative blood flow to the spleen, measured in the same rats, was not significantly changed. Laser Doppler measurements also identified a significant increase in rat bladder blood flow after outlet obstruction and showed that increased blood flow could be detected as early as 1 hour post-obstruction. Interestingly, despite the significant differences in bladder blood flow between control and early post-obstructed rat bladders, NOS activities of control and obstructed rat bladders were comparable. The increase in bladder blood flow precedes the urothelial, fibroblast and smooth muscle cell hyperplasia, and the smooth muscle hypertrophy that occurs after obstruction. We propose that, in response to surgical induction of partial outlet obstruction, acute up-regulation of bladder blood flow may be an initiating factor for subsequent bladder cell proliferation and smooth muscle hypertrophy. Neurourol. Urodynam. 19:195-208, 2000.

Animals↗