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T Zwergel

Publications and source records attributed to T Zwergel.

At least 19 recordsLinked to original sources
PubMed2004

Proteasome inhibitors and their combination with antiandrogens: effects on apoptosis, cellular proliferation and viability of prostatic adenocarcinoma cell cultures.

The 26S proteasome is a ubiquitin-dependent proteolytic system that has been implicated in the regulation of cell cycle progression and apoptosis. We investigated the effects of the proteasome inhibitors MG115 and PSI alone or in combination with different concentrations of the antiandrogen hydroxyflutamide on the cellular proliferation, apoptosis and viability of 10 prostatic adenocarcinoma cell cultures. Treatment with both proteasome inhibitors resulted in apoptosis induction, whereas the combinations with hydroxyflutamide generally did not, with the exception of MG115 combined with 10(-7) M hydroxyflutamide. MG115 caused a significant decrease in cellular proliferation, as did the combinations of both proteasome inhibitors with hydroxyflutamide, whereas hydroxyflutamide alone was only effective at a concentration of 10(-5) M. Cellular viability was significantly reduced when both proteasome inhibitors were combined with 10(-5) M hydroxyflutamide. Although the results varied among different cell lines, we conclude that proteasome inhibitors are able to induce apoptosis and reduce cellular proliferation. They might prove effective as antineoplastic substances in prostatic adenocarcinoma alone or in combination with antiandrogens.

Adenocarcinoma↗
PubMed2004

[Proteasome inhibitors: induction of apoptosis as new therapeutic option in prostate cancer].

New perspectives in prostate cancer genesis and putative clinical management have emerged in recent years . Apoptosis plays a major role in this environment. Proteasome inhibitors block the action of a multicatalytic proteinase complex involved in the degradation of intracellular proteins, particularly with regard to cell cycle regulation and apoptosis. Numerous in vitro studies have demonstrated the ability of these compounds to induce apoptosis and enhance the activity of conventional tumoricidal agents in many cancer cell types, including prostate cancer cells. They point out the use of these potent inhibitors as a new potential molecular approach to the therapeutic management of prostate cancer. Furthermore, the action of proteasome inhibitors has been tested in animal models and in patients with hormone refractory prostate cancer, resulting in both PSA and tumor volume decrease. PS-341 (bortezomib, Velcade) is the first proteasome inhibitor with clinical application in cancer therapy that has been used in clinical trials to date. This report reviews the current status of those papers that have tried to analyze the connection between the proteasome pathway and apoptosis. We present our results of proteasome inhibition in individual prostate cancer cell lines. Proteasomal inhibition may offer a new therapeutic access in "molecular targeting" of prostate cancer.

Animals↗
PubMed2000

Novel amplification unit at chromosome 3q25-q27 in human prostate cancer.

BACKGROUND: In prostate carcinoma, amplification of the genes c-MYC, Her2/NEU, and the androgen receptor gene has been documented, with gene amplification being related to progressive tumor growth. Recently, using comparative genomic hybridization (CGH), we provided evidence for DNA copy number gains at chromosome 3q25-q26 in prostate cancer [Sattler et al.: Prostate 39:79-86, 1999]. METHODS: In this study, additional prostatic tumors were evaluated by CGH to determine the frequency of DNA overrepresentation at 3q. Comparative PCR and Southern blot analyses were applied to determine whether known genes are involved in DNA copy number gains. RESULTS: By CGH, DNA copy number gains, all of which involved chromosome region 3q25-q26, were disclosed in 50% of the prostate tumors analyzed. There was no evidence for high-level amplification. The analysis of 12 genes from 3q25-q27 by comparative PCR revealed amplification in 6 (35.3%) of 17 tumors tested. Amplification was detected for the genes IL12A, MDS1, SLC2A2, and SOX2, with coamplification of three genes in two tumors. IL12A was amplified as single gene in three tumors and in a subline of the DU145 cell line, SLC2A2 in one tumor. CONCLUSIONS: Our studies revealed a novel amplification unit at 3q25-q27 in prostate carcinoma, with the genes IL12A, MDS1, SLC2A2, and SOX2 being located within the amplification unit. A common region of amplification was evident spanning the IL12A gene locus at 3q25-q26.2. Possibly, IL12A indicates an adjacent, till now unidentified gene which is important in the development of prostate cancer.

Blotting, Southern↗
PubMed1999

Two different forms of p53 localized differently within cells of urogenital tumours.

We analyzed the subcellular localization of p53 in prostate and bladder carcinoma cells. Using laser scanning microscopy and PAb1620, a monoclonal antibody recognizing the wildtype conformation of p53, and another monoclonal antibody directed against the mutant conformation of the protein (PAb240), we found two different subsets of p53 within the same cell. The wildtype subgroup was found in the nucleolus, whereas the mutant protein was confined to the nucleus. The results obtained by immunofluorescence were verified by Western blot analysis and immunoprecipitation. Thus, our findings demonstrate an unusual subcellular localization pattern of p53 in prostate and bladder cancer cells which may indicate another mechanism of inactivation of p53.

Blotting, Western↗
PubMed1999

Comparative genomic hybridization reveals DNA copy number gains to frequently occur in human prostate cancer.

BACKGROUND: Despite intensive studies over many years, there is only limited knowledge on the genetic changes underlying the development and progression of prostate cancer. No specific prostate carcinoma-related genetic event has yet been identified. METHODS: In order to gain an overall view of regional chromosome gains and losses, comparative genomic hybridization (CGH) was used on a series of 16 prostate adenocarcinomas. Five benign prostate hyperplasia (BPH) samples were also evaluated. RESULTS: Using CGH, chromosome alterations were observed in 81% of the prostate carcinomas analyzed. Gains of DNA copy numbers were found as the predominant imbalance, with chromosomes 3q (56%), 12q (56%), 8q (50%), Xq (50%), 4 (44%), 6q (44%), 5 (38%), 7q (38%), 9p (38%), and 13q (31%) being most frequently involved. Whereas DNA copy number gains comprised the whole chromosome or almost a whole arm of chromosomes 4, 5, 6, 9, and 13, the minimal overlapping regions on the other chromosomes were mapped to 3q25-q26, 8q21-q22, 12q13-q21, 7q31, and Xq22-q25. High-level amplifications were not found. Other chromosomes with nonrandom gains or losses of DNA sequences were discovered. The five BPH samples were found to be normal. CONCLUSIONS: Amplification events at different chromosomal sites seem important in prostate cancer development. A new chromosome region with DNA copy number gains was identified on 12q, while other regions on 3q, 7q, 8q, and Xq were confirmed or narrowed down, indicating a possible role of known or putative protooncogenes in these regions for prostate cancer growth. Our low detection rate of DNA losses may to some part be explained by CGH immanent technical limitations.

Adenocarcinoma↗
PubMed1999

Focal intratumoral heterogeneity for telomerase activity in human prostate cancer.

PURPOSE: The value of telomerase activity as a marker in clinical decision-making is closely related to how representative the analysis of a small tumor sample is for the whole tumor. We therefore evaluated the intratumoral distribution pattern of telomerase activity in prostatic carcinomas. MATERIALS AND METHODS: From 50 prostate cancer patients treated with radical prostatectomy, telomerase activity was determined using the telomeric repeat amplification protocol (TRAP assay). Comparative analysis of at least two separate cancer areas from a single tumor was performed in 42 cases. RESULTS: Telomerase activation has been demonstrated in 90% of the prostatic carcinomas. Focal intratumoral heterogeneity was found in 38.1% of the tumors with at least two different areas examined. Telomerase positivity of all samples from one given tumor was detected in 50%, telomerase negativity of all samples in 11.9%. A heterogeneous telomerase activity pattern was more frequently detected in tumors with a Gleason score < or = 7 than in those with a Gleason score > 7. Furthermore, there was an increase in the proportion of homogeneously telomerase-positive tumors with increase in severity of the Gleason score. The differences reached statistical significance. Telomerase activity was also detected in non-cancerous prostatic tissue samples. CONCLUSIONS: Telomerase activation is nearly ubiquitous in prostatic carcinomas, although a heterogeneous telomerase activity pattern within tumors might produce a false-negative result in the telomerase activity assay. This limits the value of telomerase activity assays for diagnostic means. There is evidence for a shift from telomerase-negative prostate cancer tissue toward telomerase positivity during the progression process of prostate cancer. The relatively high proportion of telomerase-positive nonmalignant prostatic tissue samples argues against cancer-specificity of telomerase activation.

Humans↗
PubMed1998

[Current conservative treatment of renal colic: value of prostaglandin synthesis inhibitors].

Prostaglandin synthesis inhibitors and parasympatholytic drugs are often used as analgetics in the case of renal colic. This paper analyzes how and whether these drug effects are important for the analgetic therapy. In an animal and in a human model with acutely obstructed kidneys we found that intravenous application of Indometacine and dipyrone significantly reduces renal pelvic pressure. The parasympatholytic drug hyoscine butylbromide did not produce any change of upper urinary tract dynamics. Inhibitors of prostaglandin synthesis thus effect pressure reduction in the renal pelvis, which is necessary for analgetic therapy. In contrast, hyoscine butylbromide does not have any influence on the acute upper urinary tract obstruction; consequently its usefulness in the treatment of renal colic is rather doubtful.

English Abstract↗
PubMed1998

A new serial transfer explant cell culture system for human prostatic cancer tissues preventing selection toward diploid cells.

An improved explant cell culture technique to avoid selection of prostatic adenocarcinoma cells toward diploid cells is described. This method is based on 1) histologically characterized tissue explants, 2) the use of polyethylenteraphthalate (PET) membranes as growth surface, which are part of special inserts in six-well-plates to allow 3) cocultivation with heterologous fibroblasts, and 4) coating of the membranes with elements of the extracellular matrix. The main characteristic of this particular approach is the serial transfer of the tissue explant from one membrane to the other. Up to ten serial transfer steps could be performed to produce cell monolayers growing out of the same tissue specimen. Using this approach, 21 prostatic carcinoma specimens that were obtained from 13 primary prostatic adenocarcinomas after radical prostatectomy were cultivated. Ploidy of the cells was monitored by fluorescence in situ DNA hybridization using the centromere specific DNA probes pUC1.77, p alpha 7t1, and pY3.4. Interestingly, a high aneuploidy rate of the cell cultures was found with maintainance of aneuploidy in 18 (86%) of the 21 paraffin-embedded cancer tissue specimens with proved aneuploidy. Although a slight decrease of the proportion of aneuploid cells during serial transfer was observed, significant aneuploid cell populations were retained up to a maximum of ten transfer steps. These findings indicate that selection toward diploid cells can be prevented by improved cell culture techniques that mimic the in vivo situation.

Adenocarcinoma↗
PubMed1998

p53 autoantibodies in patients with urological tumours.

OBJECTIVE: To determine the presence of p53 serum antibodies in patients with clinically well-defined urological cancer using a new enzyme-linked immunosorbent assay (ELISA). PATIENTS AND METHODS: The study included 73 patients with prostatic cancer, 72 with transitional cell carcinoma of the urinary tract, 37 with renal cell cancer and 16 controls with a benign disease, all of whom were tested using the ELISA for p53 autoantibodies. The specific reaction of the ELISA (positive p53 antibody titre) was confirmed by Western Blot analysis. RESULTS: Thirteen patients with cancer and one control patient (7.6% overall) were positive for p53 autoantibodies. The sensitivity of the test was low, whereas the specificity was remarkably high. Surprisingly, 9 of the 13 p53-positive patients died within a median of 3.7 months (range 2-6) and the one positive control patient died of undetected lung cancer. There was no significant correlation of p53 antibody positivity with clinical stage or tumour-specific differences. CONCLUSIONS: The expression of p53 autoantibody seems to be a very late but significant event in urological tumour development, with the worst outcome (tumour-specific death) within a few weeks of developing positivity. In histopathologically heterogeneous tumour entities, p53 autoantibodies might be independent prognostic factors in patients with urological cancers.

Autoantibodies↗
PubMed1998

Androgen receptor expression, proliferation index and aneuploidy in tissue explant cultures derived prostate carcinoma cells co-cultivated on membranes.

OBJECTIVES: An improved explant cell culture technique to avoid selection of prostatic adenocarcinoma cells toward diploid cells is described. MATERIAL AND METHODS: 21 prostatic carcinoma specimens which were obtained from 13 primary prostatic adenocarcinomas after radical prostatectomy were cultivated. Ploidy of the cells was monitored by fluorescence in situ DNA hybridization using the centromere-specific DNA probes pUC1.77, p alpha 7t1 and pY3.4. Phenotypic examination of androgen receptor (AR) expression was performed simultaneously with immunostaining by Ki-67 as proliferation marker to identify androgen-independent growing cell clones. RESULTS: Interestingly, a high aneuploidy rate of the cell cultures was found with maintenance of aneuploidy in 18 (86%) of the 21 paraffin-embedded cancer tissue specimens with proved aneuploidy. Significant aneuploid cell populations were retained up to a maximum of ten transfer steps. During serial transfer of tumor pieces the aneusomic fraction slightly decreased as well as the percentage of AR/Ki-67-positive cells. CONCLUSIONS: The presented in vitro model allows to study the proliferation of genetically abnormal cells with respect to hormone dependency in a paracrine situation.

Adenocarcinoma↗
PubMed1998

Long-term results following transurethral resection of the prostate.

Two subsets of a single-center study population with benign prostatic hyperplasia (n(1) = 232; n(2) = 214) undergoing transurethral resection (TUR) of the prostate (TURP 1979 and 1995) entered a retrospective study designed to examine the long-term follow-up. The actual data were assessed with a patient-addressed questionnaire. Preoperative voiding patterns did not differ significantly; postoperative micturition revealed comparable results for both groups. Mortality and TUR syndrome rates were reduced to very low levels. The most significant improvement was found in blood transfusions. The postoperative incidence of urethral stricture (1.7 vs. 1.5%) or bladder neck contracture (2.7 vs. 2.4%) were low and did not alter significantly. Urinary incontinence changed for both collectives (11.4 vs. 3.3%). Urodynamic investigations revealed that all (n = 21) but 1 of the patients with TURP 1979 had the incontinence due to different bladder dysfunctions, but not because of postoperative stress incontinence. The questionnaire about the patient's actual contentment after TURP 1979 showed 79% of the patients still satisfied, 12% neutral and 9% dissatisfied with their micturition. Overall the patients reported a generally favorable view of TURP outcome in the long-term follow-up.

Aged↗
PubMed1998

Genetic changes and telomerase activity in human renal cell carcinoma.

Using the sensitive telomeric repeat amplification protocol assay, we detected telomerase activity in 26 of 35 (74.3%) renal cell carcinomas analyzed. Subdivision of the tumors according to telomerase activity did not reveal an obvious association between the presence of telomerase activity and histomorphological stage, grade, tumor size, or DNA ploidy. Furthermore, no association was found between telomerase activity and a distinct chromosomal aberration pattern; namely, loss of genetic material on the short arm of chromosome 3. Telomerase activity was also detected in 6 of 35 (17.1%) normal corresponding renal tissue samples, which seems interesting in light of the supposed biological role of telomerase expression in carcinogenesis. Interestingly, telomerase activity was detected in three of the four (75%) kidneys bearing non-clear cell tumor types, whereas of the 31 kidneys with clear cell carcinomas, telomerase activity was found in only 3 (9.7%) normal tissue samples. In addition, the two renal angiomyolipomas and one of the two analyzed transitional cell carcinomas of the renal pelvis were telomerase negative.

Adult↗
PubMed1997

[Injuries of the urinary system and management in multiple trauma cases].

Some of the most common lesions in patients with multiple traumas are injuries to the urinary system. A blunt trauma of the abdomen mainly leads to injuries of the kidney, ureter and/or bladder, whereas the external genitals are often damaged by contusions, decollements and even amputation. The multiply traumatized patient must necessarily be cared for and treated through an interdisciplinary cooperation. Thus, "urologisation" of the condition must be avoided, as must the non-recognition of urological injuries. Iatrogenic lesions are primarily observed in the context of urological, gynecological and surgical interventions. Immediate recognition may lead to early treatment, thereby avoiding possible, complications. The procedure for treating multiply traumatized patients will be shown using a plan of specific steps. Symptoms of injuries to the genitourinary system are usually not obvious. In most cases micro- and macro-hematuria are the leading symptoms, but they are not always demonstrable. In the acute phase the drainage of urine must be protected. It is mainly during the third step that urological lesions require surgical treatment. Catheterisation of the urethra may only be performed when the possibility of injury to it is excluded.

Amputation, Traumatic↗
PubMed1996

Selection toward diploid cells in prostatic carcinoma derived cell cultures.

For elucidation of the growth-regulatory mechanisms in prostatic carcinoma, in vitro investigations on prostatic cell cultures are required. However, one major problem of cell culturing is the selection of particular cell types such that the cell lines representing only some of the features as compared with the tumor of origin. We studied the chromosomal composition of 20 prostatic tissue-derived cell cultures and 12 original (fresh) tissue specimens that were obtained from 13 patients with prostatic adenocarcinoma. Using fluorescence in situ DNA hybridization (FISH), evident clonal abnormalities were detected in 78% of the fresh cancer samples and in 47% of the cultured cancer samples. Of the seven cases revealing clonal abnormalities in the fresh cancer specimen, aneuploidy was detected in only two samples after cell culturing at the earliest passage studied. The aneuploid cell populations in the cultured samples were all lost during progressive subcultivation (after passage 4). Interestingly, by performing FISH on cytogenetic preparations aneuploidy was confined to the interphases, with the metaphases being found to be diploid. This finding indicates that the aneuploid cells have a proliferation disadvantage in cell culture resulting in an overgrowth of diploid cells.

Adenocarcinoma↗
PubMed1996

Management of acute hydronephrosis in pregnancy by ureteral stenting.

Acute hydronephrosis during pregnancy that fails to respond to conservative treatment can be managed by ureteral stenting or in special cases by application of a percutaneous nephrostomy tube. We report the outcome in 116 pregnant women with symptomatic hydronephrosis. In 30 cases ureteric stents were passed under local anesthesia. In 2 cases (pyeloureteral stenosis, impacted ureteric stone) percutaneous nephrostomy was necessary. Overall each course of pregnancy and disease was individually decided. In case of persisting symptoms due to acute hydronephrosis, ureteral stenting was preferred, since it is a simple, safe and effective method of internal upper urinary tract drainage.

Adult↗
PubMed1996

[Retroperitoneal extragonadal germinal choriocarcinoma: description of a case and the complex therapeutic approach].

Patients with primary extragonadal, retroperitoneal germ cell tumors usually have very advanced disease and present uncharacteristic signs and symptoms. We report a case of a patient with large retroperitoneal choriocarcinoma. After four initial cycles of chemotherapy, the patient underwent debulking surgery including angiorrhaphy and-plasty. This therapeutic management was justified, as it revealed active residual tumor. Furthermore, a large tumor mass was removed with vascular and ureteric decompression. As a result of this treatment, adjuvant chemotherapy was more effective. In conclusion, despite possible complications, we recommend this regimen in young patients.

Adult↗