Search PubMed⌕ Search

Biomedical subjects

W Wilmanns

Publications and source records attributed to W Wilmanns.

At least 55 records · Page 3Linked to original sources
PubMed1996

Association of bcl-2, bax, bcl-xL and interleukin-1 beta-converting enzyme expression with initial response to chemotherapy in acute myeloid leukemia.

Bcl-2 expression is able to confer drug resistance to chemotherapy-induced programmed cell death. Bax, a partner protein of bcl-2 with extensive aminoacid homology, is a promoter of apoptosis. Apparently the equilibrium of bcl-2 and bax hetero- and homodimers is important for the susceptibility of cells for stimuli inducing apoptosis. In this study we determined the role of bcl-2 to bax expression ratio, bcl-xL and ICE expression level for predicting clinical response to chemotherapy in acute myelold leukemia (AML). Bone marrow samples from 14 patients with AML were examined using an immunophosphatase staining method. Initial bone marrow blast portion was over 80% in all cases. Clinical response was defined by bone marrow aspiration 4 weeks after treatment initiation. There was a significant correlation between bcl-2 to bax expression ratio and clinical response (P < 0.005). No patients with a bcl-2/bax ratio >1.0 achieved complete remission after induction therapy. No significant correlation between bcl-2- and p-glycoprotein-expression was observed in this group. Conversely a high expression of ICE indicated a good clinical response (P < 0.01), whereas expression of bcl-xL had no influence on therapeutic success in this group.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

P-glycoprotein expression in patients with acute leukemia-clinical relevance.

P-glycoprotein (P-gp) is a crucial factor in the development of chemotherapy resistance in malignant disorders. Between 1989 and 1995, P-gp expression was studied in bone marrow blast cells of 322 (239 AML; 83 ALL) acute leukemia patients. 166 AML patients with the AML-6 protocol (EORTC), containing daunorubicin, vincristine and conventional-dose cytarabine (ara-C), and 63 AML patients treated with intermediate-does Ara-C plus amsacrine. Further 71 ALL patients were treated according to a German standard polychemotherapy protocol (BMFT04/1989). P-gp was determined by using monoclonal antibodies C219 and 4E3, and the cutoff point for P-gp overexpression was set at >/= 10%. A significant (P < 0.06) difference in P-gp overexpression was demonstrated between AML (21.6%) and ALL (10.2%) patients at primary diagnosis and between primary diagnosis and relapse/refractoriness in AML (21.6%; 51.0%) and ALL (10.2%; 27.2%) patients. According to FAB classification P-gp overexpression was detected in AML patients significantly (P < 0.05) more frequently in classes M4, M5a and M5b and less frequently in M3, as compared to other types. For AML patients with P-gp overexpression at primary diagnosis or early relapse/refractoriness, the predictive value for nonresponse to the AML-6 protocol was 91 and 95%, respectively, while late-relapsed AML patients with P-gp overexpression had a significantly (P < 0.05) lower predictive value of 73% for nonresponse. Additionally, in refractory and late-relapsed P-gp--overexpressing AML patients treated with intermediate-dose ara-C plus amsacrine the predictive values for nonresponse were 44 and 39%, respectively, significantly (P < 0.05) lower as compared to AML-6 protocol-treated refractory or late-relapsed AML patients. In P-gp-overexpressing treated ALL patients the predictive values of 50 and 55% for non-response were calculated at primary diagnosis and late relapse, respectively. We conclude that P-gp overexpression is a common phenomenon in AML patients at primary diagnosis or relapse, has an inverse influence on AML-6 treatment outcome and should be taken into consideration in the development of new therapy strategies.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Does serum tumor marker half-life complement pretreatment risk stratification in metastatic nonseminomatous germ cell tumors?

The goal of this study was to determine whether the serum tumor marker half-life (MHL) of human chorionic gonadotropin (HCG) and alpha-fetoprotein (AFP) during initial chemotherapy can complement pretreatment risk stratification in metastatic nonseminomatous germ cell tumors. One hundred forty-seven patients were assessable for MHL during the first two cycles of platinum-based chemotherapy. MHL calculation was based on two consecutive values using Kohn's apparent half-life formula (MHL =ln 1/2/G, where G was the gradient of the marker slope) or on three (or more) values using simple linear regression. MHL was regarded as prolonged if it was more than 3.5 days for HCG or more than 7 days for AFP. The median MHL for HCG was 2.8 days (range, 0.7-16.7) and for AFP was 6.2 days (range, 2. 6-65.4). Thirty-five of 108 patients (32%) had a prolonged MHL for HCG, 41 of 114 (36%) had a prolonged MHL for AFP, and in 59 of 147 patients (40%), either or both MHLs were prolonged. If patients with both MHLs normal were compared against patients with either or both MHLs prolonged, highly significant differences in progression-free survival (P < 0.0001) and overall survival (P = 0.0005) were demonstrated. The test accuracy was 70% for both progression-free and overall survival, and it was slightly greater than the overall predictive value of the Medical Research Council prognostic classification. A combination of Medical Research Council criteria and MHL analysis allowed us to refine prognostic assessment. Because MHL analysis is able to complement pretreatment risk stratification and can support selection of patients for early-dose intensified chemotherapy, it should be included in prospective clinical trials for patients with poor-prognosis disease.

Adolescent↗
PubMed1995

Differential effects of ifosfamide on the capacity of cytotoxic T lymphocytes and natural killer cells to lyse their target cells correlate with intracellular glutathione levels.

We established an in vitro model to study the influence of ifosfamide treatment on intracellular glutathione (GSH) levels in activated human effector cells with specific phenotypes and immunologic functions. Besides its role as the major intracellular reductant, GSH has been shown to affect the initiation and progression of lymphocyte activation after stimulation with lectins. An incubation of activated human peripheral blood lymphocytes (PBL) with 4-hydroxyifosfamide, the activated form of ifosfamide (4-OH-IF), resulted in a depletion of the intracellular GSH levels and a significant inhibition of the proliferative capacity in a dose-dependent manner. The cytotoxic activity of separated CD3- natural killer (NK) cells and CD3+ allospecific, cytotoxic T lymphocytes (CTL), either untreated or treated with 4-OH-IF at different concentrations, was compared in a standard 51chromium release assay (CML). There were three major findings. (1) The capacity of CD3+ major histocompatibility complex (MHC)-restricted CTL to lyse their specific allogeneic target cells was substantially reduced by preincubation of the effector cells with 4-OH-IF. This inhibition of the lytic activity in CD3+ CTL correlated with a substantial depletion of the intracellular GSH levels in this population. Rapid reconstitution of depleted GSH levels and restoration of cytotoxic activity of CTL was achieved by incubation of the effector cells with thiols, eg, glutathione ester (GSH-ester) or 2-mercaptoethanesulfonate (mesna). (2) In contrast, the lytic activity in CD3- NK cells was not substantially affected (up to 100 mumol/L 4-OH-IF). This result correlates with the capacity of NK cells to maintain their intracellular GSH levels after an ifosfamide treatment. (3) In comparison with CD3+ CTL, CD3- NK cells are more resistant to an ifosfamide treatment because they have higher initial GSH levels and a more than fourfold higher relative rate of GSH synthesis.

Antibodies, Monoclonal↗
PubMed1995

A stress-inducible 72-kDa heat-shock protein (HSP72) is expressed on the surface of human tumor cells, but not on normal cells.

It is suggested that members of the heat-shock protein (HSP) 70 and 90 families are involved in intracellular antigen processing and the presentation of cell-membrane-anchored antigens. We show that non-lethal heat shock (41.8 degrees C) causes comparable rates of HSP72 (about 20x) and HSP73 (about 3x) synthesis in both tumor (including human Ewing's sarcoma, ES and osteosarcoma cells, HOS58) and normal cells (including EBV-transformed B-LCL, PBL and fibroblasts derived from healthy human volunteers). However, following non-lethal heat stress and a recovery period at 37 degrees C, flow cytometric analysis with a specific MAb showed HSP72 to be expressed only on the cell surface of tumor cells. The cell-surface localization of HSP72 was confirmed by Western-blot analysis of separated membranes and by immunoprecipitation with the HSP72-specific MAb. In addition, co-incubation of untreated tumor cells with supernatants from lethally heat-shocked cells, which contain HSP72, did not lead to HSP72 cell-surface expression. Thus, non-specific association of HSP72 molecules with the outer plasma membrane is unlikely. In conclusion, despite comparable cytoplasmic HSP72 induction, human tumor cells differ from normal cells in their capacity to express HSP72 on their surface. This might imply clinical application as a means to target a stress-inducible, tumor-specific immune response.

Animals↗
PubMed1995

Expression of the Fas antigen on primary human leukemia cells.

The antigen defined by the monoclonal antibody anti-Fas can mediate apoptosis, is associated with the receptor for tumor necrosis factor, and is expressed on a limited number of human tissues. In this study we analyzed the expression of Fas on primary human leukemic cells and on mononuclear cells from other hematologic disorders. A total of 95 samples of blood or bone marrow were studied by indirect immunofluorescence. These samples included the normal controls, 47 cases of acute myelogenous leukemia (AML), 11 cases of acute lymphoblastic leukemia (ALL), 21 cases of leukemic lymphoma, seven cases of chronic myelogenous leukemia (CML), five cases of plasma cell leukemia or multiple myeloma, and five cases of myelodysplastic or myeloproliferative syndromes. Normal controls were negative without exception. Among AML, 13/47 cases (28%) were positive; among ALL, 1/11 cases (9%) was positive; among leukemic lymphomas, 3/21 cases (14%) were positive. In a case of plasma cell leukemia which strongly expressed the Fas antigen, we demonstrated that the antibody mediates cell lysis, which was synergistically enhanced by the addition of rabbit complement. In patients with AML, Fas positivity had no obvious clinical relevance. Taken together, our results show that approximately 30% of cases of AML and occasionally other leukemias express the Fas antigens, whereas normal controls are negative in our test system. These findings may be useful in the treatment of refractory leukemias or may permit the purging of autologous transplants.

Antigens, Surface↗
PubMed1995

Modulation of the endogenous leukotriene production by fish oil and vitamin E.

We investigated the effects of fish oil and vitamin E on the endogenous leukotriene production. 10 healthy volunteers were supplemented for 1 week with fish oil (containing 40 mg/kg body weight per day of eicosapentaenoic and docosahexaenoic acid), vitamin E (540 mg, i.e., 800 IU of D-alpha-tocopherol per day), or with both agents. Treatment resulted in a significant increase in the eicosapentaenoate concentration in red blood cell membranes and/or in the vitamin E concentration in serum. In addition, nine obese patients were investigated who were on a hypocaloric diet including 10 mg vitamin E/day for 8 weeks. This diet was associated with a significant decrease in serum vitamin E concentration. The urinary concentration of leukotriene E4 plus N-acetylleukotriene E4 served as a measure for the endogenous leukotriene production. Fish oil reduced leukotriene production in eight of the 10 healthy individuals. After vitamin E supplementation, urinary leukotrienes were significantly reduced in all of the healthy volunteers. The combination of vitamin E plus fish oil had no synergistic effect on leukotriene production in the individuals tested. The decrease in serum vitamin E concentration during the hypocaloric, 10 mg vitamin E/day diet was associated with an increase in urinary leukotrienes in 8 of the 9 obese patients. Urinary prostaglandin metabolites, determined as tetranorprostanedioic acid, increased or decreased in parallel with urinary leukotrienes in most individuals; however, changes were less pronounced than those observed with leukotrienes. We conclude that the endogenous leukotriene production can be reduced effectively by high doses of fish oil or vitamin E, whereas vitamin E depletion is associated with an increase in leukotriene generation.

Adult↗
PubMed1995

Prognosis after salvage treatment for unselected male patients with germ cell tumours.

Long-term outcome of salvage treatment was reviewed in 67 unselected male patients relapsing during or after their primary cisplatin-based chemotherapy for metastatic germ cell tumours. Seven patients underwent only surgery and/or radiotherapy as curatively intended salvage treatment. Thirty-five patients (52%) had a complete or partial response to salvage treatment, 20 (57%) of whom relapsed again. With a median follow-up of 90 months (range 3-143 months) 20 patients (30%) are alive with no evidence of disease, 15 continuously disease-free and five currently disease-free. The 5 year survival from start of salvage treatment is 37% for the group as a whole. Multivariate analysis identified age < or = 35 years, complete response to primary treatment and a relapse-free interval > 3 months as independent predictors of favourable outcome of salvage treatment. A group of patients with these good-risk factors (42%) had a 5 year survival of 72% compared with the remaining patients (58%) with a 5 year survival of only 11%. Whereas patients with good-risk features may be adequately managed by conventional salvage treatment, the remaining patients carry a very poor prognosis and require innovative and more aggressive approaches.

Adolescent↗
PubMed1995

Outcome analysis after post-chemotherapy surgery in patients with non-seminomatous germ cell tumours.

BACKGROUND: The goal of the study was to analyse long-term outcome after post-chemotherapy surgery in male patients with non-seminomatous germ cell tumours (NSGCT). PATIENTS AND METHODS: We reviewed the charts of 111 patients with metastatic NSGCT treated at a single institution from 1979 to 1993 who underwent post-chemotherapy resection of residual masses after normalisation of tumour markers. The prognostic relevance of the extent of tumour residuals, the comprehensiveness of surgery and the histology at resection was analysed. RESULTS: Thirteen patients (12%) harboured viable cancer, and 46 patients (41%) mature teratoma at post-chemotherapy surgery. Only seven (54%) of the 13 patients with viable cancer remained continuously disease-free. Incomplete surgery predicted an impaired outcome (62% vs. 86% survival), although only one recurrence was observed at a site of an incompletely resected mass. Moreover, a progression-free interval < or = 3 months after post-chemotherapy surgery was correlated with worse subsequent survival (p = 0.0001). CONCLUSIONS: Post-chemotherapy surgery remains an essential part of the treatment for metastatic NSGCT. Resection of viable cancer and mature teratoma is of therapeutic benefit. Viable cancer at surgery defines the need for further chemotherapy.

Adolescent↗
PubMed1995

Cysteinyl leukotriene production in anaphylactic reactions.

Anaphylactic reactions are systemic, potentially life-threatening allergic reactions. In several animal models, evidence has been presented that leukotrienes may be of major pathophysiological significance. The aim of the present study was to obtain information on cysteinyl leukotriene production in anaphylactic reactions in humans in vivo. Urinary leukotriene E4 plus N-acetyl leukotriene E4 were determined in nine patients during clinically apparent anaphylaxis and 2-11 days later following recovery. The concentrations of these established parameters of endogenous leukotriene production were strongly enhanced in urine sampled during or shortly after the anaphylactic reaction; they declined to normal or were slightly elevated subsequently. In one patient suffering from exercise-induced anaphylaxis, leukotriene production was provoked together with clinical symptoms by moderate exercise on a bicycle ergometer. Our data provide the first direct evidence that leukotrienes may be involved in anaphylactic reactions in humans in vivo.

Acetylation↗
PubMed1994

Induction of anergy in resting human T lymphocytes by immobilized anti-CD3 antibodies.

How the T cell receptor (TcR)/CD3 complex mediates not only the induction of T cell activation but also suppressive effects like T cell anergy or apoptosis is not well understood. Here we describe a series of preincubation and restimulation experiments which demonstrate that primary stimulation of resting, unseparated human T cells with mitogenic doses of immobilized anti-CD3 antibodies induces hyporesponsiveness upon restimulation of the cells. Various costimuli can prevent this type of anergy to a variable degree if present during the preincubation period, phorbol 12-myristate 13-acetate (PMA) being the most and anti-CD4 antibody the least effective. If employed together with anti-CD3 antibody during the restimulation phase of the assay, interleukin (IL)-2, IL-4 and anti-CD28 antibody break anergy almost completely. Proliferation induced by a submitogenic dose of anti-CD3 antibody supplemented by costimulatory signals (anti-CD2, anti-CD4, anti-CD28, IL-2, IL-4 or PMA) does not result in hyporesponsiveness. Taken together, these results support a modified view of the two-signal model for T cell activation according to which anergy induction in resting T cells occurs if primary proliferation is induced by high density triggering of the TcR/CD3 complex in the absence of accessory signals. We discuss possible implications of these findings for the induction of peripheral tolerance.

Adult↗
PubMed1994

Inhibition of cyclosporin A/FK506 resistant, lymphokine-induced T-cell activation by phenothiazine derivatives.

Earlier studies from our laboratory have demonstrated that phenothiazine derivatives are capable of inhibiting mitogen-induced activation of human T-cells and thymocytes. Similar to cyclosporin A, phenothiazine derivatives exert these inhibitory effects by decreasing the accumulation of lymphokine-specific mRNA. However, proliferation of T-cell blasts and of unfractionated human thymocytes can also be induced by interleukin 2. Since activation of T-cells via the interleukin 2 receptor seems to be resistant to the action of cyclosporin A, the present study was designed to investigate whether lymphokine-induced activation could be inhibited by phenothiazine derivatives. The effects of the phenothiazine derivatives chlorpromazine and/or fluphenazine have been studied and compared to the action of cyclosporin A and FK506 in human thymocytes, human T-cell blasts and in the human T-cell line H33-HJ JA1, which is an interleukin 2 producing cell line derived from Jurkat cells. As evidenced by the incorporation of [3H]-thymidine, cyclosporin A (1 microgram/ml) and FK506 (100 ng/ml) have no or only marginal inhibitory capacity on interleukin 2-induced proliferation in all T-cell systems tested. By contrast, phenothiazine derivatives (fluphenazine > chlorpromazine) exert a dose-dependent inhibition of the activation of these cells in pharmacologically relevant micromolar concentrations. Similar results were obtained by measuring the production of interferon-gamma in the supernatants of interleukin 2-induced human thymocytes. Our results suggest that the use of phenothiazines might be helpful in immunosuppressive regimens.

Cell Division↗
PubMed1994

Central nervous system as sanctuary site of relapse in patients treated with chemotherapy for metastatic testicular cancer.

Isolated central nervous system relapse in patients treated successfully with cisplatin-based chemotherapy for testicular cancer has been described infrequently. In a retrospective analysis we identified this complication in six of 417 patients. Five of the six patients had advanced pulmonary dissemination at onset of chemotherapy, and post-chemotherapy surgery did not reveal viable tumour tissue in any of these cases. All six patients developed a single cerebral metastasis during complete remission a median four months after discontinuation of chemotherapy. Five patients were treated with surgery and subsequent radiotherapy, one patient with irradiation alone. Three patients are alive relapse-free 19, 62 and 86 months after diagnosis of cerebral relapse. One patient was alive with cerebral disease for 12 months without evidence of systemic recurrence. Our data demonstrate that the brain may act as a sanctuary site in chemotherapy-treated testicular cancer. A review of the literature shows that an isolated cerebral relapse is an extremely rare complication, but carries a relatively favourable prognosis.

Adult↗