M Schuler

Publications (30)132.49 Total impact

• Article: Direct cellular interaction with activated CD4(+) T cells overcomes hyporesponsiveness of B-cell chronic lymphocytic leukemia in vitro.

  T Tretter, M Schuler, F Schneller, U Brass, M Esswein, M J Aman, C Huber, C Peschel
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  ABSTRACT: The proliferative response of clonal B cells from patients with chronic lymphocytic leukemia (B-CLL) is drastically reduced compared to normal B lymphocytes stimulated via the B cell antigen receptor complex or by CD40 ligation. In the present study we demonstrate that hyporesponsiveness of CLL-B cells can be overcome by stimulatory pathways mediated by activated CD4(+) T cells. In contrast to CD40 ligation, costimulation with activated T cells promotes a proliferative response in CLL-B cells identical to that in normal B cells. Furthermore, coculture with activated T cells improved survival of CLL-B cells in vitro. Differentiation of CLL-B cells into IgM producing cells was promoted, as well. However, the capacity for IgM secretion remained impaired compared to that of normal B cells. For T-cell-mediated B cell activation direct cellular contact with activated T helper cells is absolutely required. Prevention of CD40/CD40L interaction by CD40 antibody caused only partial inhibition of B cell activation, suggesting that additional signals are involved in T-B cell interaction. Whereas interruption of the ligand pairs CD11a/CD54, CD5/CD72, CD27/CD70 had no influence, the addition of CD58 antibody completely inhibited B cell activation by activated T cells. In costimulation with cellular signals the presence of B-cell-tropic cytokines, such as IL-2 and IL-4, was required to optimize B-CLL proliferation, as demonstrated by the use of neutralizing antibodies. We conclude from these results that proliferative hyporesponsiveness by CLL-B cells can be circumvented by antigen-nonspecific signals in addition to CD40 which are mediated by direct contact with activated T helper cells.
  Cellular Immunology 11/1998; 189(1):41-50. · 1.97 Impact Factor
• Article: A phase I study of adenovirus-mediated wild-type p53 gene transfer in patients with advanced non-small cell lung cancer.

  M Schuler, C Rochlitz, J A Horowitz, J Schlegel, A P Perruchoud, F Kommoss, C T Bolliger, H U Kauczor, P Dalquen, M A Fritz, S Swanson, R Herrmann, C Huber
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  ABSTRACT: Mutations of the tumor suppressor gene p53 are the most common genetic alterations observed in human cancer. Loss of wild-type p53 function impairs cell cycle arrest as well as repair mechanisms involved in response to DNA damage. Further, apoptotic pathways as induced by radio- or chemotherapy are also abrogated. Gene transfer of wild-type p53 was shown to reverse these deficiencies and to induce apoptosis in vitro and in preclinical in vivo tumor models. A phase I dose escalation study of a single intratumoral injection of a replication-defective adenoviral expression vector encoding wild-type p53 was carried out in patients with incurable non-small cell lung cancer. All patients enrolled had p53 protein overexpression as a marker of mutant p53 status in pretreatment tumor biopsies. Treatment was performed either by bronchoscopic intratumoral injection or by CT-guided percutaneous intratumoral injection of the vector solution. Fifteen patients were enrolled in two centers, and were treated at four different dose levels ranging from 10(7) to 10(10) PFU (7.5 x 10(9) to 7.5 x 10(12) particles). No clinically significant toxicity was observed. Successful transfer of wild-type p53 was achieved only with higher vector doses. Vector-specific wild-type p53 RNA sequences could be demonstrated in posttreatment biopsies of six patients. Transient local disease control by a single intratumoral injection of the vector solution was observed in four of those six successfully transduced patients. There was no evidence of clinical responses at untreated tumor sites. Wild-type p53 gene therapy by intratumoral injection of a replication-defective adenoviral expression vector is safe, feasible, and biologically effective in patients with advanced non-small cell lung cancer.
  Human Gene Therapy 10/1998; 9(14):2075-82. · 4.22 Impact Factor
• Article: Lack of efficacy of recombinant human interleukin-6 in patients with advanced renal cell cancer: results of a phase II study.

  M Schuler, U Bruntsch, E Späth-Schwalbe, H Schrezenmeier, C Peschel, L Färber, K J Burger, J Leissner, C Huber, W E Aulitzky
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  ABSTRACT: The present phase II study was undertaken to assess antitumoral activity, safety and tolerability of recombinant human interleukin-6 (rh IL-6) in patients with advanced renal cell cancer. Rh IL-6 was administered as a daily subcutaneous injection at a fixed dose of 150 micrograms/day for a maximum of 42 consecutive days. 12 patients with metastatic renal cell cancer without previous immunotherapy were enrolled and were evaluated for response. No objective clinical responses were observed in the trial. Toxicity was moderate and reversible and mainly comprised fever, influenza-like symptoms, fatigue and moderate hepatotoxicity. Anaemia, leucocytosis, thrombocytosis and induction of an acute phase response were observed in most patients. In conclusion, prolonged subcutaneous administration of rh IL-6 on an outpatient basis is safe and feasible. However, rh IL-6 exhibited no antitumoral activity in patients with metastastic renal cell cancer. Profound regulatory effects on haematopoiesis and inflammatory response of rh IL-6 were observed.
  European Journal of Cancer 05/1998; 34(5):754-6. · 5.54 Impact Factor
• Article: Immuntherapie des metastasierten Nierenzellkarzinoms

  M. Schuler, C. Huber
  Der Onkologe 02/1998; 4(3):251-255. · 0.17 Impact Factor
• Article: Immunomodulatory and hematopoietic effects of recombinant human interleukin-6 in patients with advanced renal cell cancer.

  M Schuler, C Peschel, F Schneller, J Fichtner, L Färber, C Huber, W E Aulitzky
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  ABSTRACT: Interleukin-6 (IL-6) is a cytokine with pleiotropic biologic activities on B cells, T cells, and hematopoietic progenitors. The present study was undertaken to assess pharmacodynamic effects of subcutaneous administration of IL-6 on blood counts, immunologic parameters, and acute-phase reactants. Blood samples were taken from patients with advanced renal cell cancer participating in a phase II trial of recombinant human IL-6. Multiparameter FACS analyses of peripheral blood mononuclear cells were performed using antibodies against CD3, CD4, CD8, HLA-DR, CD56, CD28, CD38, CD19, sIgM, and sIgG. Serum levels of IL-10, soluble CD23 (sCD23), sCD25, IL-1 receptor antagonist protein (IL-1RA), soluble tumor necrosis factor (TNF) receptors (sTNF-R) p55 and p75, and soluble IL-6 receptor (sIL-6R) were detected by ELISA systems. Levels of C-reactive protein (CRP), neopterin, fibrinogen, beta 2-microglobulin, and immunoglobulins M, G, and A were measured by standard methods. In response to administration of IL-6, a significant increment in platelet counts was observed, reaching peak levels after 21 days of treatment. In contrast, leukocyte subsets remained unaffected. No change in number of immunophenotype of peripheral blood B cells, T cells, or natural killer cells could be detected following IL-6 administration. Blood levels of sCD23, IL-10, sIL-6R, neopterin, beta 2-microglobulin, and immunoglobulin subsets were not influenced by cytokine therapy. However, administration of IL-6 led to a slow increment of acute-phase reactants CRP and fibrinogen. Furthermore, the anti-inflammatory molecules sTNF-R p55 and p75 were induced by IL-6, whereas serum levels of IL-1RA remained unchanged. Finally, an increase in blood levels of sCD25 was observed. In conclusion, IL-6 in vivo predominantly acts as a regulator of inflammation and a megakaryocyte differentiation factor.
  Journal of Interferon & Cytokine Research 12/1996; 16(11):903-10. · 3.06 Impact Factor
• Article: [Interferon-alpha in therapy of malignant hemoblastoses].

  M Schuler, W E Aulitzky, F Schneller, C Peschel, C Huber
  Der Internist 01/1996; 36(12):1133-8. · 0.30 Impact Factor
• Article: Plasma levels of IL-1, TNF alpha, IL-6, IL-8, G-CSF, and IL1-RA during febrile neutropenia: results of a prospective study in patients undergoing chemotherapy for acute myelogenous leukemia.

  H Schönbohn, M Schuler, K Kolbe, C Peschel, C Huber, W Bemb, W E Aulitzky
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  ABSTRACT: Plasma levels of IL-1, IL-6, IL-8, IL1-RA, TNF alpha, and G-CSF were prospectively studied during 23 chemotherapy cycles of 20 patients suffering from acute myelogenous leukemia. Increased plasma levels of IL-6, IL-8, and G-CSF were observed in patients with febrile neutropenia and/or major infection. Plasma levels of IL-6, IL-1, TNF alpha and IL-1-RA measured 1 day before and 1 day after the onset of febrile episodes did not accurately predict the development of major infection. In contrast, IL-8 plasma levels were significantly higher in those patients who subsequently developed major infection. The question whether IL-8 plasma levels identify high risk or low risk patients with sufficient specificity and sensitivity has to be answered in large scale clinical trials.
  Annals of Hematology 11/1995; 71(4):161-8. · 2.62 Impact Factor
• Article: Cytokines in the pathophysiology and treatment of chronic B-cell malignancies. A review.

  M Schuler, C Huber, C Peschel
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  ABSTRACT: Chronic B-cell malignancies are characterized by accumulation of transformed B cells of low proliferative index in lymphatic and extralymphatic tissues. Cytokines do not appear to play a role in the primary step of transformation. However, proliferation as well as inhibition of apoptosis of malignant B cells can readily be explained by cytokine effects. Clinical trials of interferons (IFN) and interleukin-2 alone or in combination have been performed in patients with hairy cell leukemia (HCL), CLL, and low- and intermediate-grade non-Hodgkin's lymphoma. While IFN alpha became standard therapy of HCL, responses in other entities were variable, ranging from 0 to 70% in selected populations. Combination of IFN and cytotoxic chemotherapy in general revealed no additional benefit as compared to chemotherapy alone. Perspectives for future clinical testing of cytokines in low-grade B-cell lymphomas are discussed.
  Annals of Hematology 09/1995; 71(2):57-63. · 2.62 Impact Factor
• Article: Interleukins. Clinical pharmacology and therapeutic use.

  W E Aulitzky, M Schuler, C Peschel, C Huber
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  ABSTRACT: With interleukins (IL), a new class of potential drugs has been introduced into clinical research. These signal peptides are involved in the regulation of many physiological and pathophysiological processes. IL-1, -2, -3, -4, -6 and -11 have been tested in clinical trials. The growth promoting, growth inhibiting or immunomodulatory activities of interleukins represent the theoretical basis for large scale clinical testing, predominantly in malignant disease. Dose-dependent effects on numbers of peripheral blood cells and recovery from bone marrow failure have been demonstrated for IL-1, -3, -6 and -11. Phase III trials are in progress to determine their value for clinical practice. However, investigations on the immunomodulatory activities proved to be more difficult. This is because key mechanisms for successful treatment of malignant disease by immunomodulation are not clearly defined and the methodology for assessment of immunostimulatory effects is not well established. Besides treatment of renal cell carcinoma and malignant melanoma with IL-2, no successful trials have been reported. However, phase I clinical trials with IL-1, IL-4 and IL-6 have just been completed. Thus, it seems too early to conclude on their therapeutic potential.
  Drugs 12/1994; 48(5):667-77. · 4.23 Impact Factor
• Article: Aspirin induces apoptosis through release of cytochrome c from mitochondria.

  K C Zimmermann, N J Waterhouse, J C Goldstein, M Schuler, D R Green
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  ABSTRACT: Nonsteroidal anti-inflammatory drugs (NSAID) reduce the risk for cancer, due to their antiproliferative and apoptosis-inducing effects. A critical pathway for apoptosis involves the release of cytochrome c from mitochondria, which then interacts with Apaf-1 to activate caspase proteases that orchestrate cell death. In this study we found that treatment of a human cancer cell line with aspirin induced caspase activation and the apoptotic cell morphology, which was blocked by the caspase inhibitor zVAD-fmk. Further analysis of the mechanism underlying this apoptotic event showed that aspirin induces translocation of Bax to the mitochondria and mitochondrial release of cytochrome into the cytosol. The release of cytochrome c from mitochondria was inhibited by overexpression of the antiapoptotic protein Bcl-2 and cells that lack Apaf-1 were resistant to aspirin-induced apoptosis. These data provide evidence that the release of cytochrome c is an important part of the apoptotic mechanism of aspirin.
  Neoplasia 2(6):505-13. · 5.95 Impact Factor