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B Kornhuber

Publications and source records attributed to B Kornhuber.

At least 37 records · Page 2Linked to original sources
PubMed1997

Sodium valproate inhibits in vivo growth of human neuroblastoma cells.

Sodium valproate (VPA) belongs to the group of simple branched-chain fatty acids and due its anticonvulsive activity is broadly applied in the treatment of epilepsy. We previously showed that VPA is able to induce cellular differentiation, to enhance immunogenicity and to inhibit proliferation of human neuroblastoma (NB) cells in vitro. Furthermore, we demonstrated that VPA inhibits proliferation, enhances neural cell adhesion molecule expression and decreases CD44 expression of human and rat glioma cells in vitro. In the present study we investigated the antitumoral effects of VPA on established human NB xenografts from UKF-NB-3 human NB cells in athymic (nude) mice. When the animals developed s.c. tumors of about 100 mm3 volume they were treated with 400 or 200 mg/kg/day VPA i.p. At the end of the treatment period (40 days) tumor volumes in animals treated with 400 and 200 mg/kg VPA were about 4- (p < 0.0001) and 2-fold (p < 0.0005) smaller than in the saline-treated control group, respectively. Histological examination of the remnant tumors of treated animals revealed induction of differentiation by induction of stroma-rich tumors and nodules that contained elongated NB cells. Pyknotic nuclei and apoptotic bodies indicated induction of apoptosis. We conclude that VPA is able to abrogate NB growth in vivo and may therefore be useful in the treatment of NB patients.

Animals↗
PubMed1997

Expression of human leukocyte antigens class I and class II on cultured biliary epithelial cells after cytomegalovirus infection.

The influence of cytomegalovirus (CMV) infection on the HLA expression on cultured biliary epithelial cells (BEC) was investigated. CMV-infection augmented expression of HLA class I but not of HLA class II. CMV reduced the IFN-gamma-mediated induction of the de novo expression of HLA class II while the stimulated expression of HLA class I was not impaired. Autologous but not allogeneic PBL responded to CMV-infected BEC. This response resulted in upregulation of HLA class I on BEC which was significantly higher compared with the expression on infected BEC alone or on uninfected BEC cocultured with autologous PBL. The results suggest that CMV modulates the immunogenic potential of BEC, which is important for the HLA and CMV-mediated pathomechanisms in vivo.

Cells, Cultured↗
PubMed1997

Increased efficacy of aphidicolin killing of human neuroblastoma cells in vitro by encapsulation in liposomes.

Aphidicolin is a tetracyclic diterpene antibiotic which kills human neuroblastoma cells (NB) in vitro while it has no significant effect on the viability of different human cell types including normal embryonal cells. In the present study, we tested whether aphidicolin encapsulated in liposomes kills NB cells with the efficacy superior to that of unencapsulated aphidicolin. The drug was entrapped in vesicles composed of phosphatidylcholine, phosphatidylserine and cholesterol in a molar ratio of 83:5:12. The treatment with encapsulated aphidicolin at a concentration of 200 nmol for 5 days killed all cells of three human NB cell lines. In contrast, at least 30% of the cells survived 5 days of treatment with 200 nmol unencapsulated aphidicolin. The results showed that aphidicolin killing of human NB cells may be increased by encapsulation in liposomes.

Aphidicolin↗
PubMed1996

Long-term productive human cytomegalovirus infection of a human neuroblastoma cell line.

Human neuroblastoma cell line UKF-NB-4 persistently infected with human cytomegalovirus (HCMV) strain AD169 was established to study the effects of long-term HCMV infection on virus production and phenotypic characteristics of tumour cells. The cells designated UKF-NB-4AD169 were subcultured (80 subcultures) over a period of more than 2 years after initiation of infection. UKF-NB-4AD169 cells continued to produce infectious virus in successive passages, with a titre ranging from 9 x 10(3) to 1 x 10(5) and from 2 x 10(1) to 2 x 10(2) plaque-forming units per 10(6) cells and 1 ml culture medium, respectively; 10-20% of the cells produced HCMV-specific antigens, while 6-13% produced infectious virus progeny. The number of HCMV-specific DNA copies ranged from 9 x 10(4) to 9 x 10(6) per 10(6) cells. Transmission electron microscopy confirmed the productive nature of HCMV infection. UKF-NB-4AD169 cultures proliferated, with population doubling time ranging from 24.5 to 26.6 hr (19.5 to 20.3 hr for UKF-NB-4) and cell viability from 79% to 85% (91-96% for UKF-NB-4). Significantly lower amounts of tyrosine hydroxylase and decreased activity for dopamine-beta-hydroxylase than in uninfected cells were observed in UKF-NB-4AD169 cells. However, the expression of N-myc oncoprotein was significantly increased in persistently infected cultures. Our results show that long-term productive HCMV infection of UKF-NB-4 cell line is associated with the modulation of phenotypic properties, which may be related to the biological behaviour of neuroblastoma cells.

Cell Differentiation↗
PubMed1996

Antitumor activity of sodium valproate in cultures of human neuroblastoma cells.

Valproic acid (VPA) is a simple branched-chain fatty acid that has anticonvulsant activity and is widely used in the treatment of epilepsy. VPA was found to effect growth and differentiation of human neuroblastoma (NB) cells in vitro at concentrations that have been achieved in humans with no significant adverse effects. Treatment of UKF-NB-2 and UKF-NB-3 NB cell lines with VPA at concentrations ranging from 0.5 to 2 mM resulted in neuronal morphological differentiation characterized by extension of cellular processes without significant effects on cell viability. Ultrastructural features of VPA-treated cells were consistent with the neuronal type of differentiation. VPA treatment of NB cells was associated with decreased expression of N-myc oncoprotein and increased expression of neural cell adhesion molecule in their membrane. Treatment of NB cells with 0.5 mM VPA increased their sensitivity to lymphokine-activated killer lysis. The results indicate that VPA, at non-toxic pharmacological concentrations, arrests the growth, induces differentiation and increases immunogenicity of NB cells through non-toxic mechanisms.

Cell Adhesion Molecules↗
PubMed1996

Logarithmic quantitation model using serum ferritin to estimate iron overload in secondary haemochromatosis.

Nineteen children and adolescents receiving repeated transfusions and subcutaneous desferrioxamine treatment were investigated in an attempt to quantitate iron overload non-invasively. Before patients were started on desferrioxamine individual relationships were correlated for 12 to 36 months between transfused iron, absorbed iron estimated gastrointestinally, and increasing serum ferritin concentrations. Patients with inflammation, increased liver enzymes, or haemolysis were excluded from analysis. The relationship between the variables could be described by a logarithmic regression curve (y = transfused iron [plus eventually gastrointestinally absorbed iron] = iron overload = a+b log [x = serum ferritin]) for each individual patient. All patients showed close correlation (R2) between x and y (median R2 of 0.909, 0.98, and 0.92 in thalassaemia, aplastic anaemia, and sickle cell anaemia patients, respectively). When started on desferrioxamine, current serum ferritin concentrations were used to derive the iron overload from each individual regression curve. The derived estimated iron overload ranged from 0.6 g to 31 g. Left ventricular dilatation was observed in three patients with beta thalassaemia and in one patient with aplastic anaemia with median iron overload of 20.7 (14.1-31.3) g and 24.0 g respectively. Hypothyroidism was found in four patients with beta thalassaemia and one patient with aplastic anaemia with iron overload between 14.7 (6.8 and 26.1) g and 15.1 g respectively. Human growth hormone deficiency was detected in three patients with beta thalassaemia with an iron overload of 4.2 (3.5-6.8) g; all three patients had excellent desferrioxamine compliance.

Adolescent↗
PubMed1996

Modulatory effects of human cytomegalovirus infection on malignant properties of cancer cells.

Although there is no definitive evidence of the association of human cytomegalovirus (HCMV) infection with human cancers, the oncogenic potential of HCMV has been well established by in vitro studies demonstrating the ability of UV-irradiated or infectious virus to transform a variety of cells. After prolonged passaging the transformed cell type was maintained while HCMV DNA sequences were no more detectable. Three morphological transforming regions (mtr) of HCMV have been identified. The effects of HCMV on cellular functions which may be associated with the malignant phenotype include the expression of oncogenes and transcriptional activation of growth factors and interleukin synthesis. In infected cells, HCMV induces cytoskeletal alterations and changes in expression of cell surface receptors for extracellular matrix proteins which could result in increased motility and dissemination of cancer cells. Several human neuroblastoma cell lines undergo maturation in different neural crest derived cell types upon treatment with oncogenic potential agents, i.e. retinoic acid. The persistent HCMV infection of neuroblastoma cells (> 1 year) is accompanied by the increased expression of oncoproteins (i.e. N-myc) and decreased expression of tyrosine hydroxylase and dopamine-beta-hydroxylase. The activation of the cellular metabolism is due to HCMV binding to cellular receptors (prior to virus gene expression) and to the activity of HCMV immediate early (IE) gene products. IE proteins act directly as transcriptional activators or their activity is mediated by a variety of cellular transcription factors. HCMV infection may result in activation of promoters of cellular genes coding for cytokines, replication enzymes, proto-oncogenes and viral promoters. Recently it has been demonstrated that HCMV IE proteins block apoptosis probably by suppressing the ability of the antioncogene p53 to activate a reporter gene. The interactions of HCMV with tumor suppressor proteins such as p53 or retinoblastoma (pRb) susceptibility protein are reminiscent of those mediated by the oncoproteins of DNA tumor viruses. The acquisition of a fully malignant phenotype by normal cells is thought to require several mutations in a number of cellular genes. In this connection, HCMV may play the role of a nonobligate either direct or indirect cofactor for tumor genesis, e.g. by blocking apoptosis, which may be an essential requirement for tumor progression. Due to the stimulation of growth factors and/or inhibition of antioncogenes by its gene products, HCMV may modulate the malignant potential for tumor cells.

Animals↗
PubMed1996

Epidemiology of inhibitors in haemophilia A.

One of the most serious complications of the treatment of haemophilia A is the development of inhibitors. Former studies mostly considered the prevalence of inhibitor development, thus underestimating its true risk. Prevalences ranged widely (7-18%) probably due to the populations studied and the study design. Recent prospective previously untreated patients (PUP) studies were more comparable because of similar study designs. Eight PUP studies regarding the incidence of factor VIII inhibitors were analyzed: The inhibitor incidences (Independent of severity of haemophilia) ranged from 18.4 to 28%. Evaluating only severe haemophiliacs (factor VIII < 2%) significantly higher incidences were found. After 9-36 exposure days (as medians inhibitor development occurred at 0.8-3.3 years of age (as medians).

Factor VIII↗
PubMed1995

Factor VIII inhibitors in patients with hemophilia A: epidemiology of inhibitor development and induction of immune tolerance for factor VIII.

Factor (F) VIII inhibitor development remains one of the most serious complications in the treatment of hemophilia A. Former and recent studies on inhibitor development revealed that patients with severe hemophilia A and positive inhibitor family history are at highest risk of developing an inhibitor. Comparison of recent inhibitor incidence studies on previously untreated patients indicate that the risk of inhibitor development under treatment with recombinant FVIII concentrates is comparable to the inhibitor incidence under FVIII substitution by plasma-derived concentrates. However, longer observation periods are necessary to draw final conclusions. Since inhibitor development may result in inefficacy of FVIII concentrates in the treatment of severe bleedings, the induction of immune tolerance (IT) is still of main concern. Various regimens to induce IT by application of FVIII concentrates have been conducted up to now. Success rate appears to be influenced by low to high responder status, number of exposure days before onset of treatment, and dosage of therapeutic regimen. Especially, discontinuation of IT therapy seems to be associated with failure of therapy. Taking into account available data on IT therapy, we recommend early onset of a high dosage regimen in high responder patients as soon as possible after inhibitor detection, as this is associated with higher success rate and shorter elimination time.

Adolescent↗
PubMed1994

Induction of myogenic differentiation in a human rhabdomyosarcoma cell line by phenylacetate.

Sodium phenylacetate (NaPA) at concentrations ranging from 2 to 10 mM promoted myogenic differentiation of the human alveolar rhabdomyosarcoma cell line KFR. These concentrations inhibited DNA synthesis of the cells in a dose-dependent manner without significant effect on cell viability. The morphological differentiation of small mononuclear elements to terminal, elongated multinuclear structures resembling myotubes was accompanied by the expression of skeletal muscle myosin. The proportion of differentiated myosin-positive cells which was around 0.8-1.7% in control cultures 12 days after seeding was increased by NaPA treatment up to 47%. In the cytoplasm of differentiated cells, features of sarcomerogenesis were observed. These results suggest that NaPA is an effective inducer of rhabdomyosarcoma cell differentiation at concentrations that have been achieved in humans with no significant adverse effects.

Cell Differentiation↗
PubMed1994

Aphidicolin induces myogenic differentiation in the human rhabdomyosarcoma cell line KFR.

The effects of aphidicolin, a specific inhibitor of DNA polymerase alpha, on cell growth, DNA synthesis and myogenic differentiation in the human alveolar rhabdomyosarcoma cell line KFR were studied. The treatment with aphidicolin at 5 x 10(-6) M concentration, which completely inhibited DNA synthesis and cell growth, induced morphological differentiation of small mononuclear cells to elongated, multinucleated (myotube-like) structures. The morphological differentiation was accompanied by the expression of skeletal muscle myosin; about 30% myosin-positive cells were observed after 14 days of treatment, compared to 2.3% in untreated cultures. The results showed that aphidicolin induces differentiation of human rhabdomyosarcoma cells and that multinucleated myotube-like elements may develop simply by cell fusion without cell division and DNA synthesis.

Aphidicolin↗
PubMed1994

Replication of human cytomegalovirus in a rhabdomyosarcoma cell line depends on the state of differentiation of the cells.

The replication of human cytomegalovirus (HCMV) was investigated in a new human rhabdomyosarcoma cell line (KFR) with morphological and biochemical characteristics of fetal striated muscle precursors (rhabdomyoblasts). KFR cells exhibited the unique property for spontaneous morphological transformation from a poorly-differentiated state into well-differentiated (myotube-like) rhabdomyoblasts. The poorly-differentiated rhabdomyoblasts promoted both complete viral gene expression and the production of infectious virus. In contrast, in well-differentiated rhabdomyoblasts HCMV infection was abortive. The results showed that replication of HCMV in this human rhabdomyosarcoma cell line depended on the state of cellular differentiation.

Antigens, Viral↗
PubMed1994

In vitro inhibition of human cytomegalovirus replication by desferrioxamine.

Desferrioxamine (DFO) is commonly used in therapy as a chelator of ferric ion in disorders of iron overload. We found that DFO inhibits human cytomegalovirus (HCMV) replication in infected cultures of human foreskin fibroblasts (HFF) at concentrations that have been achieved in humans with no significant adverse effects. The concentrations of DFO required for 50 and 90% reduction in the production of a HCMV-late antigen ranged for several HCMV strains from 3.1 to 4.9 microM and from 14.2 to 17.3 microM, respectively. DFO concentration of 60 microM had no significant effect on the viability of HFF cells. Inhibitory effects of DFO on HCMV replication were completely prevented by co-incubation with stoichiometric amounts of Fe3+.

Cell Division↗
PubMed1994

Suspension culture of HeLa cells in protein-free medium: sensitivity to human pathogenic viruses.

Human adherent HeLa-PF cells grown for 5 years in a protein-free 1:1 nutrient mixture of Dulbecco's modified MEM and Ham's F12 (DMEM-F12) were established in suspension culture. The cells grew in protein-free DMEM-F12 (using magnetically stirred flasks) as a monodisperse suspension with a population doubling time of 28 h. The cells were infected with poliovirus types 2 and 3, herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), respiratory syncytial virus (RSV), echovirus 6 and adenoviruses 3 and 7. Polioviruses replicated in suspension culture of HeLa-PF cells to a similar extent as in protein-free and serum-supplemented adherent cultures. RSV and HSV developed significantly lower titers while adenoviruses and echovirus 6 developed significantly higher titers in suspension than in adherent cultures. The results show that suspension culture of HeLa-PF may both provide the advantage of a high virus yield and enable cultivation of viruses which are not contaminated by serum or other proteins usually added to the culture medium.

Cell Culture Techniques↗
PubMed1993

In vitro differentiation of human neuroblastoma cells induced by sodium phenylacetate.

Sodium phenylacetate (NaPA) at concentrations ranging from 2 to 6 mM stimulated morphological differentiation of two human neuroblastoma cell lines IMR-32 and UKF-NB-3. These concentrations inhibited growth and DNA synthesis of the cells in a dose dependent manner without significant effect on cell viability. The differentiated cells showed pseudoganglia formation and extension of cellular processes. The morphological differentiation in both cell lines was accompanied by decreased expression of N-myc oncoprotein. These results suggest that NaPA at concentrations, which have been achieved in humans with no significant adverse effects, promotes differentiation of cultured human neuroblastoma cells in association with the reduced expression of the malignant phenotype.

Cell Differentiation↗