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  • Kornhuber, Bernhard  (10)
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  • 1
    Language: English
    In: Intervirology, 1996, Vol.39(4), pp.259-269
    Description: 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-β-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, protooncogenes 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 of tumor cells.
    Keywords: Original Paper ; Cytomegalovirus, Human ; Neuroblastoma ; Oncogenic Potential ; Differentiation ; Biology
    ISSN: 0300-5526
    E-ISSN: 1423-0100
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  • 2
    Language: English
    In: International Journal of Cancer, 01/03/1996, Vol.65(1), pp.90-96
    Description: 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-4 super(AD169) were subcultured (80 subcultures) over a period of more than 2 years after initiation of infection. UKF-NB-4 super(AD169) cells continued to produce infectious virus in successive passages, with a titre ranging from 9 x 10 super(3) to 1 x 10 super(5) and from 2 x 10 super(1) to 2 x 10 super(2) plaque-forming units per 10 super(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 super(4) to 9 x 10 super(6) per 10 super(6) cells. Transmission electron microscopy confirmed the productive nature of HCMV infection. UKF-NB-4 super(AD169) 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-4 super(AD169) 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.
    Keywords: Cytomegalovirus ; Cytomegalovirus ; Neuroblastoma Cells ; Man ; Tumor Cells ; Phenotyping ; Neuroblastoma Cells ; Man ; Tumor Cells ; Phenotyping ; Neurovirology ; Virus Behavior in Cell Culture ; Tyrosine 3-Monooxygenase ; Dopamine Beta -Monooxygenase ; N-Myc Protein ; Tyrosine 3-Monooxygenase ; Dopamine Beta -Monooxygenase ; N-Myc Protein ; N-Myc Protein ; Dopamine Beta -Monooxygenase ; Tyrosine 3-Monooxygenase;
    ISSN: 00207136
    E-ISSN: 10970215
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  • 3
    Language: English
    In: Cell Communication & Adhesion, 01 January 2002, Vol.9(3), pp.131-147
    Description: The precise function of cell adhesion molecules in the hematogenous phase of neuroblastoma metastasis is poorly understood. The aim of this study was to investigate whether neural cell adhesion molecule (NCAM) modulates neuroblastoma cell (NB) adhesion and transendothelial penetration in a...
    Keywords: Ncam ; Neuroblastoma ; Adhesion ; Biology
    ISSN: 1541-9061
    E-ISSN: 1543-5180
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  • 4
    Language: English
    In: Antiviral Research, 1997, Vol.33(3), pp.165-175
    Description: An l -glutamine antagonist, 6-diazo-5-oxo- l -norleucin ( l -DON), inhibits replication of vesicular stomatitis virus, poliovirus and paramyxoviruses in cultured cells. We tested the antiviral activity of l -DON against different strains of herpes simplex virus type 1 (HSV-1) in Vero cells. In the presence of a physiological plasma concentration of l -glutamine (0.5 mM) l -Don inhibited 50% production of virus plaques at concentrations ranging from 7.9 to 16 μ M. At concentrations of 40 μ M l -Don inhibited infectious virus yield by 99%. The antiviral activity of l -DON decreased with increasing l -glutamine concentrations. A concentration of 5000 μ M of l -Don had no significant effects on the viability of Vero cells. Transmission electron microscopical investigations showed that l -DON prevented mainly envelopment of viral nucleocapsids in the cytoplasm. The immunoprecipitation experiments demonstrated selective inhibition of synthesis of HSV-1 glycoproteins in l -DON treated cells. The results showed that l -DON inhibits HSV-1 replication at a late stage in the virus replication cycle, probably the cytoplasmic maturation of virions and subsequent virion egress from the cells.
    Keywords: Hsv ; Acyclovir ; 6-Diazo-5-Oxo- L-Norleucin ; Virus-Resistance ; Medicine ; Biology
    ISSN: 0166-3542
    E-ISSN: 1872-9096
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  • 5
    In: Anti-Cancer Drugs, 1997, Vol.8(10), pp.958-963
    Description: 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 anttitumoral 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 mm 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.
    Keywords: Antineoplastic Agents -- Pharmacology ; Neuroblastoma -- Drug Therapy ; Valproic Acid -- Pharmacology;
    ISSN: 0959-4973
    E-ISSN: 14735741
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  • 6
    Language: English
    In: Cancer Letters, 1993, Vol.70(1), pp.15-24
    Description: 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.
    Keywords: Neuroblastoma ; Differentiation ; Phenylacetate ; Retinoic Acid ; N- Myc ; Medicine
    ISSN: 0304-3835
    E-ISSN: 1872-7980
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  • 7
    Language: English
    In: Cell Biology International, April 1994, Vol.18(4), pp.271-278
    Description: 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.
    Keywords: Biology
    ISSN: 1065-6995
    E-ISSN: 1095-8355
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  • 8
    Language: English
    In: Cancer Letters, 1992, Vol.67(2), pp.199-206
    Description: Aphidicolin is a tetracyclic diterpene antibiotic which is known to inhibit the growth of eucaryotic cells by reversible binding to DNA polymerase alpha without significant effect on cell viability in most common human cell lines. We observed that aphidicolin at a concentration of 5 x 10(-7) M kills all cells of four human neuroblastoma cell lines. In contrast, viability of normal human embryonal cells and of human continuous cell lines including HeLa, H9, A549 and Caco-2 was influenced only moderately by aphidicolin. In addition, neuroblastoma cells were killed after treatment with 5 x 10(-7) M aphidicolin in cocultures with normal embryonal cells which continued to proliferate after removal of aphidicolin. These results show that aphidicolin provides an agent which selectively kills neuroblastoma cells in vitro.
    Keywords: Aphidicolin ; Neuroblastoma Cells ; Cell Killing ; Medicine
    ISSN: 0304-3835
    E-ISSN: 1872-7980
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  • 9
    In: Anti-Cancer Drugs, 1996, Vol.7(7), pp.766-773
    Description: 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. Ultra-structural 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.
    Keywords: Antibiotics ; Miscellaneous, Reviews ; Sodium Valproate ; Neuroblastoma ; Neuroblastoma ; Sodium Valproate;
    ISSN: 0959-4973
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  • 10
    Language: English
    In: Cancer Letters, 1994, Vol.78(1), pp.41-48
    Description: 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.
    Keywords: Rhabdomyosarcoma ; Phenylacetate ; Glutamine ; Myogenic Differentiation ; Sarcomerogenesis ; Medicine
    ISSN: 0304-3835
    E-ISSN: 1872-7980
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