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Berlin Brandenburg

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  • Vogel, J U  (12)
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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: The Journal of Infectious Diseases, 1 September 2000, Vol.182(3), pp.643-651
    Description: In fibroblasts, infection with human cytomegalovirus (HCMV) inhibits expression of the extracellular matrix proteins thrombospondin-1 and -2 (TSP-1 and TSP-2). These effects may depend on expression of HCMV immediate-early (IE) genes, which are activated by cellular transcription factor NF-kB. The influence of HCMV infection on TSP-1 and TSP-2 expression and the ability of different antiviral drugs to prevent these cellular changes in permissive cultures of human retinal glial cells were observed. Ganciclovir inhibited only HCMV late antigen (LA) expression, whereas antisense oligonucleotide ISIS 2922 and peptide SN50, inhibitors of HCMV IE expression and NF-kB activity, respectively, inhibited both IE and LA expression. ISIS 2922 and SN50, but not ganciclovir, prevented down-modulation of TSP1 and TSP-2. The results showed that HCMV-induced down-modulation of TSP-1 and TSP2 in retinal glial cells is prevented by inhibition of HCMV IE expression. These findings may be relevant to pathogenesis and treatment of HCMV retinitis.
    Keywords: Biological sciences -- Biology -- Cytology ; Biological sciences -- Biology -- Microbiology ; Health sciences -- Medical sciences -- Pharmaceutics ; Biological sciences -- Biology -- Microbiology ; Health sciences -- Medical conditions -- Infections ; Biological sciences -- Biochemistry -- Biomolecules ; Physical sciences -- Chemistry -- Chemical compounds ; Biological sciences -- Biology -- Cytology ; Biological sciences -- Biology -- Cytology ; Health sciences -- Medical conditions -- Diseases
    ISSN: 00221899
    E-ISSN: 15376613
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  • 3
    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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  • 4
    Language: English
    In: International Journal of Molecular Medicine, February 2004, Vol.13(2), pp.327-331
    Description: Recently, we reported that thrombin specifically stimulates protease-activated receptor-1 (PAR-1) signaling in RPE entailing inhibition of Sp1 dependent HCMV replication. We now studied whether thrombin modulates the expression of the proinflammatory cytokine/chemokines IL-6 and IL-8 in mock- and cytomegalovirus-infected human retinal pigment epithelial cells (RPE). Our data show that thrombin/PAR-1 stimulates IL-6 and IL-8 gene transcription and protein secretion in both mock- and HCMV-infected RPE. Thrombin/PAR-1-mediated signaling stimulated PKC and NF-κB-dependent IL-6 and IL-8 gene expression via phosphoinositide 3-kinase and further downstream via p42/44 and p38 MAPKs. Thus, thrombin/PAR-1-mediated IL-6/IL-8 gene expression is uncoupled from Sp1 inhibition and may support proinflammatory pathomechanisms probably involved in hemorrhage/HCMV retinitis progression.
    Keywords: Cytomegalovirus Infections -- Metabolism ; Interleukin-6 -- Genetics ; Interleukin-8 -- Genetics ; Pigment Epithelium of Eye -- Metabolism ; Thrombin -- Metabolism;
    ISSN: 1107-3756
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  • 5
    Language: English
    In: International Journal of Oncology, January 2002, Vol.20(1), pp.97-106
    Description: Valproic acid (VPA) has been shown to induce growth-arrest and differentiation of human neuroectodermal tumors similarly to several other fatty acids. In the present study, we show that continuous VPA treatment together with Interferon-α (INF-α) synergistically inhibited cell growth of a well-established model of neuroblastoma (NB) differentiation using the human N-myc amplified cell line BE(2)-C. Suppression of tumor growth was accompanied by morphological features of neuronal differentiation and inhibition of histone deacetylase activity. Furthermore, induction of differentiation was concomitant with altered expression of genes related to malignant phenotype such as down-regulation of N-myc, induction of bcl-2 and neural cell adhesion molecule. Production of inhibitors of angiogenesis like thrombospondin-1 and activin A was up-regulated in differentiated NB cells. Treatment with VPA alone decreased the ability of BE(2)-C cells to adhere to and penetrate human endothelium. All these effects of VPA were significantly enhanced when combined with INF-α which on its own had little or no effect. These results suggest that combination of VPA and INF-α may provide a novel therapeutic strategy for NB due to enhanced inhibition of tumor cell growth, induction of tumor differentiation and suppression of malignant biology by reduced angiogenic and decreased metastatic potentials.
    Keywords: Antineoplastic Agents -- Therapeutic Use ; Brain Neoplasms -- Drug Therapy ; Cell Differentiation -- Drug Effects ; Enzyme Inhibitors -- Therapeutic Use ; Interferon-Alpha -- Therapeutic Use ; Neuroblastoma -- Drug Therapy ; Valproic Acid -- Therapeutic Use;
    ISSN: 1019-6439
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  • 6
    In: Anti-Cancer Drugs, 2001, Vol.12(5), pp.467-473
    Description: Treatment failure in most neuroblastoma (NB) patients is related to primary and/or acquired resistance to conventional chemotherapeutic agents. Aphidicolin (APH), a tetracyclic diterpene, exhibits specific cytotoxic action against NB cells. The purpose of this study was to compare antitumoral efficacy of APH in parental NB cell lines and cell subclones that exhibit drug resistance to vincristine (VCR), doxorubicin (DOX) and cisplatin. Due to poor solubility of APH in water, γ-cyclodextrin (γ-CD) inclusion complexes of APH were used for systemic treatment of xenotransplanted parental and VCR-resistant UKF-NB-3 tumours. APH and its γ-CD inclusion complexes inhibited growth of parental and drug-resistant NB cells at equimolar doses in vitro. Growth of VCR-sensitive and -resistant NB tumors was inhibited at equal doses in a dose-dependent fashion in vivo. These results indicate that the specific cytotoxic activity of APH against NB cells in vitro and in vivo is independent of cellular mechanisms facilitating drug resistance to conventional chemotherapeutic drugs. Hence, taking into account our previous findings that APH acts synergistically with VCR and DOX, APH might be an additive tool for the therapy of NB and is suitable for evaluation in clinical studies of NB treatment protocols.
    Keywords: Aphidicolin -- Therapeutic Use ; Cell Survival -- Drug Effects ; Cyclodextrins -- Pharmacology ; Enzyme Inhibitors -- Therapeutic Use ; Neuroblastoma -- Drug Therapy ; Tumor Cells, Cultured -- Drug Effects;
    ISSN: 0959-4973
    E-ISSN: 14735741
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  • 7
    Language: English
    In: Medical Microbiology and Immunology, 2005, Vol.194(1), pp.55-59
    Description: Intracellular glutathione (GSH) plays an important regulatory role in the host response to viral infections. Replenishment of intracellular GSH is a desirable yet challenging goal, since systemic GSH supplementation is rather inefficient due to a short half-life of GSH in blood plasma. Further, GSH is not taken up by cells directly, but needs to be broken down into amino acids and resynthesized to GSH intracellularly, this process often being impaired during viral infections. These obstacles may be overcome by a novel glutathione derivative S-acetylglutathione (S-GSH), which is more stable in plasma and taken up directly by cells with subsequent conversion to GSH. In the present study, in vitro effects of supplementation with S-GSH or GSH on intracellular GSH levels, cell survival and replication of human herpes simplex virus type 1 (HSV-1) were studied in human foreskin fibroblasts. In addition, in vivo effects of supplementation with S-GSH or GSH on HSV-1-induced mortality were studied in hr/hr mice. In cell culture, viral infection resulted in a significant decrease of intracellular GSH levels. S-GSH efficiently and dose-dependently (5 and 10 mM tested) restored intracellular GSH, and this replenishment was more efficient than with GSH supplementation. In mice, S-GSH, but not GSH, significantly decreased HSV-1-induced mortality ( P 〈0.05). The data suggest that S-GSH is a suitable antiviral agent against HSV-1 both in vitro and in vivo, indicating that this drug may be of benefit in the adjunctive therapy of HSV-1 infections.
    Keywords: Intracellular glutathione ; S-acetylglutathione ; Herpes simplex virus type 1 infection ; Antiviral drugs
    ISSN: 0300-8584
    E-ISSN: 1432-1831
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  • 8
    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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  • 9
    Language: English
    In: The American Journal of Pathology, 1999, Vol.155(1), pp.285-292
    Description: Thrombospondin-1 (TSP-1) is a potent inhibitor of angiogenesis. It has been shown that promoter sequences of the TSP-1 gene can be transactivated by the wild-type tumor suppressor protein p53. As human cytomegalovirus (HCMV) infection inactivates wild-type p53 of various cell types, we investigated whether HCMV infection is associated with reduced TSP-1 production. We found, in conjunction with accumulated p53, that TSP-1 mRNA and protein expression was significantly reduced in HCMV-infected cultured human fibroblasts. To determine whether the observed TSP-1 suppression depends on p53 inactivation, the p53-defective astrocytoma cell line U373MG was infected with HCMV. In these cells TSP-1 expression was also significantly reduced by HCMV infection whereas expression of the p53 mutant variant remained unaltered. In both cell lines the decreased expression of TSP-1 mRNA occurred early after infection (4 hours), indicating that HCMV inhibits TSP-1 transcription during the immediate-early phase of infection before HCMV DNA replication. Inhibition of HCMV DNA synthesis by ganciclovir did not influence TSP-1 reduction whereas the antisense oligonucleotide ISIS 2922, complementary to HCMV immediate-early mRNA, completely prevented the HCMV-mediated TSP-1 suppression. These findings strongly suggest a novel role for HCMV in the modulation of angiogenesis due to p53-independent down-regulation of TSP-1 expression.
    Keywords: Medicine
    ISSN: 0002-9440
    E-ISSN: 1525-2191
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  • 10
    In: Anti-Cancer Drugs, 2000, Vol.11(5), pp.369-376
    Description: Bovine seminal ribonuclease (BS-RNase) is a protein with a number of biological effects. It shows antitumoral, aspermatogenic, antiembryonic, immunosuppressive and antiviral properties. The cytotoxic effects appear to be specific for tumor cells as non-malignant cells seem to be unaffected in vitro. Unfortunately, the in vivo application of BS-RNase so far was successful only when it was administered intratumorally. Therefore, the objective of the present investigation was to improve the properties of BS-RNase by attachment to nanoparticles made of polylactic acid (PLA-NP) using an adsorption method. This preparation was tested in vitro against leukemia (MOLT-4) and lymphoma (H9) cell lines sensitive and resistant to cytarabine. No difference between the nanoparticle preparation and pure BS-RNase was found in these tests. To examine the in vivo effects, the preparations were tested for their aspermatogenic and antiembryonal efficacy compared to the pure BS-RNase as a rapid test for antitumoral activity. The aspermatogenic and antiembryonal effects were enhanced by the nanoparticle preparation. Consequently, BS-RNase loaded adsorptively to PLA-NP holds promise for the in vivo use as an antitumoral agent. Further research will investigate the efficacy of this preparations in an in vivo tumor model.
    Keywords: Antineoplastic Agents -- Pharmacology ; Endoribonucleases -- Pharmacology ; Leukemia -- Drug Therapy ; Lymphoma -- Drug Therapy ; Tumor Cells, Cultured -- Drug Effects;
    ISSN: 0959-4973
    E-ISSN: 14735741
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