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Berlin Brandenburg

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  • 1
    In: International Journal of Oncology, 12/01/2004
    ISSN: 1019-6439
    E-ISSN: 1791-2423
    Source: CrossRef
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  • 2
    Language: English
    In: International Journal of Oncology, December 2004, Vol.25(6), pp.1795-1799
    Description: Valproic acid (VPA) as a differentiation inducing anti-neoplastic substance is currently tested in solid tumour and leukaemia patients. Previously, we were able to show that the anti-cancer activity of VPA was synergistically increased by interferon-α (IFN-α) in Be(2)-C neuroblastoma (NB) cells. Now, we studied the effects of VPA in combination with IFN-α on two other NB cell lines. UKF-NB-2 and UKF-NB-3 cell growth was synergistically inhibited by VPA and IFN-α. Cell cycle investigations revealed massive accumulation of cells in G0/G1-phase after a combined treatment with VPA and IFN-α. The VPA-induced accumulation of acetylated histones in NB cell nuclei that indicates inhibition of histone deacetylases was not further enhanced by the combination treatment with IFN-α. Most strikingly, VPA plus IFN-α synergistically inhibited growth of UKF-NB-3 xenograft tumours in nude mice and induced complete cures in two out of six animals, while single treatment merely inhibited tumour growth. The results of this study together with our previous report strongly encourage the clinical evaluation of VPA and IFN-α for NB patients.
    Keywords: Enzyme Inhibitors -- Pharmacology ; Interferon-Alpha -- Pharmacology ; Neuroblastoma -- Pathology ; Valproic Acid -- Pharmacology;
    ISSN: 1019-6439
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  • 3
    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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  • 4
    Language: English
    In: Intervirology, 7/1/2004, Vol.39(4), pp.259-269
    Description: Summary 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. Copyright © 1996 S. Karger AG, Basel
    Keywords: Cytomegalovirus, human ; Neuroblastoma ; Oncogenic potential ; Differentiation;
    ISSN: 0300-5526
    E-ISSN: 1423-0100
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  • 5
    Language: English
    In: Intervirology, 7/1/2004, Vol.37(6), pp.307-314
    Description: Summary Effective therapy of human immunodeficiency virus (HIV) infection is mainly based on inhibition of reverse transcriptase by nucleoside analogues such as zidovudine (azidothymidine; AZT), didanosine, and zalcitabine. A major problem associated with long-term AZT therapy is the waning efficacy (‘clinical resistance’) over time. Clinical isolates of HIV-1 with reduced susceptibility to AZT can be recovered from HIV-infected individuals under prolonged treatment. However, the clinical importance of AZT resistance is uncertain. Other factors such as increased virus burden, increased virulence, and AZT toxicity could contribute, singly or in combination, to the loss of therapeutic benefit. Recent observations based on experimental models and clinical trials suggest that cellular mechanisms (‘cellular resistance’) may account for clinical resistance to antiviral agents. In vitro experiments demonstrated that in analogy to antitumoral therapy, the acquisition of multidrug resistance, i.e., resistance of cells to multiple, structurally unrelated chemotherapeutic agents, may play a role in the failure of long-term antiretroviral therapy. The ‘cellular resistance’ may contribute directly to the failure of antiviral therapy by the generation of sub therapeutic levels of antiviral compounds and/or their active forms. Indirectly, such subtherapeutic concentrations of active substances which permit limited replication of virus may represent a selective pressure for emergence and development of a resistant virus population. Hence it is of great importance to investigate the role of cellular factors in ‘clinical resistance’ to AZT and other anti-HIV agents. More detailed knowledge of cellular interactions and antiviral agents could help to improve or develop new strategies for antiviral therapy regimens. Copyright © 1994 S. Karger AG, Basel
    Keywords: Viral resistance mechanisms ; Reverse transcriptase ; Multidrug resistance ; Glycoprotein P ; Cellular thymidine kinase;
    ISSN: 0300-5526
    E-ISSN: 1423-0100
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  • 6
    Language: English
    In: Neoplasia, November 2004, Vol.6(6), pp.725-735
    Description: The mode of the antitumoral activity of multimutated oncolytic herpes simplex virus type 1 G207 has not been fully elucidated yet. Because the antitumoral activity of many drugs involves the inhibition of tumor blood vessel formation, we determined if G207 had an influence on angiogenesis. Monolayers of human umbilical vein endothelial cells and human dermal microvascular endothelial cells, but not human dermal fibroblasts, bronchial epithelial cells, and retinal glial cells, were highly sensitive to the replicative and cytotoxic effects of G207. Moreover, G207 infection caused the destruction of endothelial cell tubes . In the Matrigel plug assay in mice, G207 suppressed the formation of perfused vessels. Intratumoral treatment of established human rhabdomyosarcoma xenografts with G207 led to the destruction of tumor vessels and tumor regression. Ultrastructural investigations revealed the presence of viral particles in both tumor and endothelial cells of G207-treated xenografts, but not in adjacent normal tissues. These findings show that G207 may suppress tumor growth, in part, due to inhibition of angiogenesis.
    Keywords: Angiogenesis ; Hsv-1 ; G207 ; Human Rhabdomyosarcoma ; Ribonucleotide Reductase ; Medicine
    ISSN: 1476-5586
    E-ISSN: 1476-5586
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  • 7
    In: International Journal of Molecular Medicine, 02/01/2004
    ISSN: 1107-3756
    E-ISSN: 1791-244X
    Source: CrossRef
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  • 8
    Language: English
    In: Medical Microbiology and Immunology, 2004, Vol.193(4), pp.195-203
    Description: Human cytomegalovirus (HCMV) retinitis causing retinal detachment and destruction of the blood-retina barrier is closely related to retinal hemorrhage/coagulation. However, the effects of procoagulants on HCMV (re)activation in retinal cells have not been investigated yet. Therefore, we studied whether thrombin modulates the expression of HCMV immediate early (IE) and late (L) genes in cultured human retinal pigment epithelial cells (RPE). Thrombin specifically stimulated the protease-activated receptor-1 (PAR-1) on RPE and, surprisingly, inhibited basal and 12,0-tetradecanoylphorbol 13-acetate-stimulated HCMV IE gene expression in infected RPE. On the other hand, HCMV strongly induced Sp1 DNA binding activity, which was prevented by thrombin/PAR1-mediated Sp1 hyperphosphorylation. Our data suggest that thrombin/PAR-1 may inhibit Sp1-dependent HCMV replication, which might be an important regulatory mechanism for HCMV persistence and replication in RPE.
    Keywords: Human cytomegalovirus ; Infectious immunity virus ; Retina ; Signal transduction ; Transcription factors
    ISSN: 0300-8584
    E-ISSN: 1432-1831
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  • 9
    Language: English
    In: Molecular pharmacology, March 2004, Vol.65(3), pp.520-7
    Description: Valproic acid (VPA) is a widely used antiepileptic agent that is undergoing clinical evaluation for anticancer therapy. We assessed the effects of VPA on angiogenesis in vitro and in vivo. In human umbilical vein endothelial cells, therapeutically relevant concentrations of VPA (0.25 to 1 mM) inhibited proliferation, migration, and tube formation. VPA 1 mM inhibited endothelial cell proliferation by 51 +/- 5%, migration by 86 +/- 11%, and tube formation by 82 +/- 3%. These changes were preceded by the hyperacetylation of histone H4, indicating the inhibition of histone deacetylase (HDAC), and a decreased expression of the endothelial nitric-oxide synthase (eNOS). The inhibition of endothelial cell tube formation by VPA was prevented by addition of the nitric oxide donor (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA NONOate). The anticonvulsive active VPA derivative 2-ethyl-4-methylpentanoic acid, which does not inhibit HDAC, did not affect endothelial cell proliferation, tube formation, or eNOS expression. VPA was also found to inhibit angiogenesis in vivo in the chicken chorioallantoic membrane assay and in a Matrigel plug assay in mice. Embryos from VPA-treated mice showed disturbed vessel formation. These results indicate that therapeutic plasma levels of VPA inhibit angiogenesis by a mechanism involving a decrease in eNOS expression preceded by HDAC inhibition.
    Keywords: Angiogenesis Inhibitors -- Pharmacology ; Endothelium, Vascular -- Drug Effects ; Neovascularization, Physiologic -- Drug Effects ; Valproic Acid -- Pharmacology
    ISSN: 0026-895X
    E-ISSN: 15210111
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