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Berlin Brandenburg

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  • 1
    Language: English
    In: The American Journal of Pathology, April 2012, Vol.180(4), pp.1370-1377
    Description: The influences of cytotoxic drugs on endothelial cells remain incompletely understood. Herein, we examined the effects of chemotherapeutic agents in experimental angiogenesis models and analyzed vessel densities in clinical neuroblastoma tumor samples. Cisplatin (20 to 500 ng/mL), doxorubicin (4 to 100 ng/mL), and vincristine (0.5 to 4 ng/mL), drugs commonly involved in neuroblastoma therapy protocols, induced pro-angiogenic effects in different angiogenesis models. They enhanced endothelial cell tube formation, endothelial cell sprouting from spheroids, formation of tip cells in the sprouting assay, expression of αvβ3 integrin, and vitronectin binding. All three drugs increased global cellular kinase phosphorylation levels, including the angiogenesis-relevant molecules protein kinase Cβ and Akt. Pharmacological inhibition of protein kinase Cβ or Akt upstream of phosphatidylinositol 3-kinase reduced chemotherapy-induced endothelial cell tube formation. Moreover, the investigated chemotherapeutics dose dependently induced vessel formation in the chick chorioallantoic membrane assay. Tumor samples from seven high-risk patients with neuroblastoma were analyzed for vessel density by IHC. Results revealed that neuroblastoma samples taken after chemotherapy consistently showed an enhanced microvessel density compared with the corresponding samples taken before chemotherapy. In conclusion, our data show that chemotherapy can activate endothelial cells by inducing multiple pro-angiogenic signaling pathways and exert pro-angiogenic effects and . Moreover, we report a previously unrecognized clinical phenomenon that might, in part, be explained by our experimental observations: chemotherapy-associated enhanced vessel formation in tumors from patients with neuroblastoma.
    Keywords: Medicine
    ISSN: 0002-9440
    E-ISSN: 1525-2191
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  • 2
    Language: English
    In: Molecular Cancer, 01 September 2009, Vol.8(1), p.80
    Description: Abstract Background Chemoresistance acquisition may influence cancer cell biology. Here, bioinformatics analysis of gene expression data was used to identify chemoresistance-associated changes in neuroblastoma biology. Results Bioinformatics analysis of gene expression data revealed that expression...
    Keywords: Medicine ; Biology
    ISSN: 1476-4598
    E-ISSN: 1476-4598
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  • 3
    In: Scientific Reports, 2015, Vol.5
    Description: Flubendazole was shown to exert anti-leukaemia and anti-myeloma activity through inhibition of microtubule function. Here, flubendazole was tested for its effects on the viability of in total 461 cancer cell lines. Neuroblastoma was identified as highly flubendazole-sensitive cancer entity in a screen of 321 cell lines from 26 cancer entities. Flubendazole also reduced the viability of five primary neuroblastoma samples in nanomolar concentrations thought to be achievable in humans and inhibited vessel formation and neuroblastoma tumour growth in the chick chorioallantoic membrane assay. Resistance acquisition is a major problem in high-risk neuroblastoma. 119 cell lines from a panel of 140 neuroblastoma cell lines with acquired resistance to various anti-cancer drugs were sensitive to flubendazole in nanomolar concentrations. Tubulin-binding agent-resistant cell lines displayed the highest flubendazole IC50 and IC90 values but differences between drug classes did not reach statistical significance. Flubendazole induced p53-mediated apoptosis. The siRNA-mediated depletion of the p53 targets p21, BAX, or PUMA reduced the neuroblastoma cell sensitivity to flubendazole with PUMA depletion resulting in the most pronounced effects. The MDM2 inhibitor and p53 activator nutlin-3 increased flubendazole efficacy while RNAi-mediated p53-depletion reduced its activity. In conclusion, flubendazole represents a potential treatment option for neuroblastoma including therapy-refractory cells.
    Keywords: Biology;
    ISSN: 20452322
    E-ISSN: 20452322
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  • 4
    Language: English
    In: Translational Oncology, December 2013, Vol.6(6), pp.685,IN10-696,IN18
    Description: Novel treatment options are needed for the successful therapy of patients with high-risk neuroblastoma. Here, we investigated the cyclin-dependent kinase (CDK) inhibitor SNS-032 in a panel of 109 neuroblastoma cell lines consisting of 19 parental cell lines and 90 sublines with acquired resistance to 14 different anticancer drugs. Seventy-three percent of the investigated neuroblastoma cell lines and all four investigated primary tumor samples displayed concentrations that reduce cell viability by 50% in the range of the therapeutic plasma levels reported for SNS-032 (〈754 nM). Sixty-two percent of the cell lines and two of the primary samples displayed concentrations that reduce cell viability by 90% in this concentration range. SNS-032 also impaired the growth of the multidrug-resistant cisplatin-adapted UKF-NB-3 subline UKF-NB-3 CDDP in mice. ABCB1 expression (but not ABCG2 expression) conferred resistance to SNS-032. The antineuroblastoma effects of SNS-032 did not depend on functional p53. The antineuroblastoma mechanism of SNS-032 included CDK7 and CDK9 inhibition-mediated suppression of RNA synthesis and subsequent depletion of antiapoptotic proteins with a fast turnover rate including X-linked inhibitor of apoptosis (XIAP), myeloid cell leukemia sequence 1 (Mcl-1), baculoviral IAP repeat containing 2 (BIRC2; cIAP-1), and survivin. In conclusion, CDK7 and CDK9 represent promising drug targets and SNS-032 represents a potential treatment option for neuroblastoma including therapy-refractory cases.
    Keywords: Medicine
    ISSN: 1936-5233
    E-ISSN: 1936-5233
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  • 5
    Language: English
    In: Cancer research, 01 April 2003, Vol.63(7), pp.1508-14
    Description: Replication restricted oncolytic viruses such as multimutated herpes simplex virus type 1 (HSV-1) G207 represent a novel and attractive approach for cancer therapy, including pediatric solid tumors. Rhabdomyosarcoma is the most common soft-tissue sarcoma of childhood and is often diagnosed already as an advanced disseminated disease. Despite aggressive therapeutic approaches, the prognosis for patients with metastatic rhabdomyosarcoma remains grim. Therefore, there is a need for novel effective drugs with superior safety and efficacy profile. In this study, we showed marked in vitro activity of HSV-1 G207 against embryonal and alveolar rhabdomyosarcoma cells. All human embryonal (KF-RMS-1, RD, and CCA) and alveolar RMS (KFR, Rh28, Rh30, and Rh41) cell lines were highly sensitive to cytotoxic and replicative effects of G207 even at a multiplicity of infection of 0.01, except embryonal Rh1 rhabdomyosarcoma cells, which were efficiently killed only upon multiplicity of infection of 1.0. i.v. G207 treatment of xenotransplanted KFR and KF-RMS-1 tumors in mice led to significant tumor growth inhibition of both tumor entities, whereas intraneoplastic G207 treatment additionally resulted in complete tumor disappearance in 25% of animals. No difference has been found between alveolar and embryonal types of rhabdomyosarcoma. Combination treatment of both cell lines with G207 and vincristine led to strongly enhanced in vitro cytotoxicity without affecting infection efficiency and replication of G207 in KFR as well as in KF-RMS-1 cells. In vivo combination treatment using i.v. G207 and vincristine resulted in complete regression of alveolar rhabdomyosarcoma in five of eight animals and significant growth inhibition of embryonal rhabdomyosarcoma. Taking into consideration the proven safety of G207 in humans, we suggest that G207 alone and in combination with vincristine should be additionally evaluated as a potential agent against human rhabdomyosarcoma.
    Keywords: Antineoplastic Agents, Phytogenic -- Pharmacology ; Rhabdomyosarcoma -- Therapy ; Simplexvirus -- Physiology ; Vincristine -- Pharmacology
    ISSN: 0008-5472
    E-ISSN: 15387445
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 6
    Language: English
    In: International Journal of Cancer, 10 March 2003, Vol.104(1), pp.36-43
    Description: Cytotoxic drug treatment of neuroblastoma often leads to the development of drug resistance and may be associated with increased malignancy. To study the effects of long‐term cytotoxic treatment on malignant properties of tumor cells, we established 2 neuroblastoma cell sublines resistant to vincristine (VCR) and doxorubicin (DOX). Both established cell lines (UKF‐NB‐2VCR and UKF‐NB‐2DOX) were highly resistant to VCR, DOX and vice‐versa but retained their sensitivity to cisplatin. UKF‐NB‐2VCR and UKF‐NB‐2DOX expressed significant amounts of P‐glycoprotein, while parental cells were P‐glycoprotein negative. GD2 expression was upregulated, whereas NCAM expression was decreased in both resistant cells. Spectral karyotype (SKY) analysis revealed complex aberrant karyotypes in all cell lines and additional acquired karyotype changes in both resistant cells. All cell lines harbored high levels of N‐myc amplification. Compared to parental cells, UKF‐NB‐2VCR and UKF‐NB‐2DOX exhibited more than 2‐fold increase in clonal growth , accelerated adhesion and transendothelial penetration and higher tumorigenicity . We conclude that development of drug resistance and acquisition of certain karyotypic alterations is associated with an increase of additional malignant properties that may contribute to the poor prognosis in advanced forms of NB. The 2 novel neuroblastoma cell sublines also provide useful models for the study of drug resistance in aggressive forms of neuroblastoma. © 2002 Wiley‐Liss, Inc.
    Keywords: Neuroblastoma ; Drug Resistance ; Mdr‐1 ; Ncam ; Gd2 ; Karyotype
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 7
    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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  • 8
    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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  • 9
    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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  • 10
    Language: English
    In: Cancer Letters, 2007, Vol.250(1), pp.107-116
    Description: The efficacy of Onconase on the growth of a panel of chemosensitive and chemoresistant neuroblastoma cell lines was investigated. Onconase decreased cell viability of chemosensitive (IMR-32, UKF-NB-3) and chemoresistant neuroblastoma cell lines characterised by high expression of P-glycoprotein (P-gp) (UKF-NB-3 DOX ) or by high P-gp expression in combination with mutated p53 (UKF-NB-3 VCR , Be(2)-C), in a similar manner. Moreover, Onconase caused cell cycle block in G1 phase and induced caspase-independent cell death. Transmission electron microscope investigations suggested that Onconase-induced autophagy contributes to Onconase-induced cell death. Antitumour activity of Onconase against naïve and drug-resistant neuroblastoma xenografts was confirmed in animals.
    Keywords: Onconase ; Neuroblastoma ; Multi-Drug-Resistance ; P-Glycoprotein ; P53 ; Medicine
    ISSN: 0304-3835
    E-ISSN: 1872-7980
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