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  • 1
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; IONIZING-RADIATION ; proliferation ; CELL ; COMBINATION ; Germany ; IN-VIVO ; KINASE ; PATHWAY ; PATHWAYS ; THERAPY ; TYROSINE KINASE ; SUPPORT ; EXPOSURE ; TISSUE ; radiation ; TISSUES ; tumour ; CONTRAST ; cell culture ; culture ; TARGET ; immunohistochemistry ; RADIATION-THERAPY ; EFFICACY ; NETHERLANDS ; SQUAMOUS-CELL CARCINOMAS ; RECEPTORS ; GLIOMAS ; PERMEABILITY FACTOR ; BRAIN-TUMORS ; TUMOR-GROWTH ; GLIOMA ; anti-angiogenic therapy,glioblastoma multiforme,radiotherapy,VEGF receptor-coexpression ; FACTOR RECEPTOR-1 ; HUMAN GLIOMAS
    Abstract: In tumour-induced angiogenesis of gliomas, vascular endothelial growth factor (VEGF) and its receptors fms-like tyrosine kinase (Flt-1) and kinase-insert-domain-containing receptor (KDR) play a major role and are promising targets for tumour therapy. Nevertheless, preliminary results of such therapies could not prove clinical efficacy and thus make a profound knowledge of VEGF regulation essential. Based on earlier results, which demonstrated an inhibitory influence of VEGF on Flt-1-expressing glioblastoma cells [1], in the present study we focused on the extent of VEGF and VEGF receptor coexpression and possible therapeutical consequences.Protein expression of VEGF, Flt-1 and KDR was analysed by immunohistochemistry in native tumour tissues of 63 glioblastomas. VEGF could be detected in all glioblastomas. Additionally and independently to the expected Flt-1 and KDR expression in tumour endothelia, we found a coexpression of VEGF with Flt-1 in tumour cells of 46 and with KDR in 45 glioblastomas. After exposure of glioblastoma cells to X-ray radiation we observed a strong dose-dependent increase of VEGF secretion in two glioblastoma cell cultures by up to 46% and 96%, respectively that originated from an increased VEGF mRNA expression. In contrast, under the same conditions secretion of HGF/SF was only slightly elevated and bFGF despite being strongly increased remained at very low overall amounts compared to VEGF. Based on previous data on an autocrine function of VEGF in Flt-1-expressing glioblastoma cells we hypothesise that the X-ray radiation induced upregulation of VEGF might result in a downregulation of tumour cell proliferation and thus lead to a reduced sensitivity to radiation therapy. Therefore our results support the idea that a combination of anti-VEGF and radiation therapy might prove a promising new option in fighting against one of the most fatal tumour types
    Type of Publication: Journal article published
    PubMed ID: 15015778
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  • 2
    Keywords: brain ; CELLS ; EXPRESSION ; SURVIVAL ; tumor ; TUMOR-CELLS ; BLOOD ; CELL ; Germany ; THERAPY ; DISEASE ; LONG-TERM ; TUMORS ; TIME ; PATIENT ; INFECTION ; prognosis ; SKIN ; T cell ; T cells ; T-CELL ; T-CELLS ; cell culture ; culture ; MEMORY ; virus ; NERVOUS-SYSTEM ; NO ; immunohistochemistry ; ASSAY ; NUMBER ; VACCINE ; SAFETY ; CD8(+) ; immune response ; IMMUNE-RESPONSE ; IMMUNITY ; T-LYMPHOCYTES ; vaccination ; T lymphocyte ; side effects ; NEWCASTLE-DISEASE VIRUS ; ESTABLISHMENT ; TUMOR CELLS ; LONG-TERM SURVIVORS ; GLIOMAS ; T lymphocytes ; IMMUNIZATION ; ONCOLOGY ; AUTOLOGOUS TUMOR ; overall survival ; NEWCASTLE-DISEASE-VIRUS ; SURVIVORS
    Abstract: Purpose Prognosis of patients with glioblastoma is poor. Therefore, in glioblastoma patients, we analyzed whether antitumor vaccination with a virus-modified autologous tumor cell vaccine is feasible and safe. Also, we determined the influence on progression-free survival and overall survival and on vaccination-induced antitumor reactivity. Patients and Methods In a nonrandomized study, 23 patients were vaccinated and compared with nonvaccinated controls (n = 87). Vaccine was prepared from patient's tumor cell cultures by infection of the cells with Newcastle Disease Virus, followed by gamma-irradiation, and applied up to eight times. Antitumor immune reactivity was determined in skin, blood, and relapsed tumor by delayed-type hypersensitivity skin reaction, ELISPOT assay, and immunohistochemistry, respectively. Results Establishment of tumor cell cultures was successful in approximately 90% of patients. After vaccination, we observed no severe side effects. The median progression-free survival of vaccinated patients was 40 weeks (v 26 weeks in controls; log-rank test, P =.024), and the median overall survival of vaccinated patients was 100 weeks (v 49 weeks in controls; log-rank test, P 〈.001). Forty-five percent of the controls survived 1 year, 11% survived 2 years, and there were no long-term survivors (greater than or equal to3 years). Ninety-one percent of vaccinated 39% survived 2 years, and 4% were long-term survivors. In the patients survived I year, vaccinated group, immune monitoring revealed significant increases of delayed-type hypersensitivity reactivity, numbers of tumor-reactive memory T cells, and numbers of CD8(+) tumor-infiltrating T-lymphocytes in secondary tumors. Conclusion Postoperative vaccination with virus-modified autologous tumor cells seems to be feasible and safe and to improve the prognosis of patients with gliobiastomas. This could be substantiated by the observed antitumor immune response. (C) 2004 by American Society of Clinical Oncology
    Type of Publication: Journal article published
    PubMed ID: 15452186
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  • 3
    Keywords: brain ; APOPTOSIS ; CANCER ; CELLS ; IN-VITRO ; SURVIVAL ; AGENTS ; CELL ; Germany ; IN-VIVO ; VITRO ; DEATH ; DRUG ; SURGERY ; LINES ; TIME ; PATIENT ; LIGAND ; primary ; INDUCTION ; tumour ; treatment ; culture ; ACID ; CELL-DEATH ; PLASMA ; RATES ; RESECTION ; PHARMACOKINETICS ; CISPLATIN ; FUTURE ; TRAIL ; AGENT ; POTENT ; REGRESSION ; IV ; GRADE ; brain tumour ; betulinic acid ; CERAMIDE ; glioblastoma multiforme WHOIV
    Abstract: Background. Glioblastoma multiforme (WHO Grade IV, GBM) is the most malignant brain tumour with a mean survival time of less than one year. Betulinic acid, ceramide and TRAIL (TNF-related apoptosis inducing ligand) represent novel therapeutic agents for potential use in GBM. Method. Primary GBM cells of 21 patients with macroscopically complete tumour resection were tested in vitro for cell death induction by betulinic acid, ceramide, TRAIL and established therapeutics (BCNU, cisplatin, doxorubicin, vincristin and gamma-irradiation). Findings. At peak plasma concentrations (PPC), Betulinic acid, ceramide and TRAIL induced cell death in primary GBM cells at higher rates than established cytotoxic drugs. Specific cell death greater than or equal to75% was observed in 43% (9/21), 38% (8/21), and 19% (4/21) for betulinic acid, ceramide, and TRAIL respectively, while this was only found in 5% (1/21) of gamma-irradiated and cisplatin-treated cells, and in none of the GBM cultures, where BCNU or vincristin were applied in PPC. Conclusion. Due to a markedly improved cell death of GBM cells as compared with established therapeutics, Betulinic acid, ceramide and TRAIL might represent potent substances for future treatment of GBM
    Type of Publication: Journal article published
    PubMed ID: 15197616
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  • 4
    Keywords: brain ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; tumor ; CELL ; Germany ; human ; MICROSCOPY ; PROTEIN ; PROTEINS ; SAMPLE ; SAMPLES ; DRUG ; FAMILY ; MEMBER ; MEMBERS ; GLYCOPROTEIN ; NO ; GLUTATHIONE ; resistance ; MEMBRANE ; NUCLEOTIDES ; REGION ; REGIONS ; LOCALIZATION ; POLYMERASE-CHAIN-REACTION ; CHAIN-REACTION ; DRUG-RESISTANCE ; MULTIDRUG-RESISTANCE ; CONJUGATE EXPORT PUMP ; ORGANIC ANION TRANSPORTER ; CHAIN ; quantitative polymerase chain reaction ; ADULT ; polymerase chain reaction ; P-GLYCOPROTEIN ; TRANSPORTER ; NEURONS ; GLYCOPROTEINS ; BASOLATERAL HEPATOCYTE MEMBRANE ; blood-brain barrier ; CEREBROSPINAL FLUID BARRIER ; CULTURED RAT ASTROCYTES ; human brain ; MICROVESSEL ENDOTHELIAL-CELLS ; MRP4 CONFERS RESISTANCE ; multidrug resistance proteins (MRPs,symbol ABCC) ; NORMAL HUMAN-TISSUES ; organic anions
    Abstract: Multidrug resistance proteins (MRPs, symbol ABCC) are membrane glycoproteins that mediate the ATP-dependent export of organic anions, including cytotoxic and antiviral drugs, from cells. To identify MRP family members possibly involved in the intrinsic resistance of human brain to cytotoxic and antiviral drugs, we analyzed the expression and localization of MRP1-MRP6 in rapidly frozen perilesional samples of several regions of adult human brain obtained during neurosurgery. Quantitative polymerase chain reaction analysis showed expression of MRP1, MRP2, MRP3, MRP4, and MRP5 mRNA, whereas MRP6 mRNA was below detectability. However, immunofluorescence microscopy of cryosections from human brain showed no reactivity for the MRP2 or MRP3 proteins. The proteins MRP1, MRP4, and MRP5 were clearly localized by confocal laser scanning microscopy to the luminal side of brain capillary endothelial cells. The MRP4 and MRP5 proteins were also detected in astrocytes of the subcortical white matter. Notably, MRP5 protein was present in pyramidal neurons. MRP proteins may, thus, contribute to the cellular efflux of endogenous anionic glutathione or glucuronate conjugates (substrates for MRP1), cyclic nucleotides (substrates for MRP4 and MRP5), or glutathione (co-substrate for MRP1 and MRP4); in addition, they may play an important role in the resistance of the brain to several cytotoxic and antiviral drugs. (C) 2004 IBRO. Published by Elsevier Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 15501592
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  • 5
    Keywords: brain ; CANCER ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; tumor ; AGENTS ; Germany ; human ; MICROSCOPY ; neoplasms ; GENE ; GENES ; PROTEIN ; PROTEINS ; DRUG ; TUMORS ; FAMILY ; CELL-LINES ; MEMBERS ; TRANSPORT ; resistance ; MEMBRANE ; PCR ; DELIVERY ; LOCALIZATION ; PHENOTYPE ; MULTIDRUG-RESISTANCE ; GLIOMAS ; chemoresistance ; multidrug resistance ; SUBCELLULAR-LOCALIZATION ; AGENT ; ONCOLOGY ; RE ; BRAIN-TUMORS ; GLIOMA ; endothelial cells ; P-GLYCOPROTEIN ; TRANSPORTER ; SUBTYPE ; BASOLATERAL HEPATOCYTE MEMBRANE ; MRP4 CONFERS RESISTANCE ; LEVEL ; SUBTYPES ; EFFLUX PUMPS ; immunofluorescence ; membrane transport proteins ; MICROVESSEL ENDOTHELIUM ; multidrug resistance protein ; MULTIDRUG-RESISTANCE PROTEINS ; oligoastrocytoma ; oligodendroglioma ; RAT ASTROCYTES ; SUBFAMILY
    Abstract: Delivery of therapeutic agents to the brain and its neoplasms depends on the presence of membrane transport proteins in the blood-brain barrier and in the target cells. The cellular and subcellular localization of these membrane transporters determines the drug accessibility to the brain and its tumors. We therefore analyzed the expression and localization of six members of the multidrug resistance protein family of ATP-dependent efflux pumps (ABCCI-ABCC6, formerly MRPI-MRP6) and of six organic anion uptake transporters (OATPIA2, OATP1B1, OATP1B3, OATP1C1, OAT2B1, and OATP4A1) in 61 human glioma specimens of different histologic subtypes. Real-thine PCRs indicated expressions of ABCO, ABCC3, ABCC4, and ABCC5. In addition, we detected expressions of the OATP uptake transporter genes SLCOIA2, SWO1C1, SLCO2B1, and SLC04A1. At. the protein level, however, only OATPIA2 and OATP2B1 were detectable by immunofluorescence microscopy in the luminal membrane of endothelial cells forming the blood-brain barrier and the blood-tumor barrier, but not in the glioma cells. ABCC4 and ABCC5 proteins were the major ABCC subfamily members in gliomas, localized both at the luminal side of the endothetial cells and in the glioma cells of astrocytic tumors and in the astrocytic portions of oligoastrocytomas. These results indicate that expression of ABCC4 and ABCC5 is associated with an astrocytic phenotype, in accordance with their expression in astrocytes and with the higher chemoresistance of astrocytic tumors as compared with oligodendrogliomas. Our data provide a basis for the assessment of the role of uptake transporters and efflux pumps in the accessibility of human gliomas for chemotherapeutic agents
    Type of Publication: Journal article published
    PubMed ID: 16357150
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