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  • tumor  (8)
  • TUMORS  (6)
Keywords
  • 1
    Keywords: CANCER ; CELLS ; EXPRESSION ; tumor ; TUMOR-CELLS ; CELL ; Germany ; KINASE ; THERAPY ; GENE ; GENE-EXPRESSION ; PROTEIN ; cell line ; TUMORS ; LINES ; DNA ; INFECTION ; REDUCTION ; CELL-LINES ; PHOSPHORYLATION ; treatment ; PARTICLES ; virus ; ISOFORM ; gene expression ; PROMOTER ; DECREASE ; ELEMENTS ; NUMBER ; CELL-LINE ; LINE ; TRANSFORMATION ; GLUCOSE ; FLUORESCENCE ; REGULATORY ELEMENTS ; adeno-associated virus ; ADENOASSOCIATED VIRUS ; VIRUS THYMIDINE KINASE ; TUMOR-CELL-LINES ; HIGH-LEVEL ; HaCaT ; Ras ; THYMIDINE KINASE ; SRC ONCOGENE ; ADENOASSOCIATED VIRUS VECTORS ; CYSTIC-FIBROSIS ; glucose transporter promoter,HSV thymidine kinase,suicide gene,AAV
    Abstract: In order to achieve tumor-specific targeting of adeno-associated virus (AAV)-mediated gene expression, the promoter of the glucose transporter isoform 1 (GLUT1) gene was cloned upstream of the enhanced green fluorescence protein (EGFP) and the herpes simplex virus thymidine kinase (HSVtk) gene. FACS analysis performed at 48 h after transient infection with rAAV/cytomegalovirus (CMV)egfp viral particles revealed an increase of fluorescence in all the cell lines tested. However, EGFP expression under control of the GLUT1 promoter element (rAAV/GTI-1.3egfp) was limited to the tumor cells and oncogene-transformed cells. Evidence for phosphorylation of the HSVtk substrates ganciclovir (GCV) and I-125-deoxycytidine was found in all transfected tumor cell lines compared to noninfected controls (HCT116: 111%; MH3924A: 130%; HaCaT-RT3: 257% increase), but not in HaCaT and HUVEC cells. Furthermore, tumor cells and the oncogene-transformed (ras) cell line HaCaT-RT3 showed a GCV-induced reduction in cell number (HCT116:-71%; MH3924A:-43% and HaCaT-RT3:-31%). No statistically relevant cytotoxic effect was observed in HaCaT (6% decrease) and HUVEC cells (2% decrease). Furthermore, a reduction of H-3-thymidine incorporation into the DNA was seen after treatment with GCV (HCT116: 38%; MH3924A: 33% and HaCaT-RT3: 37% decrease). In a therapy study of HSVtk-expressing tumors with GCV, we achieved total tumor remission
    Type of Publication: Journal article published
    PubMed ID: 14681725
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  • 2
    Keywords: CELLS ; IN-VITRO ; tumor ; TUMOR-CELLS ; AGENTS ; Germany ; IN-VIVO ; VITRO ; VIVO ; imaging ; MARKER ; TRANSPORT ; UP-REGULATION ; MAMMALIAN-CELLS ; IMAGING AGENTS ; FLUORESCENCE ; RE ; TRANSPORTER ; tumor imaging ; TUMOR-CELL ; uptake ; ANALOGS ; in vivo ; intraoperative imaging ; POLYAMINE TRANSPORT ; SERUM-ALBUMIN ; spermidine
    Abstract: Up-regulation of polyamine transporters on the surface of tumor cells and the internalization of biogenic polyamines by active transport processes may be exploited for the accumulation of spermidine derivatives as reporter molecules. We have synthesized and tested fluorophor-labeled spermidine derivatives for the development of a new class of intraoperative tumor imaging agents. In vitro uptake experiments and initial in vivo imaging studies illustrated that fluorophor tagged spermidine derivatives show tumor accumulation. (c) 2006 Elsevier Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16621552
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  • 3
    Keywords: RECEPTOR ; ANGIOGENESIS ; APOPTOSIS ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; IN-VITRO ; proliferation ; tumor ; CELL-PROLIFERATION ; FACTOR RECEPTOR ; Germany ; IN-VIVO ; INHIBITION ; MODEL ; PERFUSION ; VITRO ; imaging ; HEPATOCELLULAR-CARCINOMA ; GENE ; GENES ; METABOLISM ; TUMORS ; LINES ; TRANSDUCTION ; gene transfer ; GENE-TRANSFER ; DNA ; INDUCTION ; CELL-LINES ; signal transduction ; immunohistochemistry ; MALIGNANCIES ; ASSAY ; DESIGN ; VECTOR ; NUMBER ; STRESS ; SIGNAL-TRANSDUCTION ; LINE ; positron emission tomography ; POSITRON-EMISSION-TOMOGRAPHY ; tomography ; OXIDATIVE STRESS ; cell lines ; MALIGNANCY ; OXIDATIVE-STRESS ; TUMOR-GROWTH ; monitoring ; endothelial cells ; cell proliferation ; MIGRATION INHIBITORY FACTOR ; CHIP ; computer-assisted ; functional imaging ; ANGIOGENESIS IN-VIVO ; GLIOBLASTOMA GROWTH ; IRRADIATED SKIN ; SOLUBLE FORM ; SYMPORTER GENE
    Abstract: Purpose: Inhibition of tumor angiogenesis is emerging as a promising target in the treatment of malignancies. Therefore, monitoring of antiangiogenic approaches with functional imaging and histomorphometrical analyses are desirable to evaluate the biological effects caused by this treatment modality. Experimental Design: Using a bicistronic retroviral vector for transfer of the soluble receptor for the vascular endothelial growth factor (sFLT) hepatoma (MH3924A) cell lines with sFLT expression were generated. In human umbilical vein endothelial cells cultured with conditioned medium of sFLT-expressing hepatoma cells, the inhibitory action of secreted sFLT was determined using a Coulter counter and a thymidine incorporation assay. Furthermore, in vivo experiments were done to measure the effects on tumor growth and perfusion. Finally, the tumors were examined by immunohistochemistry (including computer-assisted morphometry) and DNA chip analysis. Results: Stable sFLT-expressing hepatoma cells inhibited endothelial cell proliferation in vitro. In vivo, growth and perfusion, as measured by (H2O)-O-15 positron emission tomography, were reduced in genetically modified tumors. However, the immunohistochemically quantified microvascularization and macrovascularization, as indicated by CD31- and alpha-actin-positive area, revealed no significant changes, whereas the number of apoptotic cells was increased in sFLT-expressing tumors, although not significantly. DNA chip analysis of tumors with gene transfer showed an increase of genes related to apoptosis, signal transduction, and oxidative stress. Conclusion: Our results suggest that sFLT expression inhibits tumor growth and perfusion and enhances expression of apoptosis-related genes in this model. Enhanced expression of genes for signal transduction, stress, and metabolism indicates tumor defense reactions
    Type of Publication: Journal article published
    PubMed ID: 15788658
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  • 4
    Keywords: CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; tumor ; TUMOR-CELLS ; Germany ; human ; IN-VIVO ; INHIBITION ; THERAPY ; VITRO ; VIVO ; imaging ; EXPOSURE ; SITE ; GENE ; GENE-EXPRESSION ; TUMORS ; LINES ; DNA ; RAT ; RATS ; CELL-LINES ; ENTRY ; gene expression ; TRANSCRIPTIONAL ACTIVITY ; ASSAY ; resistance ; VECTOR ; PROMOTER ; NUMBER ; PROSTATE-CANCER ; CELL-LINE ; LINE ; HEPATOMA ; BIODISTRIBUTION ; ESTABLISHMENT ; SODIUM/IODIDE SYMPORTER ; FEASIBILITY ; TISSUE-SPECIFIC EXPRESSION ; SODIUM-IODIDE SYMPORTER ; albumin ; ENHANCER ; TUMOR-GROWTH ; INCREASE ; TRANSFECTION ; TRANSPORTER ; HUMAN SODIUM/IODIDE SYMPORTER ; SIZE ; in vivo ; HUMAN HEPATOCELLULAR-CARCINOMA ; RADIONUCLIDE ; radionuclide gene therapy
    Abstract: We investigated the feasibility of radioiodine therapy targeting hepatoma cells (MH3924A) by tissue-specific expression of the human sodium/iodide symporter (hNIS) gene directed by the murine albumin enhancer and promoter (mAlb). Methods: The cell-specific transcriptional activity of mAlb was examined by a luciferase assay in several transiently transfected cell lines. MH3924A cells were stably transfected with the recombinant retroviral vector, in which hNIS complementary DNA expression was driven by mAlb and coupled to hygromycin resistance gene using an internal ribosomal entry site (IRES). Functional hNIS expression in hepatoma cells was confirmed by an iodide uptake assay. In imaging studies, the tumor-bearing ACl rats were intravenously injected with I-131 and imaged with a gamma-camera. Biodistribution was studied at 30 min and at 1, 3, 6, and 25 h after injection of I-131. Toxic effects of I-131 on hepatoma cells were studied in vitro and in vivo. Results: Stably transfected MH3924A cells concentrated I-125 up to 240-fold higher than the wild-type cells. The iodide uptake in stably transfected cells was inhibited by ouabain and sodium perchlorate but increased by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid. An in vitro clonogenic assay revealed an 86% decrease in colony number in stably transfected cells after exposure to 3.7 MBq/mL of I-131 and only about 8% in hNIS-negative control cells. Furthermore, the in vivo study showed intense tracer accumulation in hNIS-expressing tumors after administration of I-131. At 3 h after intraperitoneal injection, the transfected tumors accumulated I-131 19.2-fold higher than the parental tumors in a biodistribution study. Moreover, administration of a therapeutic dose of I-131 resulted in an inhibition of hNIS-expressing tumor growth, whereas control tumors continued to increase in size. Conclusion: A therapeutic effect of I-131 on hepatoma cells in vitro and in vivo has been demonstrated after tumor-specific iodide uptake induced by mAlb-directed hNIS gene expression. Because a stable transformed cell line has been used in these experiments, the clinical potential of this strategy must be evaluated after in vivo transfection of hepatoma cells
    Type of Publication: Journal article published
    PubMed ID: 16644756
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  • 5
    Keywords: CANCER ; CELLS ; EXPRESSION ; tumor ; TUMOR-CELLS ; carcinoma ; CELL ; Germany ; human ; IN-VIVO ; THERAPY ; VIVO ; GENE ; cell line ; TUMORS ; gene therapy ; LINES ; MICE ; NUCLEAR-MEDICINE ; TIME ; TRANSDUCTION ; RAT ; animals ; CELL-LINES ; treatment ; TRANSPORT ; resistance ; PROSTATE-CANCER ; NUDE-MICE ; CELL-LINE ; LINE ; WILD-TYPE ; CARCINOMA-CELLS ; CARCINOMAS ; GENE-THERAPY ; EXPERIMENTAL I-131 THERAPY ; LITHIUM ; RADIOIODINE THERAPY ; nuclear medicine ; nude mice ; THYROID-CARCINOMA-CELLS ; BICISTRONIC RETROVIRAL VECTOR ; HUMAN SODIUM/IODIDE SYMPORTER ; NA+/I-SYMPORTER ; sodium iodide symporter,gene therapy,lithium,thyroid carcinoma
    Abstract: Transfer of the human sodium iodide symporter (hNIS) has been proposed as a new principle of cancer gene therapy. This study evaluates the iodide kinetics and dosimetry of iodide in hNIS-expressing thyroid carcinoma cells under optimized conditions. Methods: Using a bicistronic retroviral vector for the transfer of the hNIS and the hygromycin resistance gene, hNIS-expressing rat thyroid carcinoma cell lines were generated. Afterward, Na(125)1 uptake and efflux were determined in genetically modified and wild-type cells in the presence or absence of modulators of iodide transport. In addition, the (131)1 distribution in thyroidablated nude mice bearing wild-type and genetically modified thyroid carcinomas was monitored after intraperitoneal administration of (131)1 with and without coadministration of lithium carbonate. Results: hNIS-expressing cell lines accumulated up to 49 times more iodide than did noninfected cells, with a maximal iodide uptake after 30 min of incubation. However, a 90% efflux of the radioactivity occurred 20 min after replacement of the medium. In mice, the hNIS-expressing tumors accumulated up to 23 and 19.5 times more iodide than did the wild-type tumors in lithium-treated and control animals, respectively. However, efflux of the radioactivity was also observed in vivo: After 24 h, hNIS-expressing tumors lost 82.5% and 80.4% of the initial activity. Dosimetric calculations showed that 1,650 MBq of (131)1 per square meter resulted in 5.4 and 5.2 Gy in hNIS-expressing tumors and 0.24 and 0.26 in wild-type tumors. Conclusion: Transduction of the hNIS gene in rat thyroid carcinoma cells induces iodide transport, which is associated with rapid efflux. Application of (131)1 in clinically relevant amounts did not result in therapeutically useful absorbed doses in hNIS-expressing tumors in vivo, even under optimized conditions of thyroid ablation and treatment with lithium carbonate
    Type of Publication: Journal article published
    PubMed ID: 15136633
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  • 6
    Keywords: CANCER ; CELLS ; EXPRESSION ; GROWTH ; tumor ; carcinoma ; CELL ; Germany ; human ; IN-VIVO ; INHIBITION ; THERAPY ; VIVO ; SYSTEM ; TOOL ; HEPATOCELLULAR-CARCINOMA ; GENE ; GENE-EXPRESSION ; EFFICIENCY ; cell line ; TUMORS ; gene therapy ; MICE ; TRANSDUCTION ; gene transfer ; GENE-TRANSFER ; INFECTION ; murine ; treatment ; PARTICLES ; virus ; ELEMENT ; TRANSGENIC MICE ; gene expression ; VECTORS ; VECTOR ; PROMOTER ; ELEMENTS ; REQUIRES ; NUDE-MICE ; CELL-LINE ; LINE ; EFFICIENT ; MELANOMA ; GROWTH-INHIBITION ; Jun ; MALIGNANT-MELANOMA ; malignant melanoma ; GENE-THERAPY ; RECOMBINANT ADENOASSOCIATED VIRUS ; THYMIDINE KINASE GENE ; REGULATORY ELEMENTS ; adeno-associated virus ; ADENOASSOCIATED VIRUS ; nude mice ; HIGH-LEVEL ; TISSUE-SPECIFIC EXPRESSION ; growth inhibition ; CYTOTOXICITY ; F ; ENHANCER ; RECOMBINANT ; GANCICLOVIR ; suicide gene therapy ; HUMAN-MELANOMA ; THERAPIES ; GLIOMA-CELLS ; MELANOMA-CELLS ; ADENOASSOCIATED VIRUS VECTORS ; REPORTER GENE ; NONDIVIDING CELLS ; human melanoma ; herpes simplex virus thymidine kinase ; melanoma inhibitory activity
    Abstract: Suicide gene therapy of malignant melanoma essentially requires efficient gene transfer and highly selective therapeutic gene expression. To achieve this, recombinant adeno-associated virus (rAAV) particles were constructed containing the tissue-specific promoter of the human melanoma inhibitory activity (hMIA) gene combined with four copies of the enhancer element of the murine tyrosinase gene. Three melanoma and one cervix carcinoma cell line were infected with rAAV particles carrying a reporter gene under control of the enhancer/hMIA promoter in order to determine transcriptional activity and specificity of this system. Viral particles containing the enhancer/hMIA promoter mediated reporter gene activity only in melanoma cells, whereas infection with a cytomegalovirus (CMV)-based promoter construct induced unspecific gene expression. Correspondingly, transient transduction with viral particles bearing the HSVtk gene under the control of the enhancer/MIA promoter elements followed by treatment with ganciclovir (GCV) resulted in growth inhibition only in melanoma cells, whereas the CMV promoter-based construct induced unspecific cytotoxicity. In vivo experiments in nude mice demonstrated that tumors originating from human melanoma cells disappeared after stable, but not transient transduction with vectors bearing the HSVtk gene under the control of the enhancer/hMIA promoter in response to GCV application. In face of higher transduction efficiency, these rAAV particles might therefore be a useful tool for suicide gene therapy of malignant melanoma
    Type of Publication: Journal article published
    PubMed ID: 15118759
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  • 7
    Keywords: GROWTH ; IN-VITRO ; tumor ; AGENTS ; Germany ; IN-VIVO ; MODEL ; THERAPY ; DRUG ; MICE ; PATIENT ; ACTIVATION ; INJECTION ; treatment ; MOUSE ; TRIAL ; ASSAY ; NUDE-MICE ; chemotherapy ; MELANOMA ; MALIGNANT-MELANOMA ; PHARMACOKINETICS ; DACARBAZINE ; ANTICANCER DRUGS ; CYTOTOXICITY ; INVITRO ; RECOMBINANT ; RE ; TUMOR-GROWTH ; ANTICANCER PRODRUG ; targeted melanoma therapy ; DRUGS ; ONSET ; in vivo ; anticancer drug ; ANTICANCER-DRUG ; BIOACTIVATION ; experimental chemotherapy ; mouse melanoma model ; N-(2-dialkylaminoethyl)benzamide conjugates
    Abstract: The in-vivo antineoplastic potential of the alkylating N-(2-dialkylaminoethyl)benzamides BZA1 and BZA2, novel melanoma targeted anticancer drugs, was evaluated in a mouse melanoma model with nude mice bearing subcutaneous SkMei28, B16 or WM266-4. The maximal tolerated dose (MTD) for the intraperitoneal application of both agents was found to be 24 mg/kg. Treatment was initiated with an intraperitoneal injection of 8 mg/kg of BZA1 or BZA2 on days 0, 2 and 4 in the case of B16 melanoma on days 0, 1 and 2 after the onset of the experiment, when the mean tumor diameter ranged within 4-6 mm. The experiment was terminated when the mean tumor diameter in the control group had reached a value of 12 mm. Tumor growth delay of these agents was compared with dacarbazine (3 x 250 mg/kg), chlorambucil (3 x 5 mg/kg) and an untreated control group. Significant tumor growth delay was observed under BZA1, BZA2 and dacarbazine treatment compared with the untreated control group in all three evaluated melanomas with insignificant differences among BZA1, BZA2 and dacarbazine. The insignificant effect of chlorambucil and the strong improvement on growth delay achieved with BZA1 and BZA2 demonstrated melanoma targeting characteristics of the N-(2-dialkylaminoethyl)benzamide structure element. Dacarbazine was more effective in the in-vivo antineoplastic assay compared with the in-vitro cytotoxicity studies, probably due to hepatic bioactivation. Similar side effect intensity of BZA2 and dacarbazine was observed, whereas BZA1 was more toxic. BZA2 might represent an alternative antimelanoma drug, especially in patients not responding to dacarbazine. (c) 2006 Lippincott Williams & Wilkins
    Type of Publication: Journal article published
    PubMed ID: 17119449
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  • 8
    Keywords: APOPTOSIS ; CELLS ; IN-VITRO ; tumor ; AGENTS ; CELL ; Germany ; MICROSCOPY ; cell line ; TUMORS ; ACCUMULATION ; LINES ; DNA ; MARKER ; BINDING ; CELL-LINES ; MEMBRANE ; NUMBER ; ALKYLATING-AGENTS ; CELL-LINE ; LINE ; MARKERS ; MELANOMA ; PROBES ; NUCLEUS ; FLUORESCENCE ; cell lines ; AFFINITY ; CYTOTOXICITY ; AGENT ; ONCOLOGY ; RE ; MELANOMA-CELLS ; PH ; TYROSINASE ; FLUORESCENCE MICROSCOPY ; DYES ; USA ; uptake ; DRUGS ; lysosomes ; BENZAMIDE ; MELANOGENESIS ; H+-ATPASE ; MEDICINE ; FLUORESCENT ; correlates ; RETENTION ; alkylating benzamides ; lysosomotropic agents ; lysosomotropic detergent ; LYSOSOMOTROPIC DETERGENTS ; melanoma marker ; ORGANELLES
    Abstract: Melanoma markers based on both N-(2-dialkylaminoethyl)-benzamides and lysosomotropic agents comprise a N-(2-dialkylaminoethyl)aminocarbamoyl pharmacophore, suggesting that benzamides and lysosomotropic probes should show affinity to melanoma and acidic cell organelles. We prepared novel fluorescent N-(2-dialkylaminoethyl)benzamides to prove this presumption. Lysosomotropic probes showed a melanin affinity comparable to benzamides. Lysosomal markers and benzamides; colocalized in acidic organelles. Various nonmelanoma cell lines showed equal benzamide uptake and retention compared with melanoma cells. In nonmelanoma cells the amount of retained benzamides correlates with the number of acidic cell organelles. Benzamides almost completely failed to accumulate in melanoma cells with neutralized acidic organelles but normal melanin content. In melanoma retention of benzamides, acidic cell organelles are the main determinant. N-(2-dialkylaminoethyl)benzamides are lysosomotropic probes with high accumulation in nonmelanoma tumors with many acidic cell organelles. Alkylating benzamides were reported previously to show a melanoma unselective, in general enhanced cytotoxicity. Alkylating benzamides can act as lysosomotropic detergents or as DNA alkylators. The ability of alkylating benzamides to disrupt the membrane of lysosomes and cause liberation of lysosomal-trapped fluorescent dyes was demonstrated by fluorescence microscopy. Whether they act as an alkylating agent or a lysosomotropic detergent in a specific cell line is dependent on the amount of acidic cell organelles. In cell lines with small amounts of acidic cell organelles alkylating benzamides act as alkylating agents, whereas in cell lines with many acidic cell organelles they act as lysosomotropic detergents. In cell lines with high amounts of acidic cell organelles they do not reach the nucleus
    Type of Publication: Journal article published
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