Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Benzamide riboside, a recently discovered inhibitor of IMP dehydrogenase (IMPDH) exhibits oncolytic activity. IMPDH is the key enzyme of de novo guanylate biosynthesis and was shown to be linked with proliferation. Therefore, IMPDH is a very good target for antitumor therapy. In order to be active, benzamide riboside has to be converted to BAD, an NAD analogue that binds to the NAD site on IMPDH. Inhibition of the enzyme by benzamide riboside selectively inhibits tumor cell growth and induces apoptosis in various human tumor cell lines. In this manuscript we describe the induction of the CD71 transferrin receptor in human promyelocytic leukemia HL-60 cells following treatment with benzamide riboside. The results indicate a possible involvement of the iron metabolism in the action of this new compound. Benzamide riboside might be clinically used in the treatment of leukemia and solid tumors, alone or as part of combination therapy. Since transferrin receptors are overexpressed in certain cancers, such as glioma and colon cancer, a combination therapy that includes benzamide riboside in transferrin-coupled liposomes will not only target cancer cells but also leads to suicidal action because benzamide riboside will upregulate transferrin receptors on cancer cells thereby make it accessible to dose-intensive chemotherapy. We therefore believe that benzamide riboside itself or derivatives of benzamide riboside might become an important addition for the treatment to diseases that are otherwise fatal.
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PMID:Benzamide riboside, a recent inhibitor of inosine 5'-monophosphate dehydrogenase induces transferrin receptors in cancer cells. 1196 39

The development of methodologies for gene transfer into the central nervous system is crucial for gene therapy of neurological disorders. In this study, different cationic liposome formulations were used to transfer DNA into C6 glioma cells and primary hippocampal and cortical neurons by varying the nature of the helper lipid (DOPE, Chol) or a mixture of DOPE and cholesterol (Chol) associated to DOTAP. In addition, the effect of the lipid/DNA (+/-) charge ratio, the association of the ligand transferrin to the lipoplexes, and the stage of differentiation of the primary cells on the levels of transfection activity, transfection efficiency, and duration of gene expression were evaluated. Mechanistic studies were also performed to investigate the route of delivery of the complexes into neurons. Our results indicate that DOTAP:Chol (1:1 mol ratio) was the best formulation to transfer a reporter gene into C6 glioma cells, primary hippocampal neurons, and primary cortical neurons. The use of transferrin-associated lipoplexes resulted in a significant enhancement of transfection activity, as compared to plain lipoplexes, which can be partially attributed to the promotion of their internalization mediated by transferrin. While for hippocampal neurons the levels of luciferase gene expression are very low, for primary cortical neurons the levels of transgene expression are high and relatively stable, although only 4% of the cells has been transfected. The stage of cell differentiation revealed to be critical to the levels of gene expression. Consistent with previous findings on the mechanisms of cell internalization, the experiments with inhibitors of the endocytotic pathway clearly indicate that transferrin-associated lipoplexes are internalized into primary neurons by endocytosis. Promising results were obtained in terms of the levels and duration of gene expression, particularly in cortical neurons when transfected with the Tf-associated lipoplexes, this finding suggesting the usefulness of these lipid-based carriers to deliver genes within the CNS.
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PMID:Improving lipoplex-mediated gene transfer into C6 glioma cells and primary neurons. 1508 89

KS Biomedix (formerly Avicenna Medica; now a subsidiary of the Xenova group) and Nycomed, together with Japanese licensee Sosei and Chinese licensee PharmaEngine, are developing TransMID, a transferrin-mediated diphtheria toxin delivery system for the potential treatment of adult, recurrent, inoperable, high-grade glioma (as TransMID-107R). It is also under investigation for other forms of brain cancer, including early brain cancer (as TransMID-107N), metastatic brain cancer (as TransMID-107M) and pediatric brain cancer (as TransMID-107P). TransMID is currently undergoing phase III clinical trials.
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PMID:Technology evaluation: TransMID, KS Biomedix/Nycomed/Sosei/PharmaEngine. 1624 84

Targeted toxins represent a new class of agents with high specificity for tumor cells. Toxins in current clinical use for the treatment of brain tumors are mostly recombinant polypeptides consisting of a tumor-selective ligand coupled to a peptide toxin of bacterial origin. Targeted toxins are highly potent - one single molecule of toxin is enough to cause cell death. Toxins are able to kill tumor cells independent of any malignancy-associated genetic alterations and/or mutations. The blood-brain barrier has been a major obstacle for using targeted toxins for treatment of malignant glioma. Convection-enhanced delivery (CED), a method for delivery of large molecules to brain tissue via continuous interstitial microinfusion, has permitted direct administration of toxins to brain tumors or to surrounding brain tissue infiltrated by tumor cells. Four targeted toxins advanced to at least phase II clinical trials and are being used for treatment of adult or pediatric patients with recurrent or progressive malignant glioma. These are IL4-P. aeruginosa exotoxin (IL4-PE, NBI-3001), tumor growth factor (TGF)alpha-P. aeruginosa exotoxin (TP-38), IL13-P. aeruginosa exotoxin (IL13-PE38), and transferrin-C. diphtheriae toxin (TransMID(trade mark), Tf-CRM107). All of these toxins have shown an acceptable profile of toxicity and safety in phase I and II clinical studies and have demonstrated some evidence for tumor response. Current phase I and II clinical protocols are exploring several parameters, such as placement of catheters for CED either intratumorally or in the brain tissue surrounding a tumor, surgical resection of tumor before or after toxin infusion, and single vs. repeated infusion. Two large randomized and controlled phase III multicenter studies using IL13-PE38 or TransMID(trade mark) are currently enrolling patients. This review summarizes the study protocols and key findings of all previously completed and currently ongoing clinical studies with targeted toxins for malignant glioma. It offers in addition an outlook into future areas of development of targeted toxins, such as improved delivery modes and non-invasive in vivo imaging of intracerebral and intratumoral distribution of toxin in patients.
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PMID:Clinical studies with targeted toxins in malignant glioma. 1847 63

Targeting viral entry is one of the major goals in the development of vectors for gene therapy. Ideally, the coupling of each new targeting motif would not require changes in vector structure. To achieve this, we developed novel metabolically biotinylated baculoviral vectors by displaying a small biotin acceptor peptide (BAP) fused either to different sites in the baculovirus glycoprotein gp64 or to the transmembrane anchor of vesicular stomatitis virus G protein. Baculoviral particles were biotinylated during vector production by coexpression of Escherichia coli biotin ligase (BirA). The insertion of BAP at amino acid position 283 of gp64 resulted in the most efficient biotin display. Unlike vectors with lower biotin display, these vectors also showed improved transduction when retargeted to transferrin, epidermal growth factor, and CD46 receptors overexpressed on rat glioma and human ovarian carcinoma cells. Biotinylated baculoviral vectors could also be concentrated by one-step magnetic particle-based capture to reach titers up to 10(10) plaque-forming units/ml. These results demonstrate the utility of metabolically biotinylated baculovirus for vector targeting and viral purification applications.
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PMID:Targeting and purification of metabolically biotinylated baculovirus. 1847 88

Despite recent advances in cancer therapy, many malignant tumors still lack effective treatment and the prognosis is very poor. Paclitaxel is a potential anticancer drug, but its use is limited by the facts that paclitaxel is a P-gp substrate and its aqueous solubility is poor. In this study, three-step tumor targeting of paclitaxel using biotinylated PLA-PEG nanoparticles and avidin-biotin technology was evaluated in vitro as a way of enhancing delivery of paclitaxel. Paclitaxel was incorporated both in biotinylated (BP) and non-biotinylated (LP) PEG-PLA nanoparticles by the interfacial deposition method. Small (mean size approximately 110 nm), spherical and slightly negatively charged (-10 mV) BP and LP nanoparticles achieving over 90% paclitaxel incorporation were obtained. The successful biotinylation of nanoparticles was confirmed in a novel streptavidin assay. BP nanoparticles were targeted in vitro to brain tumor (glioma) cells (BT4C) by three-step avidin-biotin technology using transferrin as the targeting ligand. The three-step targeting procedure increased the anti-tumoral activity of paclitaxel when compared to the commercial paclitaxel formulation Taxol and non-targeted BP and LP nanoparticles. These results indicate that the efficacy of paclitaxel against tumor cells can be increased by this three-step targeting method.
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PMID:Three-step tumor targeting of paclitaxel using biotinylated PLA-PEG nanoparticles and avidin-biotin technology: Formulation development and in vitro anticancer activity. 1855 75

We earlier showed that leucine-rich glioma inactivated 3 (LGI3) colocalizes with amyloid beta peptide (Abeta) taken up by astrocytes both in vitro and in vivo, and that LGI3 accumulated with endocytosis-associated proteins in aged monkey brains. In this study, we confirmed that LGI3 localizes to the endocytic pathway and found that its accumulation is caused by endocytic perturbation. Most notably, RNA interference experiments demonstrated that the downregulation of LGI3 clearly inhibited Abeta uptake by cultured rat astrocytes, moreover, transferrin uptake by both astrocytes and neuronal cells. Together with our earlier findings, our results suggest that LGI3 is involved in Abeta uptake by astrocytes and even endocytosis itself.
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PMID:Leucine-rich glioma inactivated 3 is involved in amyloid beta peptide uptake by astrocytes and endocytosis itself. 1862 60

Transferrin (Tf), an iron-transporting serum glycoprotein, which binds to receptors expressed at the surface of most proliferating cells with particularly high expression on erythroblasts and cancer cells, was chosen as the ligand to develop BCNU-loaded biodegradable poly(D,L-lactic acid) nanoparticles (NPs) containing a ligand, which specifically binds to glioma cells, and their anti-tumor ability was evaluated using a C6 glioma model. In vitro drug release behavior demonstrated that BCNU-loaded PLA NPs show certain sustained release characteristics. NPs with low molecular weight PLA showed a higher burst effect and a significantly faster drug release from PLA samples. The biodistribution of Tf-coated nanoparticles investigated by 99Tc-labeled SPECT showed that the surface-containing transferrin PLA nanoparticles were concentrated in the brain and no radioactive foci could be found outside the brain. Inhibition of tumor growth in the C6 tumor-bearing animal model showed that BCNU-loaded PLA NPs had stronger cytotoxicity and prolonged the average survival time of rats. Especially when treated at an early stage with a higher dosage of NPs, the average survival time of rats was prolonged 88.37%. Furthermore, one rat maintained normal behavior continuously for an observation period of up to 60 days.
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PMID:Growth inhibition against intracranial C6 glioma cells by stereotactic delivery of BCNU by controlled release from poly(D,L-lactic acid) nanoparticles. 1916 43

The development of multidrug resistance (due to drug efflux by P-glycoproteins) is a major drawback with the use of paclitaxel (PTX) in the treatment of cancer. The rationale behind this study is to prepare PTX nanoparticles (NPs) for the reversal of multidrug resistance based on the fact that PTX loaded into NPs is not recognized by P-glycoproteins and hence is not effluxed out of the cell. Also, the intracellular penetration of the NPs could be enhanced by anchoring transferrin (Tf) on the PTX-PLGA-NPs. PTX-loaded PLGA NPs (PTX-PLGA-NPs), Pluronic((R))P85-coated PLGA NPs (P85-PTX-PLGA-NPs), and Tf-anchored PLGA NPs (Tf-PTX-PLGA-NPs) were prepared and evaluted for cytotoxicity and intracellular uptake using C6 rat glioma cell line. A significant increase in cytotoxicity was observed in the order of Tf-PTX-PLGA-NPs > P85-PTX-PLGA-NPs > PTX-PLGA-NPs in comparison to drug solution. In vivo biodistribution on male Sprague-Dawley rats bearing C6 glioma (subcutaneous) showed higher tumor PTX concentrations in animals administered with PTX-NPs compared to drug solution.
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PMID:Paclitaxel-loaded PLGA nanoparticles surface modified with transferrin and Pluronic((R))P85, an in vitro cell line and in vivo biodistribution studies on rat model. 1953 Sep 13

Chemotherapy for brain glioma has been of limited value due to the inability of transport of drug across the blood-brain barrier (BBB) and poor penetration of drug into the tumor. For overcoming these hurdles, the dual-targeting daunorubicin liposomes were developed by conjugating with p-aminophenyl-alpha-D-manno-pyranoside (MAN) and transferrin (TF) for transporting drug across the BBB and then targeting brain glioma. The dual-targeting effects were evaluated on the BBB model in vitro, C6 glioma cells in vitro, avascular C6 glioma tumor spheroids in vitro, and C6 glioma-bearing rats in vivo, respectively. After applying dual-targeting daunorubicin liposomes, the transport ratio across the BBB model was significantly increased up to 24.9%. The most significant uptake by C6 glioma was evidenced by flow cytometry and confocal microscope. The C6 glioma spheroid volume ratio was significantly lowered to 54.7%. The inhibitory rate to C6 glioma cells after crossing the BBB was significantly enhanced up to 64.0%. The median survival time of tumor bearing rats after administering dual-targeting daunorubicin liposomes (22 days) was significantly longer than that after giving free daunorubicin (17 days, P=0.001) or other controls. In conclusion, the dual-targeting daunorubicin liposomes are able to improve the therapeutic efficacy of brain glioma in vitro and in animals.
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PMID:Dual-targeting daunorubicin liposomes improve the therapeutic efficacy of brain glioma in animals. 1979 48


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