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)

The existence of specific rabies virus (RV) glycoprotein (G) binding sites on the surfaces of neuroblastoma cells is demonstrated. Spodoptera frugiperda (Sf21) cells expressing G of the RV strain CVS (Gcvs-Sf21 cells) bind specifically to neuroblastoma cells of different species but not to any other cell type (fibroblast, myoblast, epithelial, or glioma). Attachment to mouse neuroblastoma NG108-15 cells is abolished by previous treatment of Gcvs-Sf2 cells with anti-G antibody. Substitutions for lysine at position 330 and for arginine at position 333 in RV G greatly reduce interaction between Gcvs-Sf21 cells and NG108-15 cells. These data are consistent with in vivo results: an avirulent RV mutant bearing the same double mutation is not able to infect sensory neurons or motoneurons (P. Coulon, J.-P. Ternaux, A. Flamand, and C. Tuffereau, J. Virol. 72:273-278, 1998) after intramuscular inoculation into a mouse. Furthermore, infection of NG108-15 cells by RV but not by vesicular stomatitis virus leads to a reduction of the number of binding sites at the neuronal-cell surface. Our data strongly suggest that these specific attachment sites on neuroblastoma cells represent a neuronal receptor(s) used by RV to infect certain types of neurons in vivo.
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PMID:Neuronal cell surface molecules mediate specific binding to rabies virus glycoprotein expressed by a recombinant baculovirus on the surfaces of lepidopteran cells. 944 3

The vast majority of brain cancers (gliomas) express a receptor (R) for interleukin 13 (IL13). In order to achieve specific targeting of the IL13R in gliomas, we have mutagenized human (h) IL13. The mutation was made to alter IL13 interaction with the shared functional IL13/4 normal tissue receptor, but not with the glioma-associated receptor. We have thus produced hIL13.E13K (glutamic acid at position 13 changed to lysine) and fused it to derivatives of Pseudomonas exotoxin A. The hIL13.E13K-based cytotoxins are less active on normal cells and thus less toxic, and are better antitumor agents compared with the cytotoxins containing nonmutagenized hIL13.
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PMID:Novel anti-brain tumor cytotoxins specific for cancer cells. 959 93

The aim of this project was to develop procedures necessary to study mechanisms of receptor mediated gene transfer by means of integrated microscopy. Plasmid DNA was incorporated into a transfection complex consisting of poly(L)lysine and transferrin to which the nuclear localization signal was conjugated. This complex was presented to cultured glioma cells. Preparation of the transfected DNA for imaging was pursued by two methods. In the first method tetramethylrhodamine, nanogold, and ferritin were linked through streptavidin to the biotinylated plasmid DNA. Trafficking of the fluorescent derivatives was studied in living cells with fluorescence microscopy. Then, selected cells were rapidly cryo-immobilized. Ultra-structural distribution of the transfected DNA was imaged with energy filtering transmission electron microscopy. In the second method, the unmodified transfected DNA was detected in cryo-immobilized cells by in situ polymerase chain reaction and in situ hybridization. For laser scanning fluorescence microscopy probes were labeled with tetramethylrhodamine. For ultrastructural analysis by electron spectroscopic imaging, probes containing incorporated digoxigenin were labeled with anti-digoxigenin boronated antibodies. Based upon the developed procedures, it has been demonstrated that the presence of the nuclear localization signal in the transfection complex resulted in rapid nuclear import of the transfected DNA.
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PMID:Preparation of plasmid DNA in transfection complexes for fluorescence and electron spectroscopic imaging. 960 25

Recombinant adenovirus (Adv)-mediated gene transduction is a powerful technology for cancer gene therapy. In this article, we report the generation of a fiber-mutant Adv vector, using the Adv genomic DNA-terminal protein complex (DNA-TPC) cotransfection method. First, a fiber-mutant construct in a plasmid carrying the right-side two-thirds of the human adenovirus type 5 (Ad5) genome (pTR) was cotransfected with Ad5 DNA-TPC, yielding the recombinant Adv with the desired fiber mutation. The DNA-TPC from the mutant Adv was then utilized to produce a second-step recombinant Adv with an expression cassette in the place of E1. By this procedure, we generated a fiber mutant, F/K20, that has a linker and a stretch of 20 lysine residues added at the C terminus of the fiber. By using Adv carrying a reporter lacZ gene (AxCAZ2) with either F/K20 or wild-type fiber (F/wt), we examined the transduction efficiency of F/K20-Adv. No significant difference in the transduction efficiency between F/K20 and F/wt-Adv was observed for a human fibroblast line, WI-38, or various tumor cell lines, including melanoma, prostate, esophageal, and pancreatic cancer lines. In clear contrast, F/K20-Adv showed a remarkably enhanced efficiency in genetic transduction of human glioma cells. In all four human glioma lines tested, the multiplicities of infection (MOIs) for transduction of 50% of the population (ED50) were decreased with F/K20-Adv compared with F/wt-Adv: 7-fold for T98G, 14-fold for U251, 9-fold for U373, and 42-fold for U87 cells. Therefore, we attempted to apply F/K20-Adv for gene therapy of malignant glioma. Glioma cells infected with F/K20-Adv carrying genes for interleukin 2 or interleukin 12 produced a high level of each cytokine at a much lower MOI than did cells infected with F/wt-Adv. Infection with F/K20-Adv carrying the wild-type p53 tumor suppressor gene resulted in an enhanced level of p53 protein expression and an increased incidence of F/K20-Adv in transduction efficiency for malignant glioma, providing promising tools for gene therapy.
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PMID:Generation of fiber-mutant recombinant adenoviruses for gene therapy of malignant glioma. 985 17

An E1B 55-kDa gene-defective adenovirus (Adv), ONYX-015, has been reported to be a highly useful replication-competent Adv that shows cytopathic effect for cancers with an abnormal p53 gene, without damaging normal tissues. In this study, we combined this Adv (Adv-E1AdB) with a fiber mutation, F/K20, which has a stretch of 20 lysine residues added at the COOH-terminus of the fiber and shows high transduction efficiency to gliomas. In U-373 MG glioma cells, the transduction efficiency of Adv-F/ K20 for lacZ was nine times higher than that of the Adv with wild-type fiber (Adv-F/wt) for lacZ. At a multiplicity of infection of 30, the replication efficiency of Adv-E1AdB-F/K20 was 11 times higher than that of Adv-E1AdB with wt fiber (Adv-E1AdB-F/wt). The ED50 value of AdvE1AdB-F/K20 to U-373 MG cells, which is a measure of the in vitro cytopathic effect, was 32 times greater than that of Adv-E1AdB-F/wt. injection of Adv-E1AdB-F/K20 suppressed the in vivo growth of tumors. The antitumoral effect of Adv-E1AdB-F/K20 was remarkably stronger than that of Adv-E1AdB-F/wt. A greater quantity of replicated virus protein (hexon) by infection with Adv-E1AdB-F/K20 was demonstrated in vitro and in vivo, compared with that of Adv-E1AdB-F/wt. In conclusion, gene therapy using Adv-E1AdB-F/K20, which drastically augmented the antitumoral effect of Adv-E1AdB, will be a promising therapeutic approach for gliomas.
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PMID:Highly augmented cytopathic effect of a fiber-mutant E1B-defective adenovirus for gene therapy of gliomas. 1041 3

The role of non-caspase protease activation in drug-induced cell death of glioma cells was examined. Neither calpain inhibitors I or II, phenylmethylsulfonyl fluoride (PMSF), Nalpha -p-tosyl-L-lysine chloromethyl ketone (TLCK), N-tosyl-L-phenylalanine chloromethyl ketone (TPCK), E64, leupeptin nor pepstatin inhibit the cytotoxicity of vincristine, cisplatin, doxorubicin, cytarabine, camptothecin, BCNU or VM26 in two malignant glioma cell lines, T98G and LN-229. However, DNA fragmentation induced by VM26 is inhibited by calpain inhibitor I, PMSF, TLCK and TPCK, and that induced by camptothecin by calpain inhibitors I and II and TPCK. Moreover, protease inhibitors fail to abrogate CD95 ligand-induced apoptosis even though DNA fragmentation is attenuated by calpain inhibitor II and TPCK. Thus, non-caspase protease activation is not required for drug-induced apoptosis of glioma cells. Protease inhibitor-mediated inhibition of DNA fragmentation operates downstream of the commitment point for cell death.
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PMID:Inhibition of drug-induced DNA fragmentation, but not cell death, of glioma cells by non-caspase protease inhibitors. 1042 75

Angiostatin is an endogenous inhibitor of tumor neovascularization that inhibits the proliferation of endothelial cells. Production of sufficient quantities of biologically active angiostatin by the enzymatic cleavage of plasminogen has proven difficult in that it has delayed clinical testing. We have cloned, expressed, and purified a recombinant human angiostatin derivative (K1-3) using a mammalian expression system. Through the addition of a secretory signal and polyhistidine sequence tag, K1-3 can be purified from post-culture medium by simple column chromatography. Purified K1-3 protein is apparently folded in an active conformation, as evidenced by its ability to bind to lysine-Sepharose. In vitro, recombinant K1-3 significantly suppressed endothelial cell proliferation in a dose-dependent manner with an IC50 of 50 nM. Using an animal model of intracranial brain tumors in immune-competent rats, systemic administration of purified recombinant K1-3 resulted in up to 85% suppression of tumor growth (P = 0.011). Growth suppression was accompanied by a 32% decrease (P = 0.01) in tumor neovascularization. This study demonstrates a simple method to produce a biologically active recombinant angiostatin derivative. The ability to suppress intracerebral tumor growth after systemic administration suggests that K1-3 is likely to have therapeutic value in the treatment of malignant glial tumors.
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PMID:Simplified production of a recombinant human angiostatin derivative that suppresses intracerebral glial tumor growth. 1058 88

P11 cells, derived from the transplantahle rat pituitary tumor 7315a, have been used previously ias a model system to study the regulation of serotonin2A (5-HT2A) receptor expression. As our laboratory has been interested in characterizing the interactions between the 5-HT2A receptor and inducible nitric oxide synthase (iNOS), we have analyzed the Pl I cell line for iNOS expression. Treatment of P ll cells with interferon-gamma and lipopolysaccharide resulted in a 23-fold increase in nitrite production and induced expression of iNOS protein. The increase in nitrite levels was attenuated by the non-selective nitric oxide synthase (NOS) inhibitor N i-nitro-L-arginine methyl ester, hut not the neuronal NOS inhibitor 7-nitroindazole. Typically, Pl 11 cells have been grown in either charcoal-stripped or dialyzed serum-containing medium. We have observed that Pl 1 cells grown under these culture conditions express basal iNOS activity, as evidenced by a 5-fold increase in nitrite accumulation over a 48-hr period, compared with that in cells grown in non-modified serum, which was inhibited by the selective iNOS inhibitor L.N6-(1-iminoethyl)-lysine. Conditioned medium from Pll cells was ahle to stimulate nitrite accumulation in C6 glioma cells, suggesting that the Pl I cells may produce a pro-inflammatory-like factor. As pro-inflammatory cytokines have been shown to modify hormone secretion from the anterior pituitary, the P11 cell line may be a useful in vitro model by which to characterize the function of cells from this organ. In addition, our data suggest that alteration of the microenvironment of the anterior pituitary may result in iNOS expression, possibly altering the function of the hypothalamic-pituitary-adrenal axis.
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PMID:Inducible nitric oxide synthase in P11 cells: expression in the presence of interferon-gamma, lipopolysaccharide, and modified serum. 1066 Jan 17

Gliomas include several histologically distinct types of tumors whose molecular profiles suggest different etiologies. Because the ERCC1 protein is essential for nucleotide excision repair and influences genomic instability, polymorphisms in ERCC1 may play a role in human tumors. We determined the presence of the A versus C polymorphism at nucleotide 8092 of ERCC1 using a single-strand conformational polymorphism assay and DNA sequencing in adults with glioma and controls from a population-based study. Among 318 alleles from 159 controls, 27% (86) were A and 73% were C. Prevalences of the CC genotype were 51% (81 of 159), 48% (30 of 62), 63% (20 of 32), and 82% (23 of 28) for controls and subjects with glioblastoma multiforme, astrocytoma, and oligoastrocytoma, respectively (Fisher's exact P = 0.009). The age-adjusted odds ratio for genotype CC in all cases versus controls was 1.4 (95% confidence interval, 0.9-2.3), whereas that for subjects with oligoastrocytoma versus controls was 4.6 (95% confidence interval, 1.6-13.2). The median age at diagnosis was 46 years for glioma patients with the CC genotype compared with 54 years for patients with the AA or AC genotype (P = 0.04). This is the first study to report a significant association of a polymorphism in ERCC1 with the risk of brain tumors. This A/C polymorphism, which may affect mRNA stability for ERCC1, also results in an amino acid substitution of lysine to glutamine in a recently described nucleolar protein (ASE-1) and T-cell receptor complex subunit CD3epsilon-associated signal transducer (CAST). This finding, if confirmed in other series, may provide a foundation on which to study novel mechanisms of carcinogenesis in subsets of glioma.
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PMID:Association of an ERCC1 polymorphism with adult-onset glioma. 1095 3

Suicide gene therapy utilizing the herpes simplex thymidine kinase (HSVtk) / ganciclovir (GCV) system has been performed to kill cancer cells. However, the low transduction efficiency of HSVtk gene into cancer cells critically limits its efficacy in cancer treatment in clinical situations. To improve delivery of the HSVtk gene into cancer cells, we transduced U-87MG and U-373MG glioma cells with adenovirus (Adv) vectors with a fiber mutant, F / K20, which has a stretch of 20 lysine residues added at the C-terminus of the fiber, for the HSVtk gene (Adv-TK-F / K20), and compared the cytopathic effect of Adv-TK-F / K20 with that of the Adv for HSVtk with wild-type fiber (Adv-TK). The cytopathic effect of Adv-TK-F / K20 in U-87MG and U-373MG cells was approximately 140 and 40 times, respectively, stronger than that of Adv-TK. At the same multiplicity of infection (MOI) in each cell line, Adv-TK-F / K20 induced a higher degree of apoptosis (U-87MG, 35%; U-373MG, 77%) than Adv-TK (U-87MG, 0.11%; U-373MG, 27%) in U-87MG (MOI 0.03) and U-373MG cells (MOI 0.1). Cleavage of poly(ADP-ribose)polymerase (PARP) was more marked in the cells that were infected with Adv-TK-F / K20 than in cells that were infected with Adv-TK. These results indicate that gene therapy utilizing Adv-TK-F / K20 may be a promising therapeutic modality for the treatment of gliomas.
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PMID:Transduction of a fiber-mutant adenovirus for the HSVtk gene highly augments the cytopathic effect towards gliomas. 1105 Apr 74


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