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)

Oxygen deprivation is an important biological feature of tumor growth. We previously showed that in glioma, anoxia increases expression of IL-8, a chemokine and angiogenic factor. Here, we analysed for the first time the biochemical mechanisms inducing the IL-8 gene upon anoxia in glioma cells, and showed that they differ from those inducing the VEGF gene. Both genes are induced in biologically and genetically heterogenous glioblastoma cell lines (LN-229, LN-Z308, U87MG, T98G), whereas, in gliosarcoma cells (D247MG), only the VEGF gene is induced. The kinetics of IL-8 and VEGF mRNA inductions differ in these cells and reoxygenation experiments showed that the induction is due to the anoxic stress per se. Furthermore, in LN-229 and LN-Z308 cell lines actinomycin D, DRB and nuclear run-on experiments showed that anoxia stimulates increased transcription of both genes. Electromobility shift assays show increased protein binding to the AP-1 site on the IL-8 promoter following anoxia treatment. Finally, in situ hybridization on glioblastoma sections shows that the in vivo expression patterns of IL-8 and VEGF genes overlap, but are not identical. Since intratumoral augmentation of IL-8 and VEGF secretion, following microenvironmental decreases in oxygen pressure, may promote angiogenesis, further definition of these pathways is essential to appropriately target them for antitumoral therapy.
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PMID:Regulation of interleukin-8 expression by reduced oxygen pressure in human glioblastoma. 1005 Aug 81

Macrophage colony-stimulating factor (M-CSF) is a potent stimulator of the effector cells such as monocytes and macrophages. To evaluate the effect of M-CSF on malignant gliomas, we transfected the rat gliosarcoma cell line (9L) with human M-CSF expression vector (pCEF-MCSF) by a liposome method. Transfectants were selected using G418-containing medium. As a control, 9L cells transfected with pRc/CMV and selected by G418 were used. The effects of M-CSF gene transfection on tumor cell proliferation in vitro and in vivo were examined. All growth rate did not change in vitro. While the control 9L cells formed progressively enlarging masses, 9L cells transfected with the M-CSF gene did not develop into tumors after the injection into rats. On the other hand, in rats receiving anti-asialo GM1 antibody, 9L cells transfected with M-CSF gene developed into tumors, though at a slower rate than control 9L cells. Histologic examination after transplantation of 9L cells transfected with M-CSF gene disclosed intense infiltration of macrophages in the tumor. Thus M-CSF gene transfection into glioma cells stimulates an antitumor effect.
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PMID:Transformation of rat glioma cells with the M-CSF gene inhibits tumorigenesis in vivo. 1006 91

Malignant gliomas frequently show genetic aberrations of genes coding for cell cycle regulatory proteins involved in the control of G1/S phase transition. These include mutation and/or deletion of the retinoblastoma (RB1) gene, homozygous deletion of the CDKN2A and CDKN2B genes, as well as amplification and overexpression of the CDK4 and CDK6 genes. The D-type cyclins (cyclin D1, D2, and D3) promote cell cycle progression from G1 to S phase by binding to and activating the cyclin dependent kinases Cdk4 and Cdk6. Here, we have investigated a series of 110 primary malignant gliomas and 8 glioma cell lines for amplification and expression of the D-type cyclin genes CCND1 (11q13), CCND2 (12p13), and CCND3 (6p21). We found the CCND1 gene amplified and overexpressed in one anaplastic astrocytoma of our tumor series. Two glioblastomas and one anaplastic astrocytoma showed CCND2 gene amplification, but lacked significant overexpression of CCND2 transcripts. Amplification and overexpression of the CCND3 gene was detected in the glioblastoma cell line CCF-STTG1, as well as in one primary glioblastoma and in the sarcomatous component of one gliosarcoma. Our data thus suggest that amplification and increased expression of CCND1 and CCND3 contribute to the loss of cell cycle control in a small fraction of human malignant gliomas.
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PMID:Amplification and expression of cyclin D genes (CCND1, CCND2 and CCND3) in human malignant gliomas. 1041 84

Glioma invasiveness is a complex process involving recognition and attachment of tumor cells to particular extracellular matrix (ECM) molecules prior to migrating into proteolytically modified matrix and inducing angiogenesis. CD44 is a group of transmembrane adhesion molecules found on a wide variety of cells including gliomas that has been suggested as the principal mediator of migration/invasion. The aim of the present study was to demonstrate whether antibody specific for the standard form of CD44 (CD44s, 85-90 kDa) might prevent invasion, thus blocking growth of the 9L gliosarcoma in vivo. High expression of CD44s on the surface of 9L cells and brain tumors was demonstrated by immunochemistry. Fluorescence-activated cell sorting (FACS) demonstrated binding saturation of anti-CD44s monoclonal antibody (mAb) to the receptor at 1 microg/5 x 10(5) cells. Blocking of CD44s in vitro resulted in a dose-dependent progressive, up to 95%+/-2.5% detachment of 9L cells from ECM-coated culture surfaces. Blocking of CD44s in vivo resulted in significantly reduced 9L brain tumors (2.5%+/-0.4%)--measured as the quotient: tumor surface (mm2)/brain surface (mm2) x 100--as compared to untreated (16.1%+/-2.2%) or sham-treated rats (16%+/-3.7% to 16.1%+/-3%). We conclude that CD44s-targeted treatment with specific mAb may be an effective means for preventing glioma progression.
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PMID:CD44s-targeted treatment with monoclonal antibody blocks intracerebral invasion and growth of 9L gliosarcoma. 1043 7

Glial cell line-derived neurotrophic factor (GDNF), a sequence-related factor of the transforming growth factor-beta family, has been identified as a potent neurotrophic factor for a variety of neuronal cell populations. At present, it is still unknown whether human gliomas in vivo are also capable of producing GDNF. We studied the expression of GDNF in 14 human glioblastomas, 1 gliosarcoma and 5 astrocytomas. Using an enzyme-linked immunosorbent assay, the amount of GDNF was quantified in human gliomas and compared to GDNF-expression in C6 glioma cells, mouse fibroblasts and normal human and rat brain. Mean concentration of GDNF in gliomas was 937 +/- 140 pg GDNF/g tissue (n = 20). C6 cells revealed the highest expression levels of 2,837 +/- 813 pg/g, whereas mouse 3T3 fibroblasts showed no detectable GDNF protein. Mean GDNF tissue levels in normal human and rat brain were significantly lower. Using reverse transcriptase-polymerase chain reaction, GDNF mRNA was detected in human gliomas and in rat C6 cells. Immunohistochemistry revealed strong GDNF- and GDNF receptor-alpha 1-expressing tumor cells in human glioma tissue. These results show that glial tumors, even in the most dedifferentiated form of glioblastoma, express GDNF at concentrations up to five times higher compared to normal human brain. This overexpression of GDNF may be of biological relevance for proliferation of glial tumors in humans.
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PMID:Glial cell line-derived neurotrophic factor (GDNF) and its receptor (GFR-alpha 1) are strongly expressed in human gliomas. 1067 19

The present study investigates nitrosourea-induced rat (Rattus norvegicus) glioma cell lines for the functional status of the p16/Cdkn2a/Ink4a gene, which encodes the p16 cdk4 inhibitor and the alternative reading frame protein, p19ARF. We detected homozygous deletions of the p16/Cdkn2a/Ink4a gene locus in 4 of 5 glioma cell lines (C6, F98, RG2, and RGL.3), but not in the 9L gliosarcoma cell line or in a rat primary fibroblast cell line. RT-PCR demonstrated expression of the p16 and p19ARF mRNAs only in 9L cells and in rat fibroblasts. Comparative genomic in situ hybridization showed that the copy number of rat chromosome RNO5 was not altered in any of the glioma cell lines investigated, indicating that the deletions result from a discrete loss in the region of the p16/Cdkn2a/Ink4a locus. This is the first report of p16/Cdkn2a/Ink4a deletions present in nitrosourea-induced rat glioma cell lines. Since this genetic alteration is also commonly observed in human malignant glial tumors, our results validate the use of chemically induced rat glioma cell lines as an experimental model in the development of gene therapy strategies.
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PMID:The p16/Cdkn2a/Ink4a gene is frequently deleted in nitrosourea-induced rat glial tumors. 1073 82

The inhibitory effects of (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and its arabinosyl derivative (E)-5-(2-bromovinyl)-1-beta-D-arabinofuranosyluracil (BVaraU) on the growth of both MDA-MB-435 human breast carcinoma and 9L rat gliosarcoma cells expressing the thymidine kinase (tk)-encoding gene of the Varicella zoster virus (VZV) or the Herpes simplex virus (HSV) were evaluated. In vitro, BVDU and BVaraU effectively killed both cell types expressing VZVtk, with 50% inhibitory concentration values ranging from 0.06 to 0.4 microM, whereas ganciclovir (GCV) lacked activity. On HSVtk+ cells, BVDU had high cytotoxic activity, with 50% inhibitory concentration values that were similar to those of GCV, whereas BVaraU was inactive. In vivo, BVDU applied intraperitoneally caused a 50% tumor growth inhibition in nude mice inoculated subcutaneously with VZVtk+ as well as HSVtk+ mammary tumor cells. In mice and at variance with the in vitro results, BVaraU had very little activity against the VZVtk+ mammary cells; GCV had the highest activity on the HSVtk+ cells, resulting in a 50% eradication of the tumors. With the 9L rat gliosarcoma model, the VZVtk/BVDU system completely failed to inhibit the development of VZVtk+ glioma tumors induced subcutaneously in syngeneic rats, although BVDU had a similar 45-minute half-life in both rats and mice. Factors other than degradation of the prodrug and related to the mode of action of these analogs are possibly involved in the observed discrepancies between the in vitro and in vivo results.
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PMID:Comparative in vitro and in vivo cytotoxic activity of (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and its arabinosyl derivative, (E)-5-(2-bromovinyl)-1-beta-D-arabinofuranosyluracil (BVaraU), against tumor cells expressing either the Varicella zoster or the Herpes simplex virus thymidine kinase. 1077 Jun 29

Brain-enriched hyaluronan binding (BEHAB)/brevican is a brain-specific extracellular matrix protein containing a cleavage site between Glu(395)-Ser(396), which bears remarkable homology to the "aggrecanase" site in the cartilage proteoglycan aggrecan. Expression of BEHAB/brevican is dramatically increased in human gliomas, notoriously invasive tumors. Recently, we showed that the rat 9L gliosarcoma cell line, which does not express BEHAB/brevican and forms non-invasive tumors when grown as intracranial grafts, can form invasive tumors when transfected with a 5' cDNA fragment of BEHAB/brevican, but not when transfected with the full-length cDNA. In marked contrast, the highly invasive CNS-1 glioma cell line expresses and cleaves BEHAB/brevican protein when grown as an intracranial graft. These results suggest that both synthesis and cleavage of BEHAB/brevican protein may play a role in the invasiveness of gliomas. We report here, using an antibody developed to the neoepitope created by BEHAB/brevican cleavage at the Glu(395)-Ser(396) site, that the CNS-1 cells are able to cleave the protein in vitro. We characterized the CNS-1-derived cleavage activity by assaying its ability to cleave BEHAB/brevican proteoglycan, and determined that the enzyme is a constitutively expressed, secreted activity. Using a variety of protease inhibitors, reverse transcriptase-polymerase chain reaction, and specific antibodies, we determined that this activity is likely to be a member of the ADAMTS family of metalloproteinases, specifically ADAMTS4. These results suggest a novel function for ADAMTS family members in BEHAB/brevican cleavage and glioma and indicate that inhibition of ADAMTS in glioma may provide a novel therapeutic strategy.
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PMID:Brain-enriched hyaluronan binding (BEHAB)/brevican cleavage in a glioma cell line is mediated by a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family member. 1080 87

A large animal tumor model for anaplastic glioma has been recently developed using immunotolerant allogeneic Beagle dogs and an established canine glioma cell line, J3T. This model offers advantages in terms of tumor morphology and similarity to human anaplastic glioma. The present study was aimed at evaluating the biological characteristics of the J3T canine glioma cell line as related to experimental gene therapy studies. Furthermore, development and morphology of canine brain tumors in a xenogeneic immunodeficient SCID mouse model was investigated. It was demonstrated that cultured J3T cells can be efficiently infected by adenovirus (AV), herpes-simplex type I (HSV), or retrovirus (RV) vectors, as well as by non-virus vectors such as cationic liposome/DNA complexes. Thus, in terms of infectability and transfectability, J3T cells seem to be closer to human glioma than the 9L rodent gliosarcoma. Cytotoxicity of selection antibiotics such as G418, puromycin, and hygromycin on J3T cells essentially resemble cytotoxicity seen with other established glioma lines, for example, 9L, U87, or U343. RV-mediated HSV-TK/GCV gene therapy demonstrated comparable LD50 for TK-expressing and control (non-expressing) J3T and 9L cells treated with Ganciclovir. Further, it was proven that J3T cells are tumorigenic and may grow heterotopically and orthotopically in a xenogeneic immunodeficient host, the SCID mouse, although morphology and growth pattern of these xenogeneic tumors differ from the demonstrated invasive phenotype in the Beagle dog.
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PMID:Characterization of a canine glioma cell line as related to established experimental brain tumor models. 1090 Dec 32

Glioblastoma multiforme (GBM) is the most common primary human brain tumor. About 7000 new cases are diagnosed yearly in the USA and GBM is almost invariably fatal within a few years after it is diagnosed. Despite current neurosurgical and radiotherapeutic tumor cytoreduction methods, in most cases occult foci of tumor cells infiltrate surrounding brain tissues and cause recurrent disease. Therefore the combination of neurosurgical and radiotherapeutic debulking methods with therapies to inhibit occult GBM cells should improve prognosis. In this study we have combined boron neutron-capture therapy (BNCT), a novel binary radiotherapeutic treatment modality that selectively irradiates tumor tissue and largely spares normal brain tissue, with immunoprophylaxis, a form of active immunization initiated soon after BNCT treatment, to treat advanced, clinically relevantly-sized brain tumors in rats. Using a malignant rat glioma model of high immunogenicity, the 9L gliosarcoma, we have shown that about half of the rats that would have died after receiving BNCT debulking alone, survived after receiving BNCT plus immunoprophylaxis. Further, most of the surviving rats display immunological-based resistance to recurrent 9LGS growth six months or more after treatment. To our knowledge this study represents the first time BNCT and immunoprophylaxis have been combined to treat advanced brain tumors in rats.
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PMID:The combination of boron neutron-capture therapy and immunoprophylaxis for advanced intracerebral gliosarcomas in rats. 1090 54


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