Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have studied the repair of X-ray-induced, potentially lethal damage (PLD) in 9 human tumour lines derived from tumours of varying radiocurability. Cells derived from 3 tumours considered non-radiocurable (1 osteosarcoma, 2 melanoma) repaired significantly more X-ray PLD than cells from 3 tumours considered radiocurable (2 breast, 1 neuroblastoma). The remaining tumour lines were intermediate in their ability for repair, and included cells from another osteosarcoma, a hypernephroma and a glioblastoma. We conclude that the repair of X-ray PLD may be an important cellular determinant of clinical radiocurability.
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PMID:Cellular repair factors influencing radiocurability of human malignant tumours. 705 52

There are three types of interferons (IFN), alpha, beta and gamma. IFN-alpha is produced in the leukocytes infected with virus, while IFN-beta is from fibroblasts infected with virus. IFN-gamma is induced by the stimulation of sensitized lymphocytes with antigen or non-sensitized lymphocytes with mitogens. It is believed that IFN-alpha and beta originated from the same ancestral gene, whereas IFN-gamma did not. IFN has not only an antiviral activity, but also various kinds of biological activities including cell growth inhibition, immunosuppressive effects, enhancement of macrophage, natural killer (NK) cell, killer (K) cell and neutrophil functions, and cell differentiation-inducing activity. IFN also shows the antitumor activity resulting from the integration of the above-mentioned biological activities. IFN is also deeply involved in the pathogenesis of various diseases, e.g., collagen diseases such as SLE and rheumatoid arthritis, insulin-dependent diabetes mellitus, fulminant hepatitis, severe pancreatitis, nephritis, multiple sclerosis, allergic diseases, and atherosclerosis. At present, IFN is clinically used in therapy against virus infections such as hepatitis B and C, and for malignancies such as renal cell carcinoma, multiple myeloma, malignant melanoma, glioblastoma, skin cancers, malignant lymphoma and chronic myelogenous leukemia.
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PMID:[Interferon-alpha, beta, gamma]. 799 28

The in vitro stimulation of T lymphocytes is frequently used as a technique to expand specific cells present at low precursor frequency in vivo. However, cells analysed after such procedures may no longer reflect those originally present in vivo because of the variable efficiency of outgrowth of different T cell subpopulations. To systematically assess this and to complement functional assays, we have analysed the TCR repertoire using a new high resolution RT-PCR method to determine TCR beta chain CDR3 transcript length. In the ex vivo analysis of tumor infiltrating lymphocytes (TIL) of renal cell carcinoma and glioblastoma patients, we observed and quantified oligoclonally expanded populations of T cells that were very susceptible to repertoire modification upon subsequent in vitro culture with autologous tumor cells. This in vitro repertoire skewing occurred preferentially with TIL rather than peripheral blood lymphocytes and we noted that tumor cells rather than normal cells of the same tissue type were the most potent inducers of the effect. It was striking that this selection was sometimes negative: certain prominent T cell populations that were highly represented in vivo disappeared after in vitro re-stimulation. This suggests that the presentation of tumor associated antigens during culture may eliminate rather than enrich for in vivo primed T cells. It is clear that in vitro functional tests cannot adequately describe all T cells with tumor specificity. Approaches that allow the assessment of potentially antigen-reactive T cell populations ex vivo are thus an important advance in the global appraisal of anti-tumor T cell immune responses.
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PMID:TCR analysis reveals significant repertoire selection during in vitro lymphocyte culture. 926 4

The structure of IL-13 receptor (IL-13R) is currently under investigation. Recently, two different human IL-13R chains, termed here IL-13R alpha and -alpha' have been cloned. We have examined various cancer and normal cell lines for the presence of mRNA for IL-13R alpha and alpha, as well as IL-4R p140 (termed beta chain) and IL-2R gamma c chains. In renal cell carcinoma, glioblastoma and ovarian carcinoma (IGROV-1) cell lines, both IL-13R alpha and alpha chains were expressed (type I IL-13R). In epidermoid, colon, ovarian adenocarcinoma (PA-1) and normal mouse fibroblast (COS7) cell lines, only IL-13R alpha' was expressed (type II IL-13R). In hematopoietic TF-1 and EBV-immortalized normal B cell lines only IL-13R alpha' but not alpha chain was expressed along with gamma c (type III or type IV IL-13R). IL-13R alpha' chain was faintly detected in human T cells. All cells expressed the IL-4Rp140 beta chain. These data provide a direct support for our model of IL-13R which consists of three different forms composed of different subunits.
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PMID:Structure of IL-13 receptor: analysis of subunit composition in cancer and immune cells. 929 58

Expression of vascular endothelial growth factor (VEGF), an angiogenic factor and endothelial cell-specific mitogen, is induced by hypoxia in various cell lines as well as in solid tumors. In this study, we report that cell density has a profound effect on the expression of VEGF in human glioblastoma cells (U87) and human fibrosarcoma cells (HT1080), an effect that is independent of hypoxia. Northern blot analysis revealed that VEGF mRNA levels were four- to eightfold higher in cells seeded at high density compared to cells seeded at low density. This upregulation of VEGF message in response to seeding at high density was not seen with other mRNAs such as those for TGF-beta1 or GAPDH. Conditioned medium switch experiments between sparse and dense cells suggested that soluble factor(s) may not account for the observed changes in VEGF expression. Incubation with genistein, a protein tyrosine kinase inhibitor, for 3 h following seeding resulted in the reduction of the VEGF mRNA levels in highly confluent cultures but not in sparse cultures. To identify protein tyrosine kinases involved in the upregulation of the steady-state levels of VEGF mRNA in highly dense cultures, we analyzed the phosphorylation state of the c-src tyrosine kinase, in high versus low confluency cultures of U87 and HT1080 cells. Interestingly, an increased phosphorylation at Tyr416 of c-src was noted in high compared to low confluency, suggesting the activation of c-src in highly confluent cultures. Because extracellular signal-regulated kinases (ERKs) such as MAP kinase have been shown to be activated by extracellular stimuli and act downstream of c-src, we examined their possible involvement in this process. We found that the tyrosine phosphorylation level of MAP kinase is higher in dense compared to sparse cultures and, moreover, 6-thioguanine (6-TG), a potent inhibitor of ERKs, reduced VEGF mRNA levels in high but not low confluency. Furthermore, reintroduction of wild-type, but not mutant, von Hippel-Lindau (VHL) gene product in 786-O cells (a renal carcinoma cell line) specifically abrogated the induction of VEGF mRNA due to high cell density. Taken together, these data suggest that VEGF gene expression is regulated by cell density, and the protooncogene c-src and the tumor-suppressor VHL are modulators of this regulation.
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PMID:High cell density induces vascular endothelial growth factor expression via protein tyrosine phosphorylation. 957 97

Vascular endothelial growth factor (VEGF) is a hypoxia inducible angiogenic and vascular permeability factor. Although VEGF expression in glioblastoma is induced by hypoxia, its expression in renal cell carcinoma and hemangioblastoma is thought to be related to mutation of the von Hippel-Lindau (VHL) gene. It is not certain whether other lesions in VHL syndrome are associated with an elevated VEGF level. We report a VHL syndrome patient with multiple hemangioblastomas and bilateral epididymal clear cell papillary cystadenomas. In situ hybridization revealed high levels of VEGF mRNA in the clear cells of the epididymal tumor and the stromal cells of the hemangioblastoma. This lends support to the notion that upregulation of VEGF is caused by loss of the wild-type VHL protein. We postulate that the elevated VEGF levels may account for the cyst formation and vascularized stroma present in these VHL-associated tumors.
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PMID:Expression of vascular endothelial growth factor in von Hippel-Lindau syndrome-associated papillary cystadenoma of the epididymis. 982 15

Although not structurally related, the pleiotropic cytokines interleukin-7 (IL-7) and interleukin-15 (IL-15) share a variety of biological functions including stimulation and maintenance of cellular immune responses. Cytokines, such as IL-7 or IL-15, elaborated by cells in situ, e.g. cancer cells, may be involved in shaping the quality of anti-tumor directed immune responses. We have analysed the constitutive and IFN-gamma-inducible expression of IL-15 or IL-7 mRNA, protein expression, and protein secretion in human tumor cell lines of distinct origin. IL-15 mRNA expression was detected in renal cell carcinoma (RCC), small cell lung carcinoma (SCLC), glioblastoma, neuroblastoma, mesothelioma cells and in EBV-transformed B-lymphocytes. IL-7-specific transcripts could be detected in colorectal cancer and in renal cell cancer cell lines. Immunohistochemical analysis demonstrated cytosolic IL-15 protein expression in renal cell cancer cells without apparent IL-15 protein secretion in vitro. Time kinetic analyses revealed that IFN-gamma mediated increase of IL-15 mRNA expression was transcriptionally regulated and dependent on de novo protein synthesis. However, enhanced IL-15 mRNA expression did not lead to effective protein secretion. In contrast, IL-7 mRNA expression in renal cell cancer or in colorectal cancer was associated with effective protein secretion which could be augmented by IFNgamma-treatment. These data suggest that both IL-7 and IL-15 mRNA are expressed in renal cell cancer, but exclusively IL-7 may be elaborated by tumor cells in situ. IL-15 regulation appears to be tightly controlled both at the transciptional and post-transcriptional level. Appropriate stimuli leading to effective IL-15 secretion from tumor cells may aid in modulating cellular immune responses directed against cancer.
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PMID:Constitutive and IFN-gamma regulated expression of IL-7 and IL-15 in human renal cell cancer. 986 5

Sodium-L-ascorbate, L-ascorbic acid, D-isoascorbic acid, sodium 5,6-benzylidene-L-ascorbate and sodium-6-beta-O-galactosyl-L-ascorbate, which produce ascorbyl radicals during the oxidative degradation, also induced cytotoxicity against cultured human renal carcinoma (TC-1) and glioblastoma multiform tumor (T98G) cell lines. On the other hand, L-ascorbic acid 2-phosphate magnesium and L-ascorbic acid 2-sulfate dipotassium salt, which do not produce the ascorbyl radical, were inactive. This suggests the possible role of the ascorbyl radical for cell death induction. T98G cells were more resistant to ascorbate analogs than TC-1 and HL-60 cells, possibly due to higher intracellular glutathione concentrations. Ascorbate treatment induced rapid elevation of both intracellular concentration of cAMP and Ca2+ in HL-60 cells, but not in TC-1 and T98G cells. However, the elevation of cAMP by theophyline and N,2-dibutyryl adenosine 3,5 cyclic monophosphate (dibutyryl cAMP) resulted in a decrease in the viable cell number. This suggests the possible role of cAMP for ascorbate-induced cell death.
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PMID:Induction of cell death by ascorbic acid derivatives in human renal carcinoma and glioblastoma cell lines. 1065 1

We have demonstrated that primary interleukin 13 (IL-13) binding protein IL-13 receptor (IL-13R) alpha chain plays an important role in IL-13 binding and internalization in the IL-13R system. Although IL-13R alpha chain is expressed on many cancer cell lines, some cancer types do not express or express low levels of this receptor chain. Consequently, these cells show no or low sensitivity to the cytotoxic effect of a recombinant chimeric protein composed of IL-13 and a mutated form of a Pseudomonas exotoxin, IL13-PE38QQR. Here we demonstrate that pancreatic cancer, renal cell carcinoma, head and neck cancer, and glioblastoma cell lines that were genetically altered to express high levels of IL-13R alpha chain increase their binding affinity for IL-13, and increase their sensitivity to IL13-PE38QQR by at least 6-fold to 1000-fold compared with mock-transfected control cells. This observation was made by protein synthesis inhibition assay and confirmed by clonogenic assay. Our studies provide a proof of principle for a novel strategy for cancer therapy that combines gene transfer and targeted cytotoxin therapy.
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PMID:Sensitization of cancer cells to interleukin 13-pseudomonas exotoxin-induced cell death by gene transfer of interleukin 13 receptor alpha chain. 1098 56

NeoPharm, under license from the NIH and the FDA, is developing a chimeric human IL-13 fused in frame to a genetically engineered truncated Pseudomonas exotoxin (PE38QQR) molecule, for its potential as an antitumor agent [266296], [281418], [290480]. NeoPharm filed an IND in 1999 for renal cell carcinoma (RCC) and glioma [319690], [325001]; an additional IND was filed in March 2000 for the treatment of glioblastoma. In December 2000, NeoPharm initiated phase I/II trials of IL-13-PE38QQR involving patients with refractory glioblastoma multiforme. This trial was being conducted by the New Approaches to Brain Tumor Therapy, a research consortium sponsored by the NCI. At that time, the first patient with brain cancer had completed treatment with IL-13-PE38QQR [393197]. In October 1999, NeoPharm initiated phase I trials of hIL-13-PE38QQR for the treatment of patients with RCC [343878]. In February 2000, Dirks & Co estimated the potential US market for hIL-13-PE38QQR to be $5.8 billion [414515].
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PMID:hIL-13-PE38QQR. NeoPharm. 1171 20


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