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)

Adenoviral vectors have recently been shown to effectively deliver genes into a variety of tissues. Since these vectors have some advantages over the more extensively investigated retroviruses, we studied the effect of two replication-defective adenovectors bearing human wild type tumor suppressor gene p53 (Adp53) and Escherichia coli beta-galactosidase gene (AdLacZ) on 9L glioma cells. Successful in vitro gene transfer was shown by DNA polymerase chain reaction (PCR), and expression was confirmed by reverse transcriptase RNA PCR and Western blot analyses. Transduction of 9L cells with the Adp53 inhibited cell growth and induced phenotypic changes consistent with cell death at low titers, while AdLacZ caused cytopathic changes only at high titers. Stereotactic injection of AdLacZ (10(7) plaque forming units) into tumor bed stained 25 to 30% of tumor cells at the site of vector delivery. Injection of Adp53 (10(7) plaque forming units), but not AdLacZ (controls), into established 4-day old 9L glioma brain tumors decreased tumor volume by 40% after 14 days. As a step toward gene therapy of brain tumors using replication-defective adenoviruses, these data support the use of tumor suppressor gene transfer for in vivo treatment of whole animal brain tumor models.
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PMID:Adenovirus-mediated p53 gene delivery inhibits 9L glioma growth in rats. 764 77

Identification of patients at risk for developing brain tumors is important for the development of preventative strategies. Because individuals with germline p53 mutations may be at increased risk, we examined DNA from brain tumor-derived cell lines and malignant and normal nervous system tissue for p53 gene mutations using the single strand conformation polymorphism assay and direct sequencing of polymerase chain reaction-amplified DNA. We found mutations in the p53 gene in eight of 22 adult glioma tissue specimens and germline mutations in two of these eight patients. In contrast, mutation of the p53 gene was not detectable in either 16 glial tumors occurring in children, glial tumor tissue from three unrelated glioblastoma multiforme patients with a familial history of cancer, or in benign meningiomas. One constitutional p53 mutation was a G to T transversion at codon 154, and the second was a C to T transition at codon 256. Both patients with germline mutations developed glioblastoma multiforme before the age of 31, although the median age for glioma patients is above 50. These findings suggest that p53 germline mutations may identify a subset of young adults predisposed to the development of high-grade astrocytic tumors.
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PMID:Constitutional p53 mutations associated with brain tumors in young adults. 766 39

A human pilocytic astrocytoma-derived cell line, a grade III astrocytoma-derived cell line, and a glioblastoma-derived cell line were transfected with the human wild-type p53 gene, in order to demonstrate the possible suppressor role of this gene in low grade as well as in high grade human astrocytomas. p53 exhibited a strong growth suppressor effect on the three cell lines studied, irrespective of the grade of malignancy of the tumours from which they originate. Furthermore, the p53 gene elicited important morphological changes in these cell lines. p53-Transfected cells displayed a flat morphology, a large cell body, and a stellate shape with long processes, characteristic of differentiated astrocytes. In addition, the growth inhibitory effect of p53 was found not to be due to induction of apoptosis. These results indicate that p53 plays a tumour suppressor role in low grade and high grade human astrocytomas and raise the possibility of the involvement of p53 in glioma cell differentiation in vitro.
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PMID:Human wild type p53 inhibits cell proliferation and elicits dramatic morphological changes in human glioma cell lines in vitro. 770 71

JC virus causes the human demyelinating disease progressive multifocal leukoencephalopathy by selective infection of glial cells. This cell specificity results from glial-specific expression of viral early genes (large and small T antigens). Analysis of transcriptional regulation by the MH1 JC virus early promoter demonstrates that glial specificity is directed by the basal promoter. Because T antigen regulates the basal region of several viral and cellular promoters, we investigated whether it controls the JC virus basal promoter in a glial-specific manner. A JC virus T antigen expression plasmid generated a 95-kDa protein which exhibited nuclear localization and physical association with p53. T antigen repressed the JC virus and SV40 early promoters 4- to 5-fold in glioma cells. Conversely, T antigen induced 100- to 200-fold activation of the JC virus early promoter in nonglial cells, whereas the SV40 promoter was repressed. Activation required the JC virus TATA box sequence and a pentanucleotide repeat immediately upstream of the TATA box, but was independent of the upstream enhancer region. These data demonstrate that the JC virus basal promoter is responsible for glial-specific gene expression and suggest a mechanism for this regulation.
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PMID:Cell-specific activation of the glial-specific JC virus early promoter by large T antigen. 776 22

Human (U251, U87, U343) and rat glioma cell lines (C6, 9L) were examined by the reverse transcriptase-polymerase chain reaction and subsequent nucleotide sequencing analysis to see whether they express wild type (wt)-p53 or mutated form (mut)-p53 messages. Results showed that U87, U343, and C6 cells expressed wt-p53 messages whereas U251 and 9L cells expressed mut-p53 messages. All these cell lines were transfected with wt-p53 cDNA or the s-myc gene linked to the mouse mammary tumor virus (MMTV) promoter. Of several G418-resistant clones obtained from each transfection, a few expressed the s-Myc or wt-p53 proteins. Independent of mutations in the intrinsic p53 gene, the cellular growth in vitro and tumorigenicity in nude mice of these clones were drastically suppressed, the extent of suppression being correlated with the expression level of the transfected gene. Flow-cytometric analysis demonstrated that both p53 and s-Myc arrested the cell cycle at the G1/S boundary. These data suggest that these genes having negative effects on tumor cell proliferation could be used in gene therapy of gliomas, which are caused by alteration of the p53 gene or by some other genetic change.
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PMID:Negative effects of wild-type p53 and s-Myc on cellular growth and tumorigenicity of glioma cells. Implication of the tumor suppressor genes for gene therapy. 780 77

The Myc family proteins represented by c-Myc are thought to play a crucial role in cellular proliferation, differentiation, transformation, and apoptosis. In this study, we demonstrated the novel role for a Myc family protein in elicitation of immunogenic phenotypes in tumor cells. Injection of rat 9L or C6 glioma cells, together with the s-myc gene linked to the cytomegalovirus promoter, completely prevented formation of both brain tumors and s.c. tumors derived from the parental glioma cells. However, introduction of the s-myc gene had no inhibitory effect on development of B104-derived neuroblastoma. In addition, unlike the s-myc gene, injection of the c-myc or wild type p53 (wt-p53) gene together with glioma cells did not modulate the tumor immunogenicity and resulted in formation of gliomas in the animals. These findings suggest that s-Myc expression may stimulate the presentation of a tumor antigen common to 9L and C6 cells to T lymphocytes and augment the activity of the host immune system, resulting in prevention of glioma formation in vivo. This success in tumor eradication indicates the possibility of application of the s-myc gene for gene therapy of human brain tumors.
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PMID:Modulation of tumor immunogenicity of rat glioma cells by s-Myc expression: eradication of rat gliomas in vivo. 784 17

Although both spatial and temporal heterogeneity confound the description of the genetic events underlying glioma tumorigenesis, it is becoming evident that chromosome 17 loss and p53 inactivating mutations are probably involved early in the pathway of tumorigenesis of some, but not all, astrocytomas. Chromosome 10 loss and epidermal growth factor receptor amplification are seen predominantly in high-grade lesions, although they have not been shown to be independent prognostic indicators. Data is accumulating on the presence of a tumor suppressor gene on chromosome 9p, although the gene remains to be identified. The roles of chromosome 22 and the NF-2 tumor suppressor gene in the tumorigenesis of sporadic and familial meningiomas are discussed here, along with other nonrandom chromosomal alterations that are seen in both astrocytomas and meningiomas.
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PMID:Molecular genetics of astrocytomas and meningiomas. 786 78

We are studying the p53 gene profile in primary glial tumors by seeking alterations in the hybridization pattern of the tumor DNA probed with a p53 gene probe. This report documents a rearranged p53 gene with loss of the normal allele in a low-grade mixed glioma which has not recurred during 4-year follow-up. The tumor had a low 5-bromodeoxyuridine (BrdU)-labeling index and low AgNOR count. The p53 protein was not detected on immunochemical staining. To our knowledge, this is the first report of an altered p53 gene in a low-grade nonrecurrent glial tumor and highlights the presence of further checks and balances on the control of cell proliferation and other malignancy-associated phenotypes, even in an already-established tumor.
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PMID:Rearranged p53 gene with loss of normal allele in a low-grade nonrecurrent glioma. 798 8

Using polymerase chain reaction-assisted single-strand conformation polymorphism (PCR-SSCP) and immunohistochemical analyses, mutations in the p53 tumor suppressor gene were examined in 19 low- and high-grade gliomas. By PCR-SSCP and nucleotide analyses, p53 gene mutation was seen in 7 gliomas. Out of the 7 mutations, 3 were located at the CpG site of the previously proposed hot-spot codons 248 and 273, 2 were at codons 171 and 214 and the other 2 were in intron 5, 1 at the splice acceptor site and the other in the vicinity of the splice donor site. The latter 4 mutations have not, or only rarely, been observed in gliomas or in other tumors. However, their effect on the structural and functional alteration of the p53 protein was suggested by positive intranuclear p53 immunostaining in neoplastic cells in 3 mutations including the 1 at the splice acceptor site. In connection with glioma grading, the p53 gene mutation was shown to have occurred in both low- and high-grade gliomas, often in most of the neoplastic cells, as suggested by lack of distinct normal bands and ladders in SSCP and direct sequencing, respectively. The absence of recurrence and malignant transformation over a considerably long postoperative time in our low-grade glioma cases suggested that the p53 gene mutation might not be sufficient for the progression from low- to high-grade gliomas. The frequency of detection of mutation was 7/19(37%) by PCR-SSCP, 8/19(42%) by immunohistochemistry and 10/19(53%) by both methods. The results of PCR-SSCP and immunohistochemistry were consistent in 14 cases (73.7%), but not in 5 cases(26.3%).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Analysis of p53 gene mutations in low- and high-grade astrocytomas by polymerase chain reaction-assisted single-strand conformation polymorphism and immunohistochemistry. 800 54

Work in the field of molecular neuro-oncology has evolved from a purely descriptive catalogue of regional mutations to the implication of specific genes in the malignant process. Reverse genetic strategies have resulted in the cloning of the neurofibromatosis-1 and neurofibromatosis-2 genes, the molecular physiology of the p53 gene, and work is in progress toward identifying specific genes in each of the other major genomic regions in which genetic events accumulate during malignant progression in human gliomas. Current studies are examining the functional role of genes implicated in glioma malignancy and investigating the mechanisms of their dysregulation in the generation of the malignant phenotype.
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PMID:Recent advances in brain tumor molecular biology. 808 Aug 50


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