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)

The development and neoplastic progression of human astrocytic tumors appears to result through an accumulation of genetic alterations occurring in a relatively defined order. One such alteration is amplification of the epidermal growth factor receptor (EGFR) gene. This episomal amplification occurs in 40-50% of glioblastomas, which also normally express endogenous receptors. Moreover, a significant fraction of amplified genes are rearranged to specifically eliminate a DNA fragment containing exons 2-7 of the gene, resulting in an in-frame deletion of 801 bp of the coding sequence of the extracellular domain. Here we used retroviral transfer of such a mutant receptor (de 2-7 EGFR) into glioblastoma cells expressing normal endogenous receptors to test whether the mutant receptor was able to augment their growth and malignancy. Western blotting analysis showed that these cells expressed endogenous EGFR of 170 kDa as well as the exogenous de 2-7 EGFR of 140-155 kDa. Although holo-EGFRs were phosphorylated on tyrosine residues only after exposure of the cells to ligand, de 2-7 EGFRs were constitutively phosphorylated. In tissue culture neither addition of EGF nor expression of the mutant EGFR affected the rate of cell growth. However, when cells expressing mutant EGFR were implanted into nude mice subcutaneously or intracerebrally, tumorigenic capacity was greatly enhanced. These results suggest that a tumor-specific alteration of the EGFR plays a significant role in tumor progression perhaps by influencing interactions of tumor cells with their microenvironment in ways not easily assayed in vitro.
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PMID:A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity. 805 51

To characterize some of the genetic events underlying the development of glioblastoma multiforme, the authors analyzed 65 astrocytic tumors (seven pilocytic astrocytomas, eight astrocytomas, 16 anaplastic astrocytomas, and 34 glioblastomas multiforme) for loss of heterozygosity for chromosome 17p, loss of heterozygosity for chromosomes 10p and 10q, amplification of the epidermal growth factor receptor (EGFR) gene, and amplification of the oncogenes N-myc, c-myc, and N-ras using Southern blot analysis. Alterations of the p53 gene (positive immunostaining for p53 protein in tumors with or without p53 gene mutations) in these 65 tumors were analyzed previously. None of the 65 tumors showed amplification or rearrangement of N-myc, c-myc, or N-ras oncogenes. The molecular analysis presented here demonstrates distinct variants of astrocytic tumors, with at least three genetic pathways leading to glioblastoma multiforme. One pathway was characterized by 43 astrocytomas with alterations in p53. Glioblastomas with p53 alterations may represent tumors that progress from lower-grade astrocytomas. This variant was more likely to show loss of chromosome 17p than tumors without p53 alterations (p < 0.04). Seventy-five percent of tumors with loss of one 17p allele demonstrated mutations in the p53 gene. Loss of chromosome 10 was associated with progression from anaplastic astrocytoma (13%) to glioblastoma (38%) (p < 0.04). Amplification of the EGFR gene was a rare (7%) but late event in tumor progression (p < 0.03). A second pathway was characterized by six astrocytomas without p53 alterations and may represent clinically de novo high-grade tumors. These tumors were more likely to show amplification of the EGFR gene (83%) than tumors with p53 alterations. Sixty percent of tumors with EGFR amplification also showed loss of chromosome 10; loss of chromosome 17p was infrequent in this variant. One or more alternative pathways were characterized by 16 astrocytomas without p53 alterations and with none of the genetic changes analyzed in this study. Glioblastomas are a heterogeneous group of tumors that may arise via multiple genetic pathways.
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PMID:Pathways leading to glioblastoma multiforme: a molecular analysis of genetic alterations in 65 astrocytic tumors. 805 51

Mutations of the p53 gene are found in various human cancers. The frequency of its mutation is reported to increase during tumor progression in most tumors. In human gliomas, mutations of the p53 gene are found in about one-third of the malignant forms and in few of the benign ones, indicating their possible involvement in tumor progression. On the other hand, we have recently shown that basic fibroblast growth factor (basic FGF) plays a crucial role in tumor progression as an autocrine growth factor in tissues of human gliomas. Therefore, we hypothesized that p53 might regulate the promoter activity of the basic FGF gene, which has several GC boxes and no typical TATA box. In this study, cotransfection assays using human glioblastoma and hepatocellular carcinoma cells and establishment of stable cell lines expressing mutant-type p53 were performed. The basic FGF gene promoter was demonstrated to be regulated by p53 at the transcriptional level and its basal core promoter was found to be responsive to p53. Expression of endogenous basic FGF was also demonstrated to be activated by mutant type p53. Wild-type p53 repressed gene expression of the basic FGF and its mutant activated it in vitro, implying one of the possible pathways in tumor progression.
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PMID:Transcriptional regulation of basic fibroblast growth factor gene by p53 in human glioblastoma and hepatocellular carcinoma cells. 809 Jul 61

We analysed 31 non-glioblastoma astrocytomas for alterations in p53 protein expression and for mutations in the p53 gene. Immunohistochemistry detected p53 protein accumulation in 71% (five of seven) of juvenile pilocytic astrocytomas (WHO grade I), 63% (five of eight) of astrocytomas (WHO grade II), and 63% (10 of 16) of anaplastic astrocytomas (WHO grade III). The single strand conformation polymorphism (SSCP) assay of exons 2-11 of the p53 gene and direct DNA sequencing identified p53 mutations in 14% (one of seven) of grade I, 25% (two of eight) of grade II, and 19% (three of 16) of grade III astrocytomas. This is the first report of a p53 mutation in grade I juvenile pilocytic astrocytomas. Immunohistochemistry and SSCP analyses gave concordant results in 55% (17 of the 31) of the tumors. A total of 14 tumors, 60-80% within each grade, showed p53 protein accumulation in the absence of detectable mutations of the p53 gene. No mdm-2 gene amplification was found in these tumors. The similar frequency of p53 alterations in tumors of grades I-III suggests that the p53 gene plays a significant role early in the formation of astrocytomas rather than late in tumor progression to higher grade. The data suggest that mechanisms other than p53 gene inactivation by mutation or mdm-2 complex formation result in the accumulation of P53 protein in > 70% of non-glioblastoma astrocytomas.
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PMID:High frequency of p53 protein accumulation without p53 gene mutation in human juvenile pilocytic, low grade and anaplastic astrocytomas. 810 40

Although intracranial gliomas carry a poor long-term prognosis, retreatment at the time of tumor progression may prolong survival and maintain or improve the quality of life. Thirty-three patients who underwent retreatment with surgery, radiotherapy, and chemotherapy were reviewed retrospectively. Median survival after initiation of retreatment was 8 months for glioblastoma, 13 months for anaplastic astrocytoma, 22 months for astrocytoma, and 47 months for oligodendroglioma/mixed glioma. Survival was significantly better for younger patients and for those with better functional status. One third of patients were neurologically improved by surgery. Surgical morbidity was minimal (2.1%); there was no surgical mortality. Chemotherapy and radiotherapy produced expected adverse reactions. Retreatment of intracranial gliomas carries acceptable risk and is beneficial in selected patients. Decisions regarding retreatment must be carefully individualized with consideration of the quality of life and the wishes of the patient and family.
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PMID:Retreatment of intracranial gliomas. 811 86

Twenty-two patients, aged 16 to 67, who had malignant gliomas after surgical resection were treated with carmustine and cisplatin intravenous infusion before, during, and after radiotherapy. All patients had subtotal or total resection, or biopsy as the initial procedure. Twenty-one patients who had at least 2 cycles of chemotherapy and finished the whole course of radiotherapy were considered to be evaluable for responses. Among them, 5 had glioblastoma multiforme, 16 had anaplastic astrocytoma. The median time to tumor progression was 35 weeks (range 12-130 weeks) and median survival time was 66 weeks (range 10-156 weeks). Early progression occurred more frequently in patients with biopsy only and subtotal resection, and in patients with glioblastoma than in those with anaplastic astrocytoma. This combined modality treatment program was associated with reversible hematologic toxicity which was severe in 2 patients, and with ototoxicity in 1 patient, nephrotoxicity in 2 patients. Combination of carmustine and cisplatin with cranial irradiation for malignant gliomas is moderately toxic and appears to offer no obvious survival advantage compared with radiation therapy plus BCNU alone.
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PMID:Combination chemotherapy with carmustine and cisplatin before, during, and after radiotherapy for adult malignant gliomas. 859 71

Proteinases and their inhibitors may play a role in the development and progression of many cancers. Several studies suggested that lysosomal proteinases cathepsin B, L, and D may be involved in the malignant progression of some human neoplastic diseases. In this study, we determined the levels of cathepsin H in human glioma progression and the significance of cathepsin H in glioma cell invasion. Levels of cathepsin H antigen were found to be significantly higher in glioblastomas and anaplastic astrocytoma when compared with normal brain tissue and low-grade gliomas. Western blotting confirmed the presence of authentic cathepsin H with a doublet at 27 and 25 kDa in normal brain tissue and tumor samples. However, the intensity of the band increased significantly in glioblastoma samples. Cathepsin H antibody inhibited the invasion of glioblastoma cell lines through Matrigel invasion assay. These data suggest that the tumor-specific increase in antigen may be a useful independent marker of tumor progression in central nervous system neoplasms.
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PMID:Expression and the role of cathepsin H in human glioma progression and invasion. 864 Jul 38

In a Phase II trial, 63 evaluable patients with recurrent glioma received i.v. infusions of carboplatin every 3 weeks beginning at a dose of 400 mg/m2. The dose was increased by 50 mg/m2 at each subsequent infusion until the maximum tolerated dose reached, as defined by a platelet count < 25,000/mm3 or an absolute neutrophil count (ANC) < 500/mm3. Treatment was then resumed at the previous dose level and continued until tumor progression occurred. There were 43 men and 20 women studied (mean age, 41 years; range, 6 months to 70.6 years). The combined response and stabilization rate was 29% for 31 patients with glioblastoma and 71.9% for 32 patients with other tumors; median time to tumor progression was 8.2 and 20.3 weeks and median survival was 25.9 and 58.3 weeks, respectively. Twenty patients had level 4 platelet toxicity and nine had level 4 ANC toxicity. Most tumors progressed before the maximum tolerated dose was reached. These results were not better than those from a previous trial of carboplatin at an initial dose of 350 mg/m2, which was escalated by 25 mg/ m2 after every two infusions. Therefore, an optimal dosing schedule was not achieved in this trial.
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PMID:Intravenous carboplatin for recurrent gliomas. A dose-escalating phase II trial. 893 82

The deleted in colorectal cancer (DCC) gene, a candidate tumor suppressor gene on chromosome 18q21, encodes a neural cell adhesion molecule family protein that is most highly expressed in the nervous system. To address the hypothesis that DCC may play a role in glioma development and/or progression, we examined DCC expression by immunohistochemistry in 57 resected human astrocytic tumors. Overall, low-grade astrocytomas were predominantly DCC positive (15 of 16, or 94%), whereas high-grade tumors significantly less often expressed the DCC protein (27 of 41, or 66%; P = 0.03). We were able to directly assess the relationship between DCC expression and tumor progression in 15 patients who initially presented with a low-grade astrocytoma and subsequently recurred with a glioblastoma. Within this panel of paired lesions from the same patient, 14 of 15 (93%) low-grade tumors expressed the DCC protein, whereas only 7 of 15 (47%) corresponding glioblastomas were DCC positive. We also observed that secondary glioblastomas resulting from malignant progression of low-grade astrocytomas were more often DCC negative (8 of 15, or 53%) compared with primary or de novo glioblastomas (6 of 26, or 23%; P = 0.05). These findings implicate DCC inactivation in glioma progression and also demonstrate that DCC expression is preferentially, but not exclusively, lost in the genetic pathway to secondary glioblastoma multiforme.
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PMID:Loss of DCC expression and glioma progression. 901 60

The Radiation Therapy Oncology Group enrolled 30 patients with recurrent malignant astrocytomas onto a phase II study (RTOG 91-13). Patients were treated with all-trans-retinoic acid at a starting dose of 120 mg/m2 per day orally continuously until disease progression. Fourteen patients had glioblastoma, 14 had anaplastic astrocytoma, and 2 had other histologies; 53% were under 50 years of age. All patients had failed radiation therapy and/or at least one chemotherapy regimen. All patients had a Karnofsky performance status score of at least 70, but only 37% had a KPS of 90-100. Forty percent had a neurologic function status of grade 1 (able to work). A minimum of 4 weeks of all-trans-retinoic acid defined adequate treatment. Twenty-five patients received adequate therapy. Most common toxicities were dry skin, cheilitis, anemia, and headache; 3 patients had grade 3 headache requiring suspension of all-trans-retinoic acid. No grade 3 hematologic toxicity was observed. Of 25 adequately treated patients, 3 showed objective regression of tumor on magnetic resonance imaging and computed tomography scans, 3 patients remained stable, and 19 patients had disease progression. The median time to tumor progression was 3.8 months and the median survival time was 5.7 months. This study suggests that this dose of single agent all-trans-retinoic acid has modest clinical activity against recurrent malignant gliomas with tolerable side effects. A response rate of 12% and a stabilization rate of 12% are lower than expected. Future studies with higher dosage or in combination with biological response modifiers or chemotherapy may be warranted.
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PMID:All-trans-retinoic acid: a phase II Radiation Therapy Oncology Group study (RTOG 91-13) in patients with recurrent malignant astrocytoma. 921 68


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