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 investigated the effects of somatostatin analogues and a synthetic bombesin/gastrin-releasing peptide (GRP) antagonist on the growth of the human malignant glioma cell lines U-87MG and U-373MG transplanted to nude mice or cultured in vitro. Nude mice bearing s.c. implanted U-87MG or U-373MG tumors were treated for 4 and 6 weeks, respectively, with various somatostatin analogues or bombesin/GRP antagonist RC-3095. Somatostatin analogues RC-160, RC-160-II, and RC-101-I, given s.c. in doses of 100 micrograms/animal/day, inhibited the growth of U-87MG xenografts as shown by more than 60% reduction in tumor volumes and 45% reduction in tumor weights compared with the control group. Bombesin/GRP antagonist RC-3095, given s.c. at a dose of 20 micrograms/animal twice daily, had the greatest inhibitory effect and decreased tumor volumes and weights by approximately 79% and 72%, respectively. The growth of U-373MG xenografts was also significantly inhibited by treatment with analogue RC-160 or antagonist RC-3095. The mean survival time of nude mice, inoculated orthotopically with U-87MG cells into the brain, was significantly prolonged by 4.9 days by treatment with antagonist RC-3095. Serum gastrin levels in animals bearing U-87MG tumors, treated with antagonist RC-3095 or somatostatin analogues, were decreased compared with controls. All three somatostatin analogues also reduced serum growth hormone levels. Receptor analyses demonstrated high-affinity binding sites for bombesin, somatostatin, and epidermal growth factor on membranes of U-87MG and U-373MG tumors. The concentration of binding sites for epidermal growth factor on both tumors was significantly decreased after in vivo treatment with antagonist RC-3095 or the somatostatin analogues. In studies in vitro, RC-3095, added to the culture medium, significantly inhibited the proliferation of U-87MG and U-373MG cells in the presence of GRP(14-27), as measured by cell number, but only a moderate suppression of growth of both cell lines was observed with somatostatin analogue RC-160. These results demonstrate that bombesin/GRP antagonist RC-3095 and somatostatin analogues such as RC-160 can inhibit the growth of human glioblastoma cell lines U-87MG and U-373MG in vitro as well as in vivo. Our work suggests the merit of further investigations of these analogues for the possible development of new approaches for treatments of patients with malignant gliomas.
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PMID:Somatostatin analogues and bombesin/gastrin-releasing peptide antagonist RC-3095 inhibit the growth of human glioblastomas in vitro and in vivo. 795 20

Epidermal growth factor receptor (EGFR) is amplified or overexpressed in many malignant gliomas and other primary brain tumors but is low or undetectable in normal brain. In the present study, this differential expression has been exploited for targeted brain tumor therapy using a TGF-alpha-Pseudomonas exotoxin recombinant toxin, TGF-alpha-PE38. In vitro experiments demonstrate that the cytotoxicity of this fusion protein is primarily determined by tumor EGFR expression and that TGF-alpha-PE38 cytotoxicity is abolished by pretreatment with excess epidermal growth factor. Treatment with i.p. TGF-alpha-PE38 in nude mice bearing glioblastoma or medulloblastoma s.c. xenografts produced tumor regression and growth delay. For intracranial xenograft implants treated with i.p. TGF-alpha-PE38, significant increases in median survival were noted only for tumors with the highest EGFR expression. However, intracranial tumors treated with a single intratumoral injection of TGF-alpha-PE38 showed increased survival in all xenografts tested. These results indicate that TGF-alpha-PE38 is active against primary human brain tumors ranging from moderate to high EGFR expression. For intracranial tumors, however, the higher survival rates produced by intracranial injection of TGF-alpha-PE38 than by continuous i.p. administration suggest that increased drug clearance or impaired drug delivery reduces the efficacy of systemic TGF-alpha-PE38. Direct delivery of TGF-alpha-PE38 into brain tumors by controlled-release biodegradable polymers or intratumoral implanted catheters, or intrathecal administration into the colony stimulating factor of patients with leptomeningeal metastasis, may represent clinically useful applications of recombinant toxin therapy in tumors with high EGFR expression.
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PMID:Transforming growth factor-alpha-Pseudomonas exotoxin fusion protein (TGF-alpha-PE38) treatment of subcutaneous and intracranial human glioma and medulloblastoma xenografts in athymic mice. 831 55

Tumor necrosis factor-alpha (TNF) markedly stimulates the synthesis and secretion of immunoreactive nerve growth factor (NGF) in quiescent mouse fibroblasts, which is a result of increase in the NGF mRNA level. NGF produced by TNF-treated fibroblasts has a molecular mass of 13 kDa on SDS-polyacrylamide gel electrophoresis, which is consistent in size with the subunit of mouse beta-NGF, and induces neurite outgrowth in paravertebral sympathetic neurons. Several peptide growth factors such as basic fibroblast growth factor (bFGF) and epidermal growth factor also stimulate NGF production in the cells, but not platelet-derived growth factor. The dose responses of TNF and bFGF to stimulate NGF production in the cells are, respectively, similar to those to induce cell proliferation. However, no correlation is observed between the ability of these growth factors to stimulate NGF production and that to induce cell proliferation. Thus, the stimulation of NGF production in the cells seems to be a specific activity of TNF and some other growth factors. TNF stimulates the synthesis and secretion of NGF also in other cells such as human glioblastoma cells. These findings suggest that TNF plays a role in regulating neuronal cell function through an indirect mechanism by which it stimulates NGF production in glial cells and fibroblasts.
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PMID:Tumor necrosis factor stimulates the synthesis and secretion of biologically active nerve growth factor in non-neuronal cells. 842 34

In 75 gliomas and 31 meningiomas, mutations at the epidermal growth factor receptor (EGFR) gene locus were restricted to gliomas. The ligands of this receptor, epidermal growth factor and transforming growth factor alpha, lacked quantitative changes at their loci in gliomas and meningiomas. EGFR gene amplification occurred in astrocytomas, oligodendrogliomas, ependymomas and glioblastomas. The frequency of this mutation significantly increased with the malignancy grade and the patient's age. Especially in glioblastomas of individuals aged over 64 years, EGFR gene mutations were observed without chromosome-10-specific allele losses. This finding contradicts the hypothesis that deletion of one entire chromosome 10 regularly precedes EGFR gene amplification in primary glioblastomas of patients aged over 50 years. It was found that most individuals whose gliomas carry an EGFR gene mutation have a poor prognosis, comparable to that of glioblastoma patients even when the tumour is graded as benign.
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PMID:Distribution of epidermal growth factor receptor gene amplification in brain tumours and correlation to prognosis. 856 31

Photodynamic therapy (PDT) could be a useful adjuvant in glioblastoma treatment. The fact that epidermal growth factor (EGF) and its receptor are involved in glioblastoma growth control led us to investigate the relationships between EGF and PDT with respect to three different glioma cell lines (C6, T98 G, U87 MG) responsive to growth stimulation by EGF. Flow cytometric analysis revealed that each cell line expressed EGF receptors. PDT was then applied to the cells using haematoporphyrin derivative (HPD) as photosensitizer and argon laser irradiation. When cells were incubated for 2 h with HPD (0.1-10 micrograms/ml) and then laser-irradiated (lambda = 514 nm; energy density 25 J/cm2), all three cell lines showed photosensitivity. The median lethal dose was respectively 3, 4.5 and 2.7 micrograms/ml for C6, T98 G and U87 MG. EGF (2-50 ng/ml) had no effect on HPD- and laser-induced toxicity when added to cells before PDT, whereas toxicity decreased for all three cell lines when EGF was added after PDT. HPD (1-2 micrograms/ml, incubation times 30-180 min) also induced an increase in EGF receptor expression for the C6 line.
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PMID:Influence of epidermal growth factor on photodynamic therapy of glioblastoma cells in vitro. 944 Jan 40

This study was undertaken to evaluate plasma levels of interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha) transforming growth factor-beta (TGF-beta), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF) in 3 pediatric and 14 adult patients receiving radiotherapy for brain tumor. Patients with glioblastoma, astrocytoma, chondrosarcoma, meningioma, schwannoma, and lung adenocarcinoma that had metastasized to the brain were included. Peripheral blood samples were collected before and after treatment with conventional photon and/or proton radiation; samples from healthy volunteers served as controls. Enzyme-linked immunosorbent assays were performed to quantitate the cytokines. Before irradiation, most patients had greater amounts of one or more of the cytokines compared with the mean obtained for control plasma. This was especially striking in patients with chondrosarcoma; the mean values for TGF-beta 1, TNF-alpha, bFGF, and EGF were 1458, 1289, 332, and 92% higher than in healthy subjects, respectively. After irradiation, bFGF and total TGF-beta 1 decreased in the majority of tested subjects. In contrast, IL-1 beta was detected only in pediatric patients (all with astrocytoma) and its levels after radiation were 33 to 67% higher than at pretreatment. EGF was found in four patients; post-treatment values were 125 to 608% higher in three of the individuals. These data show that cytokines are present at elevated concentrations in the blood circulation of patients with certain types of brain tumors and that changes in their levels can be detected after radiotherapy. Further investigations are warranted to determine whether these findings contribute to morbidity or therapeutic outcome.
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PMID:Pilot evaluation of cytokine levels in patients undergoing radiotherapy for brain tumor. 946 45

The novel quinazoline derivative 4-(3'-bromo-4'-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline (WHI-P154) exhibited significant cytotoxicity against U373 and U87 human glioblastoma cell lines, causing apoptotic cell death at micromolar concentrations. The in vitro antiglioblastoma activity of WHI-P154 was amplified > 200-fold and rendered selective by conjugation to recombinant human epidermal growth factor (EGF). The EGF-P154 conjugate was able to bind to and enter target glioblastoma cells within 10-30 min via receptor (R)-mediated endocytosis by inducing internalization of the EGF-R molecules. In vitro treatment with EGF-P154 resulted in killing of glioblastoma cells at nanomolar concentrations with an IC50 of 813 +/- 139 nM, whereas no cytotoxicity against EGF-R-negative leukemia cells was observed, even at concentrations as high as 100 microM. The in vivo administration of EGF-P154 resulted in delayed tumor progression and improved tumor-free survival in a severe combined immunodeficient mouse glioblastoma xenograft model. Whereas none of the control mice remained alive tumor-free beyond 33 days (median tumor-free survival, 19 days) and all control mice had tumors that rapidly progressed to reach an average size of > 500 mm3 by 58 days, 40% of mice treated for 10 consecutive days with 1 mg/kg/day EGF-P154 remained alive and free of detectable tumors for more than 58 days with a median tumor-free survival of 40 days. The tumors developing in the remaining 60% of the mice never reached a size > 50 mm3. Thus, targeting WHI-P154 to the EGF-R may be useful in the treatment of glioblastoma multiforme.
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PMID:4-(3'-Bromo-4'hydroxylphenyl)-amino-6,7-dimethoxyquinazoline: a novel quinazoline derivative with potent cytotoxic activity against human glioblastoma cells. 962 56

Various growth factors and basement membrane proteins have been implicated in the pathobiology of astrocytomas. The goal of this study was to determine the relative contribution of these two factors in modulating the phenotype of U-373 MG glioblastoma cells as determined by the expression of the intermediate filament proteins glial fibrillary acidic protein, vimentin, and nestin. For these determinations, cells plated in serum-free medium were treated either with growth factors binding to tyrosine kinase receptors including transforming growth factor-alpha, epidermal growth factor, platelet-derived growth factor-AA, basic fibroblast growth factor, and insulin-like growth factor-1 or with basement membrane proteins including collagen IV, laminin, and fibronectin. The changes in the expression levels of intermediate filament proteins in response to these treatments were analyzed by quantitation of immunoblots. The results demonstrate that collagen IV and growth factors binding to tyrosine kinase receptors decrease the glial fibrillary acidic protein content of U-373 MG cells. Growth factors binding to tyrosine kinase receptors also decrease the vimentin content of these cells but do not affect their nestin content. On the other hand, basement membrane proteins decrease the nestin content of U-373 MG cells but do not affect their vimentin content. The significance of these results with respect to the role played by different factors in modulating the phenotype of neoplastic astrocytes during tumor progression is discussed.
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PMID:Effects of growth factors and basement membrane proteins on the phenotype of U-373 MG glioblastoma cells as determined by the expression of intermediate filament proteins. 977 47

Glioblastoma multiforme is a highly invasive primary brain tumor with a disappointingly high local recurrence rate and mortality despite intensive multimodality treatment programs. Therefore, new agents that are capable of inhibiting the infiltration of normal brain parenchyma by glioblastoma cells are urgently needed. Here, we show that the novel quinazoline derivatives 4-(4'-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline (WHI-P131) and 4-(3'-bromo-4'hydroxylphenyl)-amino-6,7-dimethoxyquinazoline (WHI-P154) are potent inhibitors of glioblastoma cell adhesion and migration. Specifically, both compounds inhibited at micromolar concentrations: (a) integrin-mediated glioblastoma cell adhesion to the extracellular matrix proteins laminin, type IV collagen, and fibronectin; (b) integrin-independent epidermal growth factor-induced adhesion of glioblastoma cells to poly-L-lysine-coated tissue culture plates; (c) fetal bovine serum-induced polymerization of actin and actin stress fiber formation as well epidermal growth factor-stimulated formation of focal adhesion plaques in serum-starved glioblastoma cells; and most importantly, (d) glioblastoma cell migration in in vitro assays of tumor cell invasiveness using tumor cell spheroids and/or Matrigel-coated Boyden chambers. Further preclinical development of WHI-P131 and WHI-P154 may provide the basis for the design of more effective adjuvant chemotherapy programs for glioblastoma multiforme.
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PMID:Inhibition of human glioblastoma cell adhesion and invasion by 4-(4'-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline (WHI-P131) and 4-(3'-bromo-4'-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline (WHI-P154). 979 79

We previously reported that schwannoma-derived growth factor (SDGF), a member of heparin-binding epidermal growth factor (EGF) family, participates in autocrine pathways and promotes rat glioma cell growth. To investigate the potential role of similar molecules in human gliomas, we examined 7 human glioma cell lines and 11 glioblastoma specimens for expression of the human homologue of SDGF, amphiregulin (AR), as well as heparin-binding EGF-like growth factor (HB-EGF). Northern blot analysis revealed that only one cell line and no tumor specimens expressed AR mRNA. In contrast, HB-EGF mRNA was expressed in all human glioma cell lines and its level of expression was two- to five-fold higher than that of control brain tissues in 8 of 11 glioblastoma cases. Immunohistochemistry demonstrated that membrane-anchored HB-EGF (proHB-EGF) and EGFR were co-expressed in 44% of 34 human malignant gliomas. Introduction of exogenous HB-EGF (10 ng/ml) increased human glioma cell proliferation, and anti-HB-EGF blocking antibodies reduced the growth of glioma cells by 30-40%, confirming the presence of an autocrine loop. When added to the medium, transforming growth factor-alpha, basic fibroblast growth factor, or HB-EGF rapidly induced HB-EGF mRNA expression. These results indicate that HB-EGF and proHB-EGF contribute to the growth of human malignant glioma cells, most likely through autocrine and juxtacrine mechanisms.
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PMID:Heparin-binding epidermal growth factor-like growth factor stimulates mitogenic signaling and is highly expressed in human malignant gliomas. 979 95


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