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

Deregulation of protein kinase activity has been shown to play a central role in the pathogenesis of human cancer. The molecular pathogenesis of chronic myelogenous leukemia (CML) in particular, depends on formation of the bcr-abl oncogene, leading to constitutive expression of the tyrosine kinase fusion protein, Bcr-Abl. Based on these observations, imatinib was developed as a specific inhibitor for the Bcr-Abl protein tyrosine kinase. The expanding understanding of the basis of imatinib-mediated tyrosine kinase inhibition has revealed a spectrum of potential new antitumor applications beyond the powerful activity already reported in the treatment of CML. Imatinib has shown activity in vivo against PDGF-driven tumor models including glioblastoma, dermatofibrosarcoma protuberans and chronic myelomonocytic leukemia. Antiangiogenic effects have been demonstrated by inhibition of PDGF-, VEGF (vascular endothelial growth factor)- and bFGF- (basic fibroblast growth factor) induced angiogenesis in vivo, and by inhibition of angiogenesis and tumor growth in an experimental bone metastasis model. Imatinib has been shown to reduce interstitial fluid pressure in an experimental colonic carcinoma model by blocking PDGF-mediated effects on tumor-associated blood vessels and stromal tissue. It is also a potent inhibitor of the Kit receptor tyrosine kinase, and has demonstrated activity clinically against the Kit-driven gastrointestinal stromal tumor (GIST) and experimentally in small-cell lung cancer cell lines. The pharmacology of imatinib and its activity in various tumor models is discussed.
 ...
PMID:Pharmacology of imatinib (STI571). 1252 70

The effect of combining SU5416 with fractionated radiotherapy or with low molecular weight (LMW) heparin (dalteparin) was studied in U87 human glioblastoma xenografts in nude mice. SU5416 is antiangiogenic by a specific inhibition of the vascular endothelial growth factor receptor 2 (VEGFR-2), and heparins are assumed to bind VEGF. Both SU5416 (100 mg/kg every second day in 5 days) and 3 Gyx5 produced moderate, yet significant, growth inhibition. Tumors treated with concomitant irradiation and short-term SU5416 maintained a lower growth rate during regrowth than the other treatment groups (P=.007). Dalteparin (1000 IE/kg subcutaneously once a day) had no growth-inhibitory effect on its own, but when this LMW heparin was added to the SU5416 schedule, a significantly enhanced growth inhibition was obtained. VEGF protein content in tumors was not significantly altered by SU5416, but a significant decrease in VEGF levels was found in tumors treated with concomitant dalteparin and SU5416 compared with controls (P=.03). We conclude that: 1) an additive growth-inhibitory effect is obtained by combining SU5416 and fractionated radiotherapy; and 2) LMW heparin (dalteparin), in combination with SU5416, decreases the level of VEGF in tumors and increases the growth-inhibitory effect of SU5416.
 ...
PMID:Improved effect of an antiangiogenic tyrosine kinase inhibitor (SU5416) by combinations with fractionated radiotherapy or low molecular weight heparin. 1265 88

Neovascularization and invasion are key features of malignant gliomas. Matrix metalloproteinases (MMPs) are supposed to play a major role mediating these processes. To analyze the expression patterns of MMPs in microvascular human cerebral endothelial cells (HCEC), we isolated endothelial cells from normal human brain microvessels. Characterization of cellular origin was performed by immunostaining, using the endothelial cell markers Ulex europaeus Agglutinin-1, von-Willebrand-Factor and Glucose-transporter-1. Contamination by other cell types was tracked by immunohistochemistry for GFAP (astrocytes), ASM (pericytes) and CD68 (macrophages). Secretion of MMPs was evaluated by ELISA and zymography. To determine whether HCEC show any difference in MMP expression compared to endothelial cells of other origin we analyzed human umbilical vein endothelial cells (HUVEC). HCEC show a decrease of MMP-3 and MMP-2 protein when treated with SU5416, a VEGF-R2 (KDR/flk-1) inhibitor, whereas MMP expression remained unchanged in HUVEC. To determine whether these findings show any effect in the motility of these cells we used a three-dimensional co-culture assay of avascular glioblastoma spheroids with primary HCEC spheroids. Untreated controls showed invasion of both cell populations into each other whereas treatment of the co-cultures with SU5416 resulted in complete inhibition of endothelial cell invasion hence indicating that flk-1 related motility of endothelial cells is critically involved in this process and can be studied with this assay. The results of different effects of anti-angiogenic treatment on proteolytic properties of two endothelial cell populations suggest that neovascularization of human brain tumors in vitro is dependent on the surrounding endothelial cell type and should therefore be studied with organ-specific human microvascular cerebral endothelial cells.
 ...
PMID:Influence of VEGF-R2 inhibition on MMP secretion and motility of microvascular human cerebral endothelial cells (HCEC). 1277 73

Intracavitary levels of VEGF, bFGF, IL-8 and IL- 12 were evaluated by ELISA in 45 patients, 7 with recurrent anaplastic astrocytoma (rAA), 12 with glioblastoma (GBM) and 26 with recurrent glioblastoma (rGBM). In 25 patients plasma levels of the molecules were also quantitated. Twenty-three healthy controls were also studied for plasma concentrations of the same molecules. Plasma levels of VEGF (mean 33.89 +/- 6.71 pg/ml) and bFGF (mean 11.1 +/- 3.24 pg/ml) were higher in patients than in controls (mean 16.78 +/- 3.7 pg/ml for VEGF, mean 0.21 +/- 0.09 pg/ml for bFGF) (p = 0.04 and p = 0.001, respectively) while plasma IL-12 levels were lower (mean 45.6 +/- 1.5 pg/ml in patients, mean 79.7 +/- 1.3 pg/ml in controls) (p = 0.009). Intracavitary VEGF levels were 5-53.307 fold higher (mean 90,900 +/- 24,789 pg/ml) than in the corresponding plasma. Also IL-8 concentrations were higher in intracavitary fluid (mean 6,349.76 +/- 1,460.93 pg/ml) than in plasma (mean 43.44 +/- 24.82 pg/ml). Maximum VEGF levels were found in tumor fluid of recurrent glioblastoma patients (mean 147,678 +/- 39.903 pg/ml), intermediate levels in glioblastoma patients (mean 20,322 +/- 11,892 pg/ml) and lower levels in rAA patients (mean 9,111 +/- 5,789 pg/ml). The data also suggest that higher intracavitary levels of VEGF and IL-8, and lower IL-12 levels, may be correlated with shorter adjunctive survival times, but more data will need to be collected to establish this correlation clearly.
 ...
PMID:Intracavitary VEGF, bFGF, IL-8, IL-12 levels in primary and recurrent malignant glioma. 1277 82

The development of targeted treatment strategies adapted to individual patients requires identification of the different tumor classes according to their biology and prognosis. We focus here on the molecular aspects underlying these differences, in terms of sets of genes that control pathogenesis of the different subtypes of astrocytic glioma. By performing cDNA-array analysis of 53 patient biopsies, comprising low-grade astrocytoma, secondary glioblastoma (respective recurrent high-grade tumors), and newly diagnosed primary glioblastoma, we demonstrate that human gliomas can be differentiated according to their gene expression. We found that low-grade astrocytoma have the most specific and similar expression profiles, whereas primary glioblastoma exhibit much larger variation between tumors. Secondary glioblastoma display features of both other groups. We identified several sets of genes with relatively highly correlated expression within groups that: (a). can be associated with specific biological functions; and (b). effectively differentiate tumor class. One prominent gene cluster discriminating primary versus nonprimary glioblastoma comprises mostly genes involved in angiogenesis, including VEGF fms-related tyrosine kinase 1 but also IGFBP2, that has not yet been directly linked to angiogenesis. In situ hybridization demonstrating coexpression of IGFBP2 and VEGF in pseudopalisading cells surrounding tumor necrosis provided further evidence for a possible involvement of IGFBP2 in angiogenesis. The separating groups of genes were found by the unsupervised coupled two-way clustering method, and their classification power was validated by a supervised construction of a nearly perfect glioma classifier.
 ...
PMID:Classification of human astrocytic gliomas on the basis of gene expression: a correlated group of genes with angiogenic activity emerges as a strong predictor of subtypes. 1458 54

Investigation of the predictive value of a radiosurgery-relevant treatment of glioblastoma spheroids. Organotypic multicellular spheroids were cultured and irradiated (20 Gy). Morphology, apoptosis and immunohistochemical expression of p53, p21, MIB-1, TGF-beta and VEGF were examined 4 h, 24 h, 7 days, and 14 days following treatment. Cell proliferation decreased, while apoptosis was increased. No morphological damage was observed. p53 expression was significantly increased after 4 h. TGF-beta and VEGF expression were only slightly altered. Particularly early changes in proliferation and apoptosis can be observed in spheroids. Individual response differences suggest spheroids of human gliomas to be useful for monitoring radiosurgery effects.
 ...
PMID:Effect of single dose irradiation on human glioblastoma spheroids in vitro. 1471 87

The cysteine proteinase cathepsin B has been implicated in tumor progression by virtue of its increased mRNA and protein levels, as well as its localization at the invading front of the tumor. In this study, we examined whether blocking cathepsin B expression in human glioblastoma SNB19 cells affects angiogenesis. Stable transfectants of human glioblastoma cells with a plasmid containing antisense cathepsin B cDNA showed decreased migration rates in wound- and spheroid-migration assays. Analysis showed a reduction in VEGF protein and MMP-9 activity in the cathepsin B antisense cDNA-transfected cells. Regarding angiogenesis in vitro, we found that the conditioned medium of glioblastoma cells with downregulated cathepsin B expression reduced cell-cell interaction of human microvascular endothelial cells, resulting in the disruption of capillary-like network formation. Furthermore, a marked reduction in microvasculature development was seen in an in vivo dorsal air sac assay of glioblastoma cells with downregulated cathepsin B expression. Taken together, these results provide evidence that inhibition of cathepsin B expression can suppress glioblastoma-induced neovascularization.
 ...
PMID:Blockade of cathepsin B expression in human glioblastoma cells is associated with suppression of angiogenesis. 1473 Mar 46

Brain specific angiogenesis inhibitor (BAI)-1 is a novel p53-inducible anti-angiogenic molecule. We examined the expression of BAI-1 in glial tumors and its association with patient survival. The expression of BAI-1 was evaluated in 20 brain tumors (meningiomas, pituitary adenomas, hemangiopericytomas, hemangioblastomas), 2 normal brain samples, 5 benign gliomas, and 26 glioblastomas. In the 26 glioblastoma tumors, we also evaluated the expression of VEGF, p53, p53 mutations, and MIB-1 to determine their association with survival. BAI-1 mRNA was expressed in all benign gliomas, normal brain, and 9 out of 26 glioblastomas, but not in the other tumors. Low VEGF and aberrant high expression of p53 were associated with a favorable outcome in univariate survival analysis, but they were not independent factors in multivariate analysis. For the treatment response, BAI-1 expression was associated with better response to radiation therapy (p=0.014). When we divided the patients into groups according to the expression patterns of BAI-1 and VEGF mRNA, the median survival of 9 patients with high VEGF expression and no expression of BAI-1 was just 6 months, while the median survival of the other 17 patients was 14 months (p=0.013). Glioblastomas with no BAI-1 and high VEGF mRNA expression are more often associated with poor clinical outcome. These findings suggest that the balance between the angiogenic and anti-angiogenic factors is important in the progression of glioblastoma and its response to treatment.
 ...
PMID:Expression of VEGF and brain specific angiogenesis inhibitor-1 in glioblastoma: prognostic significance. 1501 Aug 86

We demonstrate that human umbilical vein endothelial cells (HUVEC) grown in co-culture (CC) with U87 glioblastoma cells transfected with green fluorescent protein (GFP-U87) exhibit resistance to radiation-mediated apoptosis. cDNA macroarray analysis reveals increases in the accumulation of RNAs for HUVEC genes encoding cell adhesion molecules, growth factor-related proteins, and cell cycle regulatory/DNA repair proteins. An increase in protein expression of integrin alphav, integrin beta1, MAPK(p42), Rad51, DNA-PK(CS), and ataxia telangiectasia gene (ATM) was detected in HUVEC grown in CC with GFP-U87 cells compared with HUVEC grown in mono-culture. Treatment with anti-VEGF antibody decreases the expression of integrin alphav, integrin beta1, DNA-PK(CS) and ATM with a corresponding increase in ionizing radiation (IR)-induced apoptosis. These data support the concept that endothelial cells growing in the tumor microenvironment may develop resistance to cytotoxic therapies due to the up-regulation by tumor cells of endothelial cells genes associated with survival.
 ...
PMID:Glioblastoma cells block radiation-induced programmed cell death of endothelial cells. 1513 73

Neuropilin-1 is a VEGF165- and semaphorin receptor expressed by endothelial cells and tumor cells. The specific function of neuropilin-1 is not fully known, but in the developing nervous system neuropilin, as a semaphorin receptor, has been shown to influence neuronal guidance. The expression of neuropilin-1 was studied in low-grade and high-grade astrocytic tumors, the latter characterized by extensive angiogenesis. We examined 20 low-grade astrocytomas (WHO grade II) and 46 glioblastomas (WHO grade IV) immunohistochemically for neuropilin-1, p53 and EGFR. The glioblastomas were according to the p53 and EGFR expression classified as 35 primary--de novo--glioblastomas, 9 secondary glioblastomas, and 2 uncertain cases. Furthermore, the presence of mast cells was evaluated to search for any potential function in angiogenesis. The glioblastomas expressed neuropilin-1 in the endothelial cells of the proliferating vessels and the majority of the glioblastomas had immunoreactive neoplastic astrocytes, with no difference between the glioblastoma subgroups. Six out of twenty of the low-grade astrocytomas were negative in the endothelial cells and 8 out of 20 in the tumor cells for neuropilin-1. Mast cells were observed in the collagen matrix around larger vessels in the leptomeninges, but not adjacent to malignant tumor vessels or as part of the tumor process itself. Increased expression of neuropilin-1 is shown in endothelial cells and in neoplastic astrocytes of glioblastomas. Less neuropilin-1 expression is found in about half of the low-grade astrocytomas in both neoplastic astrocytes and endothelial cells. The results suggest a correlation between neuropilin-1 and vascularity in human astrocytic tumors and a possible role for neuropilin-1 as a receptor for VEGF-induced angiogenesis.
 ...
PMID:Vascular endothelial growth factor (VEGF) receptor neuropilin-1's distribution in astrocytic tumors. 1523 40


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>