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)

Expression of inducible nitric oxide synthase (iNOS) in malignant glioma and other tumors has been extensively documented. Massive production of NO by iNOS has been shown to exert tumoricidal effects. However, NO may enhance vasodilation and promote neovascularization, thereby facilitating tumor growth. Compared to the effects of NO on tumor cell death and survival, correlation between NO and cytotoxicity of chemotherapeutic reagents in glioma have been less well characterized. Another gene product often linked to tumor malignancy is hypoxia-inducible factor-1 (HIF-1). HIF-1 is a transcription factor that renders malignant tumors adaptive to hypoxic stress during massive vascularization and tumor invasion. Interestingly, HIF-1 also contributes to iNOS induction under hypoxia. We have characterized the interrelationship between iNOS, HIF-1 and chemoresistance. We note that increased NO synthesis by cytokine exposure or iNOS overexpression neutralized the cytotoxicity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), but not cisplatin, in rat C6 glioma cells. Both BCNU and CCNU are chloroethylnitrosoureas that kill tumor cells via carbamoylating and alkylating actions. Further studies indicated that iNOS only neutralized carbamoylating action of chloroethylnitrosoureas. Expression of iNOS may inhibit HIF-1 activity under hypoxia in C6 glioma cells transfected with a VEGF promoter-driven luciferase gene. Pretreatment of C6 cells with N-acetyl-l-cysteine (NAC), an antioxidant, nullified the inhibitory effect of iNOS on HIF-1 binding. That NO generated by iNOS expression inhibits HIF-1 activity in hypoxic C6 cells reveals a negative feedback loop in the HIF-1 --> iNOS cascade. Together these results suggest a complicated role of NO in malignant tumor growth, survival and invasion.
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PMID:NO-mediated chemoresistance in C6 glioma cells. 1207 59

Photodynamic therapy (PDT) is an innovative strategy for the treatment of solid neoplasms of the brain. Aside from inducing cell death in tumor cells, PDT induces endothelial cell death and promotes formation of blood clots; however, exact mechanisms that trigger these phenomena remain largely unknown. We now used Western blotting to analyze secretion of regulators of angiogenesis to the supernatants of one glioma, one macrophage, and one endothelial cell line following Hypocrellin-A and -B photodynamic therapy. We observed induction of proangiogenic VEGF (vascular endothelial growth factor) and of antiangiogenic sFlt-1, angiostatin, p43, allograft inflammatory factor-1, and connective tissue growth factor. Release of thrombospondin-1 was diminished in a glioma cell line supernatant. Endostatin release was induced in glioma cells and reduced in macrophages and endothelial cells. These data show that a wide range of antiangiogenic factors are secreted by brain tumor cells following Hypocrellin photochemotherapy. However, VEGF release is also induced thus suggesting both favorable and deleterious effects on tumor outgrowth.
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PMID:Release of regulators of angiogenesis following Hypocrellin-A and -B photodynamic therapy of human brain tumor cells. 1240 83

Inactivation of the tumor suppressor gene PTEN and overexpression of VEGF are two of the most common events observed in high-grade malignant gliomas. The purpose of this study was to determine whether PTEN controls VEGF expression in gliomas under normoxic conditions. Transfer of PTEN to human glioma cells resulted in the transduction of a functional PTEN protein as evidenced by the upregulation of p27 and modification of the phosphorylation status of Akt. Under normoxic conditions, enzyme-linked immunosorbent assay and Northern blot analyses showed downregulation of VEGF in PTEN-treated cells. Moreover, conditioned media from PTEN-treated glioma cells significantly diminished the ability of endothelial cells to grow and migrate. Western blot assays demonstrated that, in a normoxic environment, PTEN downregulates HIF-1 alpha. Finally, promoter activity assays showed that the VEGF promoter region containing the HIF-1alpha binding site is necessary and sufficient for PTEN-mediated downregulation of VEGF. Experiments with PI3-K inhibitors and kinase assays suggested that PI3-K is mediating the effect of PTEN on VEGF, and not the p42/p48 or p38 MAP kinases. These results indicate that restoration of PTEN function in gliomas may induce therapeutic effect by downregulating VEGF. Furthermore, this close functional relationship between PTEN and VEGF suggests that a better understanding of the transduction signal regulated by PTEN might enhance the knowledge of the cause and physiology of vascular and inflammatory diseases.
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PMID:Mechanisms underlying PTEN regulation of vascular endothelial growth factor and angiogenesis. 1250 54

Focal adhesion kinase (FAK) and hypoxia-inducible factor (HIF-1alpha) are both up-regulated in glioblastoma multiforme (GBMs), particularly in invasive zones. Because FAK may play an important role in the invasion of glioma cells into the surrounding brain, we sought an agent that causes down-regulation of FAK phosphorylation as a potential inhibitor of brain tumor invasion and growth. Geldanamycin (GA), a benzoquinone ansamycin antibiotic, binds to heat shock protein 90 (Hsp90) and interferes with its function. GA inhibits the proliferation of various non-glial cells and has anti-tumor activity. Moreover, GA blocks HIF-regulated transcription of VEGF and inhibits the VEGF-induced phosphorylation of FAK and migration of endothelial cells. Here, we tested the effect of GA on glioma cell migration in vitro and its potential to down-regulate HIF-1alpha induction. Our results demonstrate that GA (i) decreases U87MG, LN229, and U251MG glioma cell migration; (ii) reduces cell migration independent of p53 and PTEN status; (iii) prevents migration at non-toxic concentrations; (iv) reduces phosphorylation of FAK; and (v) inhibits cobalt chloride (CoCl(2))-mediated induction of HIF-1alpha in glioma cells. To the best of our knowledge, this is the first report showing that GA can inhibit phosphorylation of FAK concomitant with a decrease in cellular migration. One of the most clinically relevant aspects of this study is that GA interferes with the induction of HIF-1alpha that has been linked with glioma cell migration and angiogenesis. Given the fact that GA is a small lipophilic molecule capable of penetrating the blood brain barrier together with the data presented here provide a strong rationale for its use or its analogues in the treatment of highly invasive GBMs.
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PMID:Geldanamycin inhibits migration of glioma cells in vitro: a potential role for hypoxia-inducible factor (HIF-1alpha) in glioma cell invasion. 1281 34

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.
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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

Until recently, it was generally accepted that the vascularization of solid tumors occurred exclusively through the sprouting and co-option from pre-existing blood vessels. Growing evidence now suggests that bone marrow-derived endothelial progenitor cells (EP) circulate in the blood and may play an important role in the formation of new blood vessels in certain tumors. Whether endothelial progenitors participate in the vascularization of brain tumors has not yet been evaluated. In this study, we examined the contribution of EP to tumor angiogenesis in a murine glioma tumor model. Donor bone marrow cells obtained from transgenic mice constitutively expressing beta-galactosidase or GFP either ubiquitously or transcriptionally regulated by an endothelial specific promotor Tie-2 were injected into lethally irradiated adult mice. After bone marrow reconstitution by donor cells, mice were implanted with syngeneic GL261 murine glioma cells. Morphological and confocal 3-dimensional analysis showed that the majority of the engrafted donor marrow cells were expressing hematopoietic and/or microglia markers, but did not appreciably contribute to the tumor vasculature. Implantation of glioma cells genetically engineered to overexpress VEGF produced highly vascularized tumors. However, the number of endothelial progenitors incorporated in the tumor vasculature did not increase. These data strongly suggest that neovascularization in the brain might fundamentally be regulated by the sprouting of pre-existing vessels and implicate that circulating endothelial progenitors do not play a significant role in this process.
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PMID:Minor contribution of bone marrow-derived endothelial progenitors to the vascularization of murine gliomas. 1465 62

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.
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PMID:Expression of VEGF and brain specific angiogenesis inhibitor-1 in glioblastoma: prognostic significance. 1501 Aug 86

Seven new macrolides having a 12-membered ring, which we termed pladienolides, were isolated from the fermentation broth of Streptomyces platensis Mer-11107. Six of the seven pladienolides inhibited hypoxia-induced reporter gene expression controlled by human VEGF promoter with IC50 values of 0.0018-2.89 microM. They also demonstrated growth-inhibitory activity against U251 human glioma cells in vitro. Pladienolides are highly potent inhibitors of both hypoxia signals and cancer cell proliferation, and thus may be useful as antitumor agents.
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PMID:Pladienolides, new substances from culture of Streptomyces platensis Mer-11107. I. Taxonomy, fermentation, isolation and screening. 1515 2

Inhibition of angiogenesis is an important strategy to block tumor growth and invasion. We discuss herein results from our ongoing investigations on platelet factor-4 (PF-4) and the VEGF/VEGFR system. Platelet factor-4 (PF-4) is an anti-angiogenic ELR-negative chemokine. PF-4 inhibits endothelial cell proliferation and migration, and angiogenesis in vitro and in vivo. We have studied the structure and anti-angiogenic activities of a C-terminal fragment of PF-4 named PF-4 CTF. This molecule retains anti-angiogenic activity, blocks the interaction of angiogenesis factors with their receptors and may also be improved by mutation or domain-swapping. It seems, therefore, to be a good candidate for further development. Furthermore, we have developed a cyclic vascular endothelial growth inhibitor (Cyclo VEGI) from the structure of VEGF-A. In aqueous solution, cyclo-VEGI adopts an alpha helix conformation. Cyclo-VEGI inhibits binding of iodinated VEGF(165) to endothelial cells and angiogenesis. Furthermore, cyclo-VEGI significantly blocks the growth of established intracranial glioma in nude and syngeneic mice and improves survival.
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PMID:Recent developments in the inhibition of angiogenesis: examples from studies on platelet factor-4 and the VEGF/VEGFR system. 1531 95

N-Phenyl-N'-{4-(4-quinolyloxy)phenyl}ureas were found to be a novel class of potent inhibitors for the vascular endothelial growth factor receptor 2 (VEGFR-2) tyrosine kinase through synthetic modifications of a lead compound and structure-activity relationship studies. A representative compound 6ab, termed Ki8751, inhibited VEGFR-2 phosphorylation at an IC(50) value of 0.90 nM, and also inhibited the PDGFR family members such as PDGFRalpha and c-Kit at 67 nM and 40 nM, respectively. However, 6ab did not have any inhibitory activity against other kinases such as EGFR, HGFR, InsulinR and others even at 10000 nM. 6ab suppressed the growth of the VEGF-stimulated human umbilical vein endothelial cell (HUVEC) on a nanomolar level. 6ab showed significant antitumor activity against five human tumor xenografts such as GL07 (glioma), St-4 (stomach carcinoma), LC6 (lung carcinoma), DLD-1 (colon carcinoma) and A375 (melanoma) in nude mice and also showed complete tumor growth inhibition with the LC-6 xenograft in nude rats following oral administration once a day for 14 days at 5 mg/kg without any body weight loss.
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PMID:Novel potent orally active selective VEGFR-2 tyrosine kinase inhibitors: synthesis, structure-activity relationships, and antitumor activities of N-phenyl-N'-{4-(4-quinolyloxy)phenyl}ureas. 1574 79


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