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)

In order to identify response predictors for a post-operative glioblastoma therapy consisting of tamoxifen, carboplatin and radiotherapy, expression of 12 antigens was evaluated in 36 newly diagnosed tumours and 13 recurrences. Results were correlated with the clinical course of the disease. Antigen expression was assessed immunohistochemically for CD44s, TGF-beta2, TGF-alpha, progesterone receptor, estrogen receptor, EGFR, urokinase, urokinase inhibitor 1, CD87, p53 protein and Ki-67. Vessel density was determined by labelling of endothelia with von Willebrand factor. Response to chemotherapy correlated positively with cell density (p < 0.05) and negatively with CD44 over-expression (p < 0.02). Further, a positive correlation between age and CD44 expression (p < 0.05) and a negative correlation between age and p53 accumulation (p < 0.01) was found. In tumour recurrences expression of CD44 was significantly higher in local recurrences than in distant multifocal recurrences (p < 0.02), suggesting that CD44 may predominantly be associated with cell adhesion in glioblastomas.
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PMID:CD44 expression and tumour cell density correlate with response to tamoxifen/carboplatin chemotherapy in glioblastomas. 1501 79

A bispecific immunotoxin (IT) called DTAT13 was synthesized in order to target simultaneously the urokinase-type plasminogen activator receptor (uPAR)-expressing tumor neovasculature and IL-13 receptor expressing glioblastoma cells with the goal of intratumoral administration for brain tumors. The recombinant hybrid was created using the non-internalizing N-terminal fragment (ATF) of uPA and the IL-13 molecule for binding plus the catalytic and translocation portion of diphtheria toxin (DT) for killing. The 71 kDa protein was highly selective for human glioblastoma in vitro showing no loss on binding compared with DTAT and DTIL13 controls. In vivo, DTAT13 caused the regression of small tumors when administered at 10 micro g/day given on a five-dose schedule every other day. DTAT13 was able to target both overexpressed uPAR and the vasculature, as demonstrated by its ability to kill HUVEC cells. Also, mortality studies indicated that DTAT13 was less toxic than DTAT or DTIL13. These findings indicate that bispecific IT may allow treatment of a broader subset of antigenically diverse patients while simultaneously reducing the exposure to toxin required than if two separate agents were employed.
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PMID:A bispecific immunotoxin (DTAT13) targeting human IL-13 receptor (IL-13R) and urokinase-type plasminogen activator receptor (uPAR) in a mouse xenograft model. 1504 12

Induction of the urokinase-type plasminogen activator (uPA) by hepatocyte growth factor/scatter factor (HGF/SF) plays an important role in tumor cell invasion and metastasis that is mediated through the Met receptor tyrosine kinase. Geldanamycins (GA) are antitumor drugs that bind and inhibit HSP90 chaperone activity at nanomolar concentrations (nM-GAi) by preventing proper folding and functioning of certain oncoproteins. Previously, we have shown that a subset of GA derivatives exhibit exquisite potency, inhibiting HGF/SF-induced uPA-plasmin activation at femtomolar concentrations (fM-GAi) in canine MDCK cells. Here, we report that (1) inhibition of HGF/SF-induced uPA activity by fM-GAi is not uncommon, in that several human tumor glioblastoma cell lines (DBTRG, U373 and SNB19), as well as SK-LMS-1 human leiomyosarcoma cells are also sensitive to fM-GAi; (2) fM-GAi drugs only display inhibitory activity against HGF/SF-induced uPA activity (rather than basal activity), and only when the observed magnitude of uPA activity induction by HGF/SF is at least 1.5 times basal uPA activity; and (3) not only do fM-GAi derivatives strongly inhibit uPA activity but they also block MDCK cell scattering and in vitro invasion of human glioblastoma cells at similarly low drug concentrations. These effects of fM-GAi drugs on the Met-activated signaling pathway occur at concentrations well below those required to measurably affect Met expression or cell proliferation. We also examined the effect of Radicicol (RA), a drug with higher affinity than GA for HSP90. RA displays uPA activity inhibition at nanomolar levels, but not at lower concentrations, indicating that HSP90 is not likely the fM-GAi molecular target. Thus, we show that certain GA drugs (fM-GAi) in an HGF/SF-dependent manner block uPA-plasmin activation in tumor cells at femtomolar levels. This inhibition can also be observed in scattering and in vitro invasion assays. Our findings also provide strong circumstantial evidence for a novel non-HSP90 molecular target that is involved in HGF/SF-mediated tumor cell invasion.
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PMID:Geldanamycins exquisitely inhibit HGF/SF-mediated tumor cell invasion. 1578 29

The cellular receptor for urokinase-type plasminogen activator receptor (uPAR) is a member of the glycosylphosphatidylinositol (GPI) anchored protein family. It is a specific cell surface receptor for its ligand, urokinase-type plasminogen activator, which catalyzes the formation of plasmin from plasminogen to generate the proteolytic cascade and leads to the breakdown of the extracellular matrix. uPAR has been shown to correlate with a propensity to tumor invasion and metastasis in several types of non-central nervous system tumors. In this study, the authors examined the immunohistochemical expression of uPAR in 65 primary brain tumors (5 pilocytic astrocytomas, 5 diffuse astrocytomas, 6 anaplastic astrocytomas, 8 glioblastomas, 5 oligodendrogliomas, 4 oligoastrocytomas, 6 anaplastic oligoastrocytomas, 4 gangliogliomas, 4 ependymomas, 5 medulloblastomas, 6 schwannomas, 5 meningiomas, 2 atypical meningiomas). The specimens were evaluated for intensity of immunostaining (0-3 scale), cellular localization of staining, and specific or unique patterns of staining. Some degree of uPAR expression was observed in all tumors. A significant positive correlation (P = 0.0006) between tumor grade and staining intensity was identified within the astrocytoma/glioblastoma subgroup, suggesting a possible correlation with anaplastic change and propensity to tumor invasion. Expression of uPAR in nonmalignant, noninvasive tumors such as schwannoma and meningioma suggests that uPAR may have other biologic functions in addition to promotion of tumor invasion.
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PMID:Expression of urokinase-type plasminogen activator receptor (uPAR) in primary central nervous system neoplasms. 1589 33

Invasive and proliferative phenotypes are fundamental components of malignant disease, yet basic questions persist about whether tumor cells can express both phenotypes simultaneously and, if so, what are their properties. Suitable in vitro models that allow characterization of cells that are purely invasive are limited because proliferation is required for cell maintenance. Here, we describe glioblastoma cells that are highly invasive in response to hepatocyte growth factor/scatter factor (HGF/SF). From this cell population, we selected subclones that were highly proliferative or displayed both invasive and proliferative phenotypes. The biological activities of invasion, migration, urokinase-type plasminogen activation, and branching morphogenesis exclusively partitioned with the highly invasive cells, whereas the highly proliferative subcloned cells uniquely displayed anchorage independent growth in soft agar and were highly tumorigenic as xenografts in immune-compromised mice. In response to HGF/SF, the highly invasive cells signal through the MAPK pathway, whereas the selection of the highly proliferative cells coselected for signaling through Myc. Moreover, in subcloned cells displaying both invasive and proliferative phenotypes, both signaling pathways are activated by HGF/SF. These results show how the mitogen-activated protein kinase and Myc pathways can cooperate to confer both invasive and proliferative phenotypes on tumor cells and provide a system for studying how transitions between invasion and proliferation can contribute to malignant progression.
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PMID:Proliferation and invasion: plasticity in tumor cells. 1602 25

Complete resection of malignant glioblastomas is usually impossible because of diffuse and widespread invasion of tumor cells, and complementary approaches need to be developed in order to improve the efficacy of current treatments. Consumption of fruits and berries has been associated with decreased risk of developing cancer and there is great interest in the use of molecules from dietary origin to improve anticancer therapies. In this work, we report that the aglycons of the most abundant anthocyanins in fruits, cyanidin (Cy), delphinidin (Dp), and petunidin (Pt), act as potent inhibitors of glioblastoma cell migration. Dp clearly exhibited the highest inhibitory potency, this effect being related to the ortho-dihydroxyphenyl structure on the B-ring and the presence of a free hydroxyl group at position 3. Dp decreases the expression of both urokinase-type plasminogen activator receptor (uPAR) and the low-density lipoprotein receptor-related protein (LRP), acting at the transcriptional levels. In addition, Dp upregulated urokinase-type plasminogen activator (uPA) and downregulated the plasminogen activator inhibitor-1 (PAI-1) but decreased, in a concentration-dependent manner, the uPA-dependent conversion of plasminogen to plasmin, indicating that the upregulation of uPA observed with these compounds was not associated with induction of the plasminolytic activity. Overall, these results demonstrate that Dp, Pt, and Cy affect plasminogen activation, thus leading to the inhibition of glioblastoma cell migration and therefore they may be helpful for the development of new strategies for cancer prevention and therapy.
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PMID:Anthocyanidins inhibit migration of glioblastoma cells: structure-activity relationship and involvement of the plasminolytic system. 1682 70

A gene splicing technique was used to create a hybrid fusion protein DTAT encoding the 390 amino acid portion of diphtheria toxin (DT(390)), a linker, and the downstream 135-amino terminal fragment portion of human urokinase plasminogen activator. DTAT was assembled to target human glioblastoma cell lines in a murine intracranial model. Previously published in vitro studies demonstrated that DTAT was highly selective and toxic to human glioblastoma cell lines in a flank tumor model. The purpose of this study was to determine the toxicity, specificity and possible therapeutic efficacy of DTAT in an intracranial model. Convection enhanced delivery of DTAT resulted in about a 16-fold increase in maximum tolerated dose. Intracranial administration of DTAT on an every-other-day basis in nude mice with established U87 MG brain tumors resulted in significant reductions in tumor volume and significantly prolonged survival (p < 0.0001). Magnetic resonance imaging proved to be a powerful tool in mice and rats for demonstrating tumor growth in a xenograft intracranial model, assessing the efficacy of DTAT in tumor volume reduction and detecting DTAT-associated intracranial toxicity and vascular damage. These results suggest that the DTAT recombinant fusion protein is highly effective in an intracranial model and DTAT might be an effective treatment for glioblastoma.
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PMID:Intracranial therapy of glioblastoma with the fusion protein DTAT in immunodeficient mice. 1707 92

Aggressive and infiltrative invasion is one of the hallmarks of glioblastoma. Low-density lipoprotein receptor-related protein (LRP) is expressed by glioblastoma, but the role of this receptor in astrocytic tumor invasion remains poorly understood. We show that activation of protein kinase C-alpha (PKC-alpha) phosphorylated and down-regulated LRP expression. Pretreatment of tumor cells with PKC inhibitors, phosphoinositide 3-kinase (PI3K) inhibitor, PKC-alpha small interfering RNA (siRNA), and short hairpin RNA abrogated phorbol 12-myristate 13-acetate-induced down-regulation of LRP and inhibited astrocytic tumor invasion in vitro. In xenograft glioblastoma mouse model and in vitro transmembrane invasion assay, LRP-deficient cells, which secreted high levels of urokinase-type plasminogen activator (uPA), invaded extensively the surrounding normal brain tissue, whereas the LRP-overexpressing and uPA-deficient cells did not invade into the surrounding normal brain. siRNA, targeted against uPA in LRP-deficient clones, attenuated their invasive potential. Taken together, our results strongly suggest the involvement of PKC-alpha/PI3K signaling pathways in the regulation of LRP-mediated astrocytoma invasion. Thus, a strategy of combining small molecule inhibitors of PKC-alpha and PI3K could provide a new treatment paradigm for glioblastomas.
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PMID:Protein kinase C-alpha-mediated regulation of low-density lipoprotein receptor related protein and urokinase increases astrocytoma invasion. 1797 65

Previous study reported that the activation of Ras pathway cooperated with E6/E7-mediated inactivation of p53/pRb to transform immortalized normal human astrocytes (NHA/hTERT) into intracranial tumors strongly resembling human astrocytomas. The mechanism of how H-Ras contributes to astrocytoma formation is unclear. Using genetically modified NHA cells (E6/E7/hTERT and E6/E7/hTERT/Ras cells) as models, we investigated the mechanism of Ras-induced tumorigenesis. The overexpression of constitutively active H-RasV12 in E6/E7/hTERT cells robustly increased the levels of urokinase plasminogen activator (uPA) mRNA, protein, activity and invasive capacity of the E6/E7/hTERT/Ras cells. However, the expressions of MMP-9 and MMP-2 did not significantly change in the E6/E7/hTERT and E6/E7/hTERT/Ras cells. Furthermore, E6/E7/hTERT/Ras cells also displayed higher level of uPA activity and were more invasive than E6/E7/hTERT cells in 3D culture, and formed an intracranial tumor mass in a NOD-SCID mouse model. uPA specific inhibitor (B428) and uPA neutralizing antibody decreased uPA activity and invasion in E6/E7/hTERT/Ras cells. uPA-deficient U-1242 glioblastoma cells were less invasive in vitro and exhibited reduced tumor growth and infiltration into normal brain in xenograft mouse model. Inhibitors of Ras (FTA), Raf (Bay 54-9085) and MEK (UO126), but not of phosphatidylinositol 3-kinase (PI3K) (LY294002) and of protein kinase C (BIM) pathways, inhibited uPA activity and cell invasion. Our results suggest that H-Ras increased uPA expression and activity via the Ras/Raf/MEK signaling pathway leading to enhanced cell invasion and this may contribute to increased invasive growth properties of astrocytomas.
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PMID:H-Ras increases urokinase expression and cell invasion in genetically modified human astrocytes through Ras/Raf/MEK signaling pathway. 1838 43

Toxic cyanobacterial blooms are a rich source of metabolites having a variety of biological activities. Two main groups of cyclic peptides, depsipeptides and ureido linkage-containing peptides, reportedly inhibit serine peptidases. We characterised their inhibitory properties against selected peptidases and investigated their influence on cell viability. The depsipeptide planktopeptin BL1125 is a strong linear competitive tight-binding inhibitor of leukocyte (K(i)=2.9 nm) and pancreatic (K(i)=7.2 nm) elastase and also of chymotrypsin (K(i)=6.1 nm). Anabaenopeptins B and F show no inhibition against chymotrypsin, but inhibit both elastases. The tested cyclic peptides do not inhibit trypsin, urokinase, kallikrein 1 or cysteine peptidases. All three tested cyanopeptides show no short-term cytotoxicity in concentrations of up to 10 mum, but impair the metabolic activity of normal human astrocytes after prolonged exposure (48-96 h), whereas glioblastoma cells, tumour cells of the same type, are resistant. Strong inhibition and relative selectivity of the tested cyanopeptides suggests that they are potential candidates for application in inflammatory diseases and possibly some types of cancers.
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PMID:Cytotoxic and peptidase inhibitory activities of selected non-hepatotoxic cyclic peptides from cyanobacteria. 1871 22


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