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)

A human glioblastoma multiforme (M27) tested in early cell cultures by indirect immunofluorescence staining showed SV40-related tumor (T)-antigen, 95% of the cells being positive. SV40-related viral capsid (V)-antigen was absent in all cells tested. Experiments to rescue this virus were performed by fusing M27 cells with CV-I monkey cells, which were permissive for SV40, using polyethylene glycol (PEG) as fusion factor. We succeeded in isolating virus particles SV40-GBM which electron microscopy showed to correspond in size and morphology to papovaviruses. Serological tests (hemagglutination, neutralization, fluorescent antibody) revealed that the virus is indistinguishable from SV40. Despite this apparent antigenic identity SV40-GBM differs slightly from SV40 wild type. This virus can propagate and produce CPE in both CV-I cells and primary fetal human kidney cells. Furthermore digestion of SV40-GBM DNA with the HindII/III restriction endonucleases revealed minor differences compared with the SV40 DNA. Therefore the virus SV40-GBM obtained from glioblastoma cells seems to be closely related to the SV40-PML viruses described earlier.
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PMID:Isolation of a SV40-like Papovavirus from a human glioblastoma. 9 81

O6-Benzylguanine effectively inactivates the DNA-repair protein O6-alkylguanine-DNA alkyltransferase in tumor cells and has been shown to increase the cytotoxicity of chloroethylnitrosoureas. This study was undertaken to ascertain the optimal vehicle for further toxicological evaluation and eventual clinical trials of O6-benzylguanine. The solubility, metabolism, bioavailability and effectiveness of O6-benzylguanine as an adjuvant therapy with BCNU were compared using two vehicles, cremophor-EL and PEG 400. Nude mice bearing s.c. D456 MG glioblastoma xenografts were injected i.p. with 10-30 mg/kg O6-benzylguanine dissolved in either 40% PEG 400/saline or 10% cremophor-EL/saline. The number of tumor regressions noted after treatment with 10 mg/kg O6-benzylguanine followed by 12.7 mg/kg BCNU were 8/9 for the drug dissolved in PEG and 1/10 for the drug given in cremophor-EL. Using the same treatment regimen but increasing the dose of O6-benzylguanine to 30 mg/kg led to a growth delay of 45.2 and 11.5 days for the drug dissolved in PEG 400 and cremophor-EL, respectively, although the number of regressions observed were the same for both treatments. 8-[3H]-O6-Benzylguanine was more rapidly distributed to the tumor when it was delivered in PEG vehicle than when it was given in cremophor-EL. In contrast, there was a 3-fold greater amount of O6-benzylguanine in the small intestine of mice at 1 h after i.p. injection of the drug in cremophor-EL as compared with PEG 400. The rate and extent of metabolism in the liver was the same, whether the parent drug was given in PEG 400 or in cremophor-EL. These studies demonstrate that O6-benzylguanine is a more effective enhancer of the antitumor activity of BCNU when it is given in PEG 400 than when it is delivered in cremophor-EL, which may be due to a more rapid distribution of the drug to the tumor.
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PMID:Biodistribution of O6-benzylguanine and its effectiveness against human brain tumor xenografts when given in polyethylene glycol or cremophor-EL. 798 87

We investigated the role of radiation-induced mitogen activated protein kinase (MAPK) pathway activity in the regulation of proliferation, cell survival and vascular endothelial growth factor (VEGF) production in primary astrocytes and in T9 and RT2 glioblastoma cells derived from Fisher 344 rats. In these cells, ionizing radiation (2 Gy) caused activation of the MAPK pathway which was blocked by specific inhibitor drugs. Blunting of radiation-induced MAPK activity weakly enhanced radiation-induced apoptosis 24 h after exposure in RT2 cells. Furthermore, blunting of MAPK activation weakly enhanced the ability of radiation to reduce RT2 cell growth in clonogenic growth assays. These findings argue that inhibition of MAPK signaling reduces proliferation and enhances cell killing by ionizing radiation in transformed astrocytes. Proliferation and survival of cancer cells has been linked in vivo to enhanced expression of angiogenic growth factors. Recently we demonstrated that the gene product of a novel rodent radiation-responsive gene, progression elevated gene 3 (PEG-3), could enhance vascular endothelial growth factor (VEGF) promoter activity in rodent fibroblasts, leading to increased VEGF protein levels and tumorigenic behavior in vivo. Thus PEG-3 and VEGF expression could be expected to directly correlate with the oncogenic potential of transformed cells. RT2 cells expressed more PEG-3 and VEGF protein than T9 cells, and were more tumorigenic in vivo than T9 cells. Radiation activated the PEG-3 promoter via MAPK signaling and ectopic over-expression of PEG-3 enhanced both basal MAPK activity and basal VEGF promoter activity. Basal MAPK activity partially correlated with basal VEGF promoter activity and VEGF protein levels in primary astrocytes, T9 and RT2 cells. Radiation increased the activity of the VEGF promoter and VEGF protein levels in primary astrocytes, T9 and RT2 cells which were dependent upon MAPK function. Furthermore, inhibition of AP-1 transcription factor signaling by dominant negative c-Jun (TAM67) also significantly reduced basal, and to a lesser extent radiation-induced, VEGF promoter function in RT2 cells. Collectively, our data demonstrate that radiation-induced MAPK signaling can both protect cells from radiation-induced cell death as well as enhance protein levels of pro-angiogenic factors such as VEGF. Enhanced VEGF expression in RT2 cells may be mediated via MAPK and JNK pathway signaling which converges upon the AP-1 transcription factor complex.
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PMID:Ionizing radiation modulates vascular endothelial growth factor (VEGF) expression through multiple mitogen activated protein kinase dependent pathways. 1142 76

The objective of this study was to evaluate a poly(DL-lactic-co-glycolic acid)/poly(ethylene glycol) (PLGA/PEG) delivery system for nuclear factor-kappa B (NFkappaB) decoy phosphorothioated oligonucleotides (ODNs). PLGA/PEG microparticles loaded with ODNs were fabricated with entrapment efficiencies up to 70%. The effects of PEG contents (0, 5, and l0 wt%), ODN loading densities (0.4, 4, and 40 microg/mg), and pH of the incubation medium (pH 5, 7.4. and 10) on ODN release kinetics from the PLGA/PEG microparticles were investigated in vitro for up to 28 days. The release profiles in pH 7.4 phosphate buffered saline (PBS) were characterized by an initial burst during the first 2 days, a linear release phase until day 18, and a final release phase for the rest of the period. Up to 85% of the ODNs were released after 28 days in pH 7.4 PBS regardless of the ODN loading density and PEG content. Higher ODN loading densities resulted in lower entrapment efficiencies and greater initial burst effects. The bulk degradation of PLGA was not significantly affected by the PEG content and ODN loading density, but significantly accelerated at acidic buffer pH. Under acidic and basic conditions, the aggregation of microparticles resulted in significantly lower cumulative mass of released ODNs than that released at neutral pH. The effects of pH were reduced by the incorporation of PEG into PLGA microparticles. Since the PLGA degradation products are acidic, PLGA/PEG microparticles might provide a better ODN delivery vehicle than PLGA microparticles. These results suggest that PLGA/PEG microparticles are useful as delivery vehicles for controlled release of ODNs and merit further investigation in cell culture and animal models of glioblastoma.
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PMID:Controlled release of NFkappaB decoy oligonucleotides from biodegradable polymer microparticles. 1205 17

Tumor growth and metastasis are angiogenesis dependent. Overexpression of integrin alphavbeta3 in angiogenic vessels as well as various malignant human tumors suggests the potential of suitably labeled antagonists of this adhesion receptor for radionuclide imaging and therapy of tumors. Small head-to-tail cyclic peptides including the Arg-Gly-Asp (RGD) amino acid sequence have been radiolabeled and studied in preclinical animal models. However, the fast blood clearance, high kidney and liver uptake, and rapid washout from tumors make this type of tracer ineffective for clinical applications. In this study we modified the cyclic pentapeptide c(RGDyK) with monofunctional methoxy-PEG (mPEG, M.W. = 2,000) and labeled the RGD-mPEG conjugate with 125I. We studied the tumor targeting efficacy and in vivo pharmacokinetic properties of 125I-RGD-mPEG by means of direct tissue sampling and autoradiography in mice xenografted subcutaneously with U87MG glioblastoma. Compared to the 125I-RGD analog, this PEGylated RGD peptide revealed faster blood clearance, lower kidney uptake, and prolonged tumor uptake without compromising the receptor targeting ability.
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PMID:Pharmacokinetics and tumor retention of 125I-labeled RGD peptide are improved by PEGylation. 1474 66

We have previously labeled cyclic RGD peptide c(RGDyK) with fluorine-18 through conjugation labeling via a prosthetic 4-[18F]fluorobenzoyl moiety and applied this [18F]FB-RGD radiotracer for alphav-integrin expression imaging in different preclinical tumor models with good tumor-to-background contrast. However, the unfavorable hepatobiliary excretion and rapid tumor washout rate of this tracer limit its potential clinical applications. The aims of this study were to modify the [18F]FB-RGD tracer by inserting a heterobifunctional poly(ethylene glycol) (PEG, M.W. =3,400) between the 18F radiolabel and the RGD moiety and to test this [18F]FB-PEG-RGD tracer for brain tumor targeting and in vivo kinetics. [18F]FB-PEG-RGD was prepared by coupling the RGD-PEG conjugate with N-succinimidyl 4-[18F]fluorobenzoate ([18F]SFB) under slightly basic conditions (pH=8.5). The radiochemical yield was about 20-30% based on the active ester [18F]SFB, and specific activity was over 100 GBq/micromol. This tracer had fast blood clearance, rapid and high tumor uptake in the subcutaneous U87MG glioblastoma model (5.2+/-0.5%ID/g at 30 min p.i.). Moderately rapid tumor washout was observed, with the activity accumulation decreased to 2.2+/-0.4%ID/g at 4 h p.i. MicroPET and autoradiography imaging showed a very high tumor-to-background ratio and limited activity accumulation in the liver, kidneys and intestinal tracts. U87MG tumor implanted into the mouse forebrain was well visualized with [18F]FB-PEG-RGD. Although uptake in the orthotopic tumor was significantly lower (P<0.01) than in the subcutaneous tumor, the maximum tumor-to-brain ratio still reached 5.0+/-0.6 due to low normal brain background. The results of H&E staining post mortem agreed with the anatomical information obtained from non-invasive microPET imaging. In conclusion, PEGylation suitably modifies the physiological behavior of the RGD peptide. [18F]FB-PEG-RGD gave improved tumor retention and in vivo kinetics compared with [18F]FB-RGD.
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PMID:MicroPET imaging of brain tumor angiogenesis with 18F-labeled PEGylated RGD peptide. 1511 44

Glioblastomas are highly vascularized tumors and anti-angiogenic strategy is one of the most promising therapeutic approaches to treat brain tumors. Interferon alpha (IFN-alpha) as a single agent or combined with standard chemo-therapy has been shown to inhibit various tumors, but the effect of combination anti-angiogenic therapy on brain tumors has not been well studied. We determined the optimal dose and schedule of pegylated IFN-alpha (PEG-IFN-alpha) against U-87MG human glioblastoma cells growing orthotopically in nude mice, since several clinical trials reported that PEG-IFN-alpha administered at higher or lower doses was less effective. The group treated two times per week with injections of 10 KU of PEG-IFN-alpha for 4 weeks showed significant decreases in cell proliferation and angiogenesis. Moreover, the optimal dose and schedule of PEG-IFN-alpha determined in this study and combined with paclitaxel treatment potently inhibited tumor growth in vivo. The mechanisms of the significant therapeutic effects were most likely caused by directly inhibiting cell proliferation and angiogenesis, and rendering apoptosis increased. Specifically PEG-IFN-alpha/paclitaxel combination induced apoptosis of tumor-associated endothelial cells more than that of tumor cells. These results suggest that optimal biological dosage and scheduling of PEG-IFN-alpha and paclitaxel combination is a potent strategy for glioblastoma patients as a new synergistic anti-endothelial treatment.
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PMID:Synergistic effect and condition of pegylated interferon alpha with paclitaxel on glioblastoma. 1668 40

A novel method for synthesis of anti-EGFR immunoliposomes using folate-folate binding protein (FBP) affinity is described. An anti-EGFR antibody (cetuximab or C225) was covalently linked to FBP via a thioether bond. Liposomes incorporating a lipophilic folate derivative (folate-PEG-cholesterol) were prepared by polycarbonate membrane extrusion. Anti-EGFR immunoliposomes were then obtained by combining FBP-C225 and folate-liposomes and evaluated for uptake and cytotoxicity in EGFR-overexpressing U87 human glioblastoma cells. Anti-EGFR immunoliposomes constructed via folate-FBP affinity exhibited excellent stability under physiological pH, and quickly released the bound FBP-C225 upon low pH (pH 3.5) treatment. Flow cytometry and fluorescence microscopy showed similar receptor-specific binding and internalization for both folate-FBP affinity-coupled and covalently coupled C225-immunoliposomes, but not for the non-targeted IgG-immunoliposomes. C225-immunoliposomes loaded with anticancer drug doxorubicin were more cytotoxic than non-targeted immunoliposomes in EGFR-overexpressing U87 glioma cells. Folate-FBP affinity is a potential method for construction of immunoliposomes and may have applications in synthesis of targeted drug carriers in general.
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PMID:Construction of anti-EGFR immunoliposomes via folate-folate binding protein affinity. 1721 81

The cell adhesion molecule integrin alpha vbeta 3 plays a key role in tumor angiogenesis and metastasis. A series of (18)F-labeled RGD peptides have been developed for PET of integrin expression based on primary amine reactive prosthetic groups. In this study, we report the use of the Cu(I)-catalyzed Huisgen cycloaddition, also known as a click reaction, to label RGD peptides with (18)F by forming 1,2,3-triazoles. Nucleophilic fluorination of a toluenesulfonic alkyne provided (18)F-alkyne in high yield (nondecay-corrected yield: 65.0 +/- 1.9%, starting from the azeotropically dried (18)F-fluoride), which was then reacted with an RGD azide (nondecay-corrected yield: 52.0 +/- 8.3% within 45 min including HPLC purification). The (18)F-labeled peptide was subjected to microPET studies in murine xenograft models. Murine microPET experiments showed good tumor uptake (2.1 +/- 0.4%ID/g at 1 h postinjection (p.i.)) with rapid renal and hepatic clearance of (18)F-fluoro-PEG-triazoles-RGD 2 ( (18)F-FPTA-RGD2) in a subcutaneous U87MG glioblastoma xenograft model (kidney 2.7 +/- 0.8%ID/g; liver 1.9 +/- 0.4%ID/g at 1 h p.i.). Metabolic stability of the newly synthesized tracer was also analyzed (intact tracer ranging from 75% to 99% at 1 h p.i.). In brief, the new tracer (18)F-FPTA-RGD2 was synthesized with high radiochemical yield and high specific activity. This tracer exhibited good tumor-targeting efficacy and relatively good metabolic stability, as well as favorable in vivo pharmacokinetics. This new (18)F labeling method based on click reaction may also be useful for radiolabeling of other biomolecules with azide groups in high yield.
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PMID:Click chemistry for (18)F-labeling of RGD peptides and microPET imaging of tumor integrin alphavbeta3 expression. 1803 Sep 91

Effective targeting of drugs to cells requires that the drug reach the target cell and interact specifically with it. In this study, we synthesized a biomacromolecular, multivalent construct intended to target glioblastoma tumors. The construct was created by linking three dodecapeptides, reported to bind the alpha 6beta1 integrin, with poly(ethylene glycol) linkers. The construct is intended to be delivered locally, and it demonstrates a more homogeneous and more rapid perfusion profile in comparison with quantum dots. The binding specificity of the construct was investigated by using glioblastoma cells and normal human astrocyte cells. The results reveal qualitative differences in binding between glioma and normal human astrocyte cells, with a moderate increase in binding avidity due to multivalency (0.79 microM for the trivalent construct versus 4.28 microM for the dodecapeptide). Overall, biomacromolecular constructs appear to be a promising approach for targeting with high biocompatibility, good perfusion abilities, and specificity.
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PMID:Specificity and mobility of biomacromolecular, multivalent constructs for cellular targeting. 1803 7


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