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)

Human brain gliomas overexpress the receptor for epidermal growth factor (EGF), and radiolabeled EGF is a potential peptide radiopharmaceutical for imaging human brain tumors, should this peptide be made transportable through the blood-brain barrier (BBB) in vivo. Peptide drug delivery to the brain may be facilitated by conjugating peptide radiopharmaceuticals to BBB drug delivery vectors such as the OX26 monoclonal antibody (MAb), which undergoes receptor-mediated transcytosis through the BBB via the brain capillary endothelial transferrin receptor. EGF was biotinylated with NHS-XX-biotin, where NHS = N-hydroxysuccinimide and -XX- = bis (aminohexanoyl) spacer arm. The [125I]EGF-XX-biotin rapidly bound to C6 rat glioma cells transfected with the human EGF receptor. However, no binding to the C6 EGF receptor was detected when the [125I]EGF-XX-biotin was bound to a conjugate of streptavidin (SA) and the OX26 MAb. An alternative linker strategy using poly(ethylene glycol) (PEG) of 3400 Da molecular mass (PEG3400) was evaluated, wherein EGF was monobiotinylated with NHS-PEG3400-biotin. Attachment of the [125I]EGF-PEG3400-biotin to the OX26/SA conjugate did not impair binding of the construct to the EGF receptor in C6 glioma cells. The length of the -PEG- spacer arm and the -XX- spacer arm was >200 atoms and 14 atoms, respectively. These studies demonstrate that the use of the extended PEG linker releases steric hindrance of MAb transport vectors on binding of EGF to its cognate receptor on glioma cells. Attachment of EGF peptide radiopharmaceuticals to BBB drug delivery systems such as the OX26 MAb using extended PEG linkers allows for retention of the bifunctionality of the conjugate with binding to both EGF and transferrin receptors.
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PMID:Retention of biologic activity of human epidermal growth factor following conjugation to a blood-brain barrier drug delivery vector via an extended poly(ethylene glycol) linker. 989 61

Protein kinase C (PKC) designates a family of kinases that regulate many essential functions including cell growth and differentiation. The tight regulation of PKC activity is crucial for maintaining normal cellular proliferation and excessive activity leads to abnormal or uncontrolled cell growth. Recent reports indicate that malignant glioma cell lines express 100 to 1000-fold higher PKC activity when compared to non-neoplastic astrocytes. This high activity correlates well with the proliferation of tumor cells in vitro. We recently reported on the anti-proliferative properties of selective PKC inhibitors on the growth of U-373MG human astrocytoma cell line, and their ability to block mitogen-activated protein (MAP) kinase pathway activated by substance P (SP) neuropeptide receptor signaling via a PKC-dependent mechanism. Therefore, inhibiting PKC activity by selective PKC inhibitors may present a promising approach for improving astroglial brain tumor therapy. For this purpose, we constructed a high throughput model cell system to evaluate the efficacy of PKC inhibitors. This system is based on the measurement of light production in U-373MG cells stably transfected with the luciferase reporter gene whose expression depends on the transcriptional activation of GAL4-Elk1 fusion protein by enzyme components of the MAP kinase pathway and the upstream activation of PKC (PKC activation-->MAP kinases-->GAL4-Elk1 phosphorylation-->luciferase expression-->luciferase activity). In brief, we have demonstrated that the PKC activator 12-O-tetradecanoyl phorbol 13-acetate (TPA)-induced luciferase activity in this cell system is mediated via the MAP kinase pathway and can be blocked in the presence of MEK1 selective inhibitors (PD 098059 or U0126). We also demonstrated that TPA-induced luciferase activity in U-373MG stable clones can be blocked by PKC inhibitors (CGP 41251, Go 6976, and GF 109203X) in a concentration dependent manner. In contrast, epidermal growth factor (EGF)-induced luciferase activity, which is independent of PKC activation (Ras-->Raf-1-->MEK1-->MAP kinases-->GAL4-Elk1 phosphorylation-->luciferase expression-->luciferase activity) can only be blocked using a selective EGF receptor inhibitor (AG 1478). In conclusion, we have constructed a model cell system for the high throughput screening and identification of PKC inhibitors potentially active against astrocytoma cells in culture.
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PMID:A high throughput system for the evaluation of protein kinase C inhibitors based on Elk1 transcriptional activation in human astrocytoma cells. 991 10

Bispecific antibodies (bsAbs) directed to tumor-associated antigens and to receptors mediating T-cell activation, such as the TCR/CD3 complex and the co-stimulatory CD28 molecule, are capable of activating T cells at the surface of tumor cells, resulting in tumor-cell killing. Here we report the pre-clinical characterization of bispecific-antibody fragments (bsFab2) directed to 2 different glioblastoma-associated antigens: the EGF receptor (EGFR) and a chondroitin-sulfate proteoglycan (CSPG). Using cultured glioblastoma cells expressing both target antigens, we found that the ability of anti-tumor x anti-CD28 bsFab2 to mediate "targeted T-cell co-stimulation" is superior for constructs targeting the CSPG molecule, correlating with an approximately 6-fold higher expression level of this antigen on the cell surface. In contrast, bsFab2 triggering CD3 are more effective if they contain EGFR-target specificity. This indicates that the activity of anti-tumor x anti-CD3 constructs critically depends on properties of the antigen other than its expression level on the cell surface, e.g., its mobility in the membrane. These findings prompted us to use EGFR-targeting bsFab2 in an ongoing clinical trial with glioma patients.
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PMID:Role of target antigen in bispecific-antibody-mediated killing of human glioblastoma cells: a pre-clinical study. 993 65

Epidermal growth factor (EGF) is a potential peptide radiopharmaceutical for detection of brain tumors, because many human gliomas overexpress the EGF receptor (EGFR). The transport of EGF to the brain, however, is restricted by the blood-brain barrier (BBB). The purpose of the present study was to develop a vector-mediated brain delivery system for radiolabeled EGF. Human EGF was monobiotinylated with NHS-PEG3400-biotin, where NHS is N-hydroxysuccinimide and PEG3400 is poly(ethylene glycol) of 3400 Da molecular mass. EGF-PEG3400-biotin was radiolabeled with either 125I or 111In through the metal chelator, diethylenetriaminepentaacetic acid (DTPA). The radiolabeled EGF was then conjugated to a BBB delivery vector comprised of a complex of the OX26 monoclonal antibody (MAb) to the rat transferrin receptor, which was coupled to streptavidin (SA). Following intravenous injection in rats, the 125I conjugate was rapidly degraded in vivo, while the 111In conjugate was metabolically stable. The brain delivery of [111In]DTPA-EGF-PEG3400-biotin was enabled by conjugation with OX26/SA and was optimized by co-injection of unlabeled EGF to saturate EGF receptors in the liver. The specific binding of the [111In]DTPA-EGF-PEG3400-biotin conjugated to OX26/SA to the EGF receptor was confirmed in C6 rat glioma cells, which had been transfected with a gene encoding for the human EGF receptor under the regulation of a dexamethasone-inducible promoter. In vivo studies of C6-EGFR experimental tumors in Fischer 344 rats demonstrated successful brain imaging only when the peptide radiopharmaceutical was conjugated to the BBB delivery system, although the C6-EGFR tumors did not express EGFR in vivo. In conclusion, these studies describe the molecular formulation of a peptide radiopharmaceutical that can be used for imaging brain tumors behind the BBB.
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PMID:Epidermal growth factor radiopharmaceuticals: 111In chelation, conjugation to a blood-brain barrier delivery vector via a biotin-polyethylene linker, pharmacokinetics, and in vivo imaging of experimental brain tumors. 1034 84

Leflunomide, a novel immunomodulatory drug, has two biochemical activities: inhibition of tyrosine phosphorylation and inhibition of pyrimidine nucleotide synthesis. In the present study, we first showed that A77 1726 [N-(4-trifluoromethylphenyl-2-cyano-3-hydroxycrotoamide)], the active metabolite of leflunomide, was more effective at inhibiting the tyrosine kinase activity of platelet-derived growth factor (PDGF) receptor than that of epidermal growth factor (EGF) receptor, and had no effect on the tyrosine kinase activity of the fibroblast growth factor receptor. In the presence of exogenous uridine, A77 1726 was more effective at inhibiting the PDGF-stimulated proliferation of PDGF receptor-overexpressing C6 glioma than the EGF-stimulated proliferation of EGF receptor-overexpressing A431 cells. In vivo studies demonstrated that leflunomide treatment strongly inhibited the growth of the C6 glioma but had only a modest effect on the growth of the A431 tumor. Uridine co-administered with leflunomide did not reverse the antitumor activity of leflunomide on C6 and A431 tumors significantly. Quantitation of nucleotide levels in the tumor tissue revealed that leflunomide treatment significantly reduced pyrimidine nucleotide levels in the fast-growing C6 glioma but had no effect on the relatively slow-growing A431 tumor. Whereas uridine co-administration normalized pyrimidine nucleotide levels, it had minimal effects on the antitumor activity of leflunomide in both tumor models. Immunohistochemical analysis revealed that leflunomide treatment significantly reduced the number of proliferating cell nuclear antigen-positive cells in C6 glioma, and that uridine only partially reversed this inhibition. These results collectively suggest that the in vivo antitumor effect of leflunomide is largely independent of its inhibitory effect on pyrimidine nucleotide synthesis. The possibility that leflunomide exerts its antitumor activity by inhibition of tyrosine phosphorylation or by a yet unidentified mode of action is discussed.
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PMID:In vitro and in vivo antitumor activity of a novel immunomodulatory drug, leflunomide: mechanisms of action. 1051 84

VEGF (vascular endothelial growth factor), one of the most potent angiogenic factors, has recently been identified as an inducer of neoangiogenesis in many tumors including gliomas. VEGF itself appears to be regulated through different pathways. Since malignant gliomas frequently show EGF receptor amplification and express IL-1, a pivotal regulatory cytokine involved in angiogenesis, we analyzed interactions between EGF/EGF receptor and IL-1/IL-1 receptor and VEGF in the established glioblastoma cell lines U-87 MG and A-172. Basal VEGF expression was an order of magnitude higher in U-87 MG compared to A-172. IL-1 caused a fast and strong increase of VEGF secretion in U-87 MG which appeared to harbor an intracellular VEGF pool for enhanced exocytosis. The IL-1 receptor antagonist (IL-1-ra) reversed this effect suggesting an IL-1 receptor-associated mechanism. In contrast, VEGF secretion could not be increased by exogenous IL-1 exposure in A-172, which apparently lacked an intracellular VEGF pool for augmented exocytosis. However, IL-1-ra treatment alone caused a significant reduction of basal VEGF secretion in both U-87 MG and A-172. This suggests that baseline secretion of VEGF involves IL-1 receptor activation by endogenously produced IL-1. EGF also stimulated the secretion of VEGF into the cell supernatant. However, this effect, observed in both U-87 MG and A-172, was delayed and only occurred following replenishment of the intracellular VEGF pool. EGF upregulated the amount of VEGF mRNA. In general, the effects of IL-1 and EGF on VEGF were additive, suggesting independent mechanisms. Since IL-1 appears to be involved in VEGF secretion in glial tumors through an autocrine/paracrine mechanism, recombinant human IL-1-ra may evolve as a new agent for anti-angiogenic glioma therapy.
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PMID:Differential control of VEGF synthesis and secretion in human glioma cells by IL-1 and EGF. 1057 18

Present day imaging of brain tumors requires a disrupted blood-brain barrier (BBB). However, the BBB is intact in the early stages of brain tumor growth, when diagnosis is most critical. Relative to normal brain, brain tumor cells frequently overexpress peptide receptors, such as the receptor for epidermal growth factor (EGF). Peptide radiopharmaceuticals such as radiolabeled EGF could be used to image early brain tumors, should these radiopharmaceuticals be made transportable through the BBB. The present studies describe a bifunctional molecule that contains both biologically active human EGF radiolabeled with 111In and an anti-transferrin receptor monoclonal antibody that undergoes transcytosis through the BBB via the endogenous transferrin transport system. The two domains of the bifunctional conjugate are separated by a Mr 3400 polyethyleneglycol linker, which releases steric hindrance and allows the conjugate to bind to both the EGF receptor, to image the brain tumor, and to the transferrin receptor, to enable transport through the BBB. Successful imaging of experimental brain tumors with this system is demonstrated in nude rats bearing cerebral implants of human U87 glioma.
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PMID:Imaging brain tumors by targeting peptide radiopharmaceuticals through the blood-brain barrier. 1062 7

We have previously documented that the vast majority of high-grade gliomas over-express binding sites for interleukin 13 (IL13) in situ. We now extend this analysis to evaluate the distribution of the binding of IL13 among other brain tumors. Tumor specimens from patients with low-grade gliomas, oligodendrogliomas, ependymomas, pilocytic astrocytomas, gliosarcomas, medulloblastomas, meningiomas, and metastases to the brain were analyzed and compared to a new series of glioblastoma multiforme (GBM) samples. Serial tumor tissue sections were incubated with 125I-labeled (i) IL13, (ii) antibody against transferrin (Tf) receptor, and (iii) epidermal growth factor (EGF). Most (17/18) GBMs stained specifically for IL13 binding sites while sections from 3/11 low-grade gliomas, 5/5 high-grade gliomas (grade III), 3/5 oligodendrogliomas (all three were anaplastic), and 1/2 gliosarcomas also showed specific binding for IL13. We did not detect IL13 binding sites in medulloblastomas (0/4) and found them only in 2/20 meningiomas. Metastases to the brain (4/12, i.e., lung adenocarcinomas and renal cell carcinoma) showed some binding of 125I-IL13. The presence of receptors for Tf was ubiquitous among all studied tumors while EGF receptor expression was much more variable. Since it appears that primarily the least differentiated forms of gliomas possess IL13 binding sites in abundance, it is plausible that IL 13 receptor expressed in low-grade gliomas might be a prognostically significant marker associated with their progression to high-grade gliomas. Finally, we demonstrate that the glioma-associated IL13 receptor is truly more restrictive in nature also due to its selective representation among brain tumors of glial origin.
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PMID:Expression of a restrictive receptor for interleukin 13 is associated with glial transformation. 1108 73

After adoptive transfer of pre-activated lymphocytes into the operation cavity of glioma patients, tumor regression and improved survival have been reported in some patients. Results were most impressive when bispecific antibodies with tumor x CD3 specificity were also applied. In this study, we attempted to avoid time-consuming pre-activation procedures for adoptively transferred cells by using a combination of bispecific antibodies directed to the EGF receptor (EGFR) on tumor cells and to CD3 and CD28 on T cells. Eleven patients with high-grade malignant glioma received 3 injections of 2 bispecific antibody fragments (EGFR x CD3 and EGFR x CD28) together with freshly isolated autologous lymphocytes via an Ommaya reservoir. Intracavitary fluid aspirated during immunotherapy was examined for markers of T-cell activation. Increased levels of soluble IL-2 receptor and TNF-alpha were detected in the intracavitary fluid of all patients tested. Two of the 11 treated patients experienced a beneficial response to therapy as defined by a transient contrast enhancement in subsequent MRI scans and prolonged survival. Side effects were transient and consisted of fever, nausea, headache and aggravation of pre-existing neurologic deficits. These adverse effects were most likely due to the antibody construct containing anti-CD3 specificity. Two patients developed cerebral edema and required steroid treatment.
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PMID:Local immunotherapy of glioma patients with a combination of 2 bispecific antibody fragments and resting autologous lymphocytes: evidence for in situ t-cell activation and therapeutic efficacy. 1114 49

Amplification and/or mutations of the epidermal growth factor (EGF) receptor have been frequently reported in human malignant gliomas, the most common primary tumor of the adult central nervous system. We have analyzed a panel of established human glioma cell lines for EGF receptor expression. The EGF receptor was expressed in all of the glioma cell lines tested, with highest levels found in the cell line U343MG-a. In addition, various amounts of a truncated form of the EGF receptor were detected. The platelet-derived growth factor (PDGF) alpha receptor, analyzed for comparison, was expressed at low levels in human glioma cells, with the exception of U-118MG and U-373MG cells. The truncated form of the EGF receptor has been discussed as a constitutively active variant of the receptor. Using antibodies directed against the active form of the EGF receptor, we show here that the truncated variant of the EGF receptor in U343MG-a cells is not in the active conformation. However, the full-length EGF receptor, highly expressed in U343MG-a cells, was very rapidly activated following EGF treatment. In line with this, phosphorylation and activation of the mitogen-activated protein kinase/extracellular signal-regulated protein kinase (ERK) in U343MG-a cells required administration of EGF. Moreover, using highly specific riboprobes we observed that EGF signaling increased the Egr-1 mRNA concentration in human glioma cells within 30 min. The increase in the Egr-1 mRNA concentration was followed by a transient synthesis of the Egr-1 protein. Likewise, Egr-1 mRNA and protein concentrations were increased in U-118MG and U-373MG cells treated with PDGF. The synthesis of Egr-1 in human glioma cells as a result of EGF or PDGF stimulation indicates that Egr-1 may be an important "late" part of the EGF and PDGF-initiated signaling cascades suggesting that Egr-1 functions as a "third messenger" in glioma cells connecting growth factor stimulation with changes in gene transcription.
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PMID:Epidermal growth factor and platelet-derived growth factor induce expression of Egr-1, a zinc finger transcription factor, in human malignant glioma cells. 1153 37


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