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)

Epidermal growth factor, EGF, and 131I or 125I-labelled tyrosine were conjugated to the sugar polymer dextran. The conjugates bound to EGF-receptor rich human glioma cells in culture and the binding was mainly receptor specific because cells presaturated with nonradioactive EGF gave strongly reduced binding. The 131I labelled conjugates were used in tests on cellular retention and therapeutical effects. 131I activity delivered to the cells as EGF-dextran-tyrosine-131I remained cell-associated for much longer periods of time than 131I activity delivered by only EGF. The amount of cell-associated 131I activity was nearly constant for up to 25 hours. The 131I labelled conjugate gave, after a one hour incubation period for binding followed by a 25 hour incubation in nonradioactive medium, a good therapeutical effect. This effect, which corresponded to about 3.0 Gy of external 60Co radiation, was due to the specifically bound 131I. The comparatively small effects of nonbound 131I in the culture medium, present only during the first incubation hour, were measured in control experiments with presaturated receptors and were corrected for in the evaluation of the EGF-receptor mediated effects. Control experiments showed that neither nonradioactive EGF nor non-radioactive EGF-dextran conjugates gave measurable effects on clonogenic growth. The results obtained were promising and the possibilities to use EGF-dextran conjugates for therapy should be further examined.
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PMID:Effects of EGF-dextran-tyrosine-131I conjugates on the clonogenic survival of cultured glioma cells. 128 Dec 25

The proliferation rates of gliomas may be modulated by the protein kinase C (PKC) signal transduction system. The present study was undertaken to further examine the role of PKC system in growth regulation of gliomas in vitro by measurement of PKC activity over various phases of tumor growth and by assessing its potential role as a signal transduction system induced by serum mitogens and the known glioma mitogens epidermal growth factor and fibroblast growth factor. All human glioma lines examined, and the rat glioma C6, displayed high PKC activity relative to nonmalignant glial cells, which correlated with their proliferation rates over their respective growth phase. Frozen surgical human malignant glioma specimens also displayed high PKC activity. The relatively selective PKC inhibitor staurosporine (SP) reduced PKC activity and corresponding growth rates in a dose-related manner. Stimulation of PKC with phorbol esters under different concentrations of serum in the growth medium indicated that the high PKC activity, which correlated with their rapid growth rates, is highly susceptible to down-regulation by these agents. Epidermal growth factor and fibroblast growth factor increased both PKC activity and the growth rate of glioma line A172; addition of SP reduced the growth rate to levels observed in SP-treated control tumors, indicating that PKC may be a common signal transduction system induced by these mitogens. These results implicate PKC as an important signal transduction system regulating glioma growth, and offers a potential target for tumor inhibition.
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PMID:Protein kinase C activity correlates with the growth rate of malignant gliomas: Part II. Effects of glioma mitogens and modulators of protein kinase C. 140 58

Epidermal growth factor (EGF) has been shown to stimulate DNA synthesis and cell division in normal glia. At least half of malignant human gliomas (MHG) express high levels of the EGF receptor (EGFR), which are above those detected in normal brain. The demonstration that antibodies against the EGFR inhibit the growth of squamous cell carcinoma line A-431, with large numbers of EGFR, in vitro and in vivo raises the possibility that these agents could be used therapeutically against malignant human gliomas either alone or conjugated to other agents. We have measured the growth effects of EGF and an anti-EGFR monoclonal antibody, 528 (Ab-528), on four well-characterized human malignant glioma cell lines, D-263 MG, D-247 MG, U-343 MGa Cl 2:6, and D-37 MG, with 2.9 x 10(4), 1.5 x 10(5), 8.6 x 10(5) and 1.59 x 10(6) EGFRs per cell, respectively. EGF significantly increased cell number in D-263 MG and D-37 MG by 65% and 74%, respectively, had no effect on D-247 MG, and significantly decreased cell number in U-343 MGa Cl 2:6 by 39%. U-343 MGa Cl 2:6 growth was inhibited 19% by Ab-528, but Ab-528 had no effect on growth of the other MHG lines. Ab-528 significantly inhibited all EGF-mediated growth effects. These studies demonstrate that, although Ab-528 alone has little antiproliferative activity on MHG, it successfully competes with EGF to reduce the biological effects of EGF-EGFR binding. Therefore, this antibody could potentially be used to target radioisotopes to MHG via the EGFR for diagnosis and therapy.
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PMID:Growth effects of epidermal growth factor (EGF) and a monoclonal antibody against the EGF receptor on four glioma cell lines. 326 34

Specific and recurring chromosomal and genetic alterations have been identified in gliomas and could described a model of tumoral progression from benin glioma to glioblastoma multiforme. However, the heterogeneity of profiles of molecular alterations that have been observed in gliomas seems to reflect the variety of clinical evolutions which characterise those tumors. Loss of genetic material on chromosomes 17, 9 and 19, then of chromosome 10 have been associated to pathogenesis of glioma and a pejorative prognostic value have been attributed to the alteration of chromosome 10. Gliomas also express growth factors and growth factors receptors that may be important in promoting tumor growth, like Epidermal growth factor (EGF), fibroblast growth factors (FGF) and vascular endothelial growth factor (VEGF). Tumoral invasion which characterise also gliomas, may involve proteases like plasminogen activators (PA) and metalloproteases, under the regulation of specific receptors and inhibitors. PA inhibitor type 1 (PAI1), associated to the most aggressive form of gliomas, may also participate to tumoral neoangiogenesis. Description and understanding of these alterations may contribute to develop new treatment modalities in gliomas.
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PMID:[Biological profiles of malignant gliomas]. 767 50

Epidermal growth factor (EGF) content in urine from patients with glial tumors was examined by radioimmunoassay techniques with labeled human EGF and its rabbit EGF polyclonal antibody. There was no cross-reaction with transforming growth factor-alpha, which has a common receptor with EGF. Forty glial tumors were divided into three groups according to the clinical stage: Samples from Group A patients were obtained before therapy and/or after biopsy; in these patients a large volume of tumor was apparent on computerized tomography (CT). Group B samples were obtained after gross total removal of the tumor and/or chemo- and radiation therapy; these patients showed a small volume of residual tumor on CT. Samples from Group C patients were obtained after gross tumor total removal and/or chemo- and radiation therapy; no tumor was detected on CT scans in these patients. Urinary EGF levels in Group A samples were statistically significantly higher than in samples from healthy individuals (p < 0.001), Group B patients (p < 0.10), and Group C patients (p < 0.02). In addition, high-grade glial tumors in Group A cases showed a significantly higher level of urinary EGF than low-grade tumors in Group A patients (p < 0.05), or patients with meningioma (p < 0.02), metastatic brain tumor (p < 0.05), and cerebral infarction (p < 0.001). Longitudinal changes of urinary EGF levels in glioma patients mostly synchronized with the clinical course and therapeutic interventions. Therefore, urinary EGF, as a glial tumor marker, may be of practical value for diagnosing a malignant glioma and evaluating for the efficacy of chemo- and radiation therapy.
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PMID:Urinary epidermal growth factor in patients with gliomas: significance of the factor as a glial tumor marker. 836 Jul 38

Epidermal growth factor (EGF) and platelet-derived growth (PDGF) are suggested to be involved in the proliferation of human gliomas. We examined the effects of these growth factors on two human malignant glioma cell lines. Treatment of the A172 glioblastoma and the Hs683 glioma cell line with EGF and PDGF resulted in the tyrosine autophosphorylation, and hence activation, of the respective growth factor receptors. In addition, both cell lines responded to EGF and PDGF with increased deoxyribonucleic acid (DNA) synthesis. Because the intrinsic protein tyrosine kinase activity of this class of growth factor receptors is indispensable for their functioning, we tested the effects of specific protein tyrosine kinase inhibitors on growth factor-induced DNA synthesis and glioma cell proliferation. Genistein inhibited both EGF- and PDGF-stimulated autophosphorylation of the receptors and induction of DNA synthesis. However, genistein seemed to be cytotoxic to the cells. The tyrphostins RG 50875 and RG 13022 dose-dependently inhibited DNA synthesis induced by EGF, PDGF, and serum. RG 13022 completely blocked the EGF- and PDGF-induced DNA synthesis at a concentration of 50 mumol/L. The tyrphostins showed no selectivity in blocking either EGF or PDGF signaling. With concentrations up to mumol/L, no cytotoxic side effects of the tyrphostins were observed. Both tyrphostins also inhibit serum-driven cell growth in a dose-dependent manner. These results support the hypothesis that activated protein tyrosine kinase receptors are involved in the proliferation of A172 and Hs683 glioma cells. Selective inhibitors of protein tyrosine kinases, therefore, might have the potential to contribute to the treatment of growth factor-dependent gliomas.
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PMID:Inhibitors of protein tyrosine phosphorylation reduce the proliferation of two human glioma cell lines. 874 58

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

Epidermal growth factor (EGF) receptor (EGFR) is commonly amplified and/or mutated in high-grade gliomas. Abnormal signaling from this receptor tyrosine kinase is believed to contribute to the malignant phenotypes seen in these tumors. Highly specific small molecule inhibitors of this receptor tyrosine kinase have been developed and may potentially improve the treatment of these highly aggressive brain tumors. A glioma cell line overexpressing EGFR was developed to mimic the situation of a malignant glioma with amplified EGFR, and this line was used to characterize the response to specific EGFR inhibitors. Treatment of our in vitro glioma model with the EGFR kinase inhibitors ZD1839 (Iressa) or PD153035, synthetic anilinoquinazolines with high specificity for EGFR, resulted in significant suppression of EGFR autophosphorylation even with very low levels of drug. However, significantly higher levels of drug were required to fully inhibit signaling through the phosphatidylinositol 3'-kinase/AKT and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (ERK) pathways. Interestingly, not all downstream signaling pathways displayed this resistance to inhibition. EGF-dependent activation of signal transducers and activators of transcription-3 occurred at low doses of EGFR inhibitors. The uncoupling of EGFR autophosphorylation and signaling through AKT and ERK was not dependent on EGFR overexpression. In addition, although this response was seen in other glioma and the SK-BR3 breast cancer cell lines, it was not universally present. The SQ20B head and neck squamous carcinoma cell line demonstrated loss of EGF-dependent AKT and ERK activation even at low doses of inhibitor. Despite significant loss of EGF-dependent autophosphorylation, the inability of low levels of EGFR inhibitor to suppress some downstream signaling pathways in our model glioma cell line permitted continued EGF-responsive decreases in the expression of the cyclin-dependent kinase inhibitor p27KIP and EGF-dependent proliferation/cell cycle progression. Although the mechanism responsible for the differential sensitivity of the various signal transduction pathways to EGFR inhibitors remains unclear, signaling through erbB2 does not appear to be involved. The ability of certain tumor cells to maintain signaling through AKT and ERK under EGFR inhibition may represent a potential mechanism of resistance by which a tumor cell may escape the antiproliferative activity of this new class of drugs.
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PMID:Resistance to small molecule inhibitors of epidermal growth factor receptor in malignant gliomas. 1461 44

Epidermal growth factor (EGF)-mediated Ca2+ signaling in multiple cell lines derived from human gliomas and in the A431 epidermoid carcinoma cell line was observed using fluorescence videomicroscopy. Bath application of EGF evoked an oscillatory increase in [Ca2+]i in 4 different human glioma cell lines as well as the A431 cell line. This effect was blocked by the EGF receptor tyrosine kinase inhibitors gefitinib and erlotinib, as well as by the EGFR antibody cetuximab. In addition to this acute Ca2+ signaling response, transient exposure to EGF also potentiated subsequent Ca2+ signaling responses to other stimuli. Tumor cells transiently exposed to EGF (5 minutes), showed a sustained increase in propagation of intercellular Ca2+ waves, which have been previously shown to involve release of ATP and activation of purinergic receptors. Cells transiently exposed to EGF also showed a sustained potentiation of the Ca2+ signaling response to ATP. In contrast to the acute Ca2+ signaling response to EGF, this sustained potentiation of purinergic intercellular signaling was not blocked by gefitinib or erlotinib, while it was blocked by cetuximab. These results indicate that while the acute Ca2+ signaling response requires tyrosine kinase activation, the sustained potentiation of intercellular signaling occurs via a distinct pathway. Distinct intra- and intercellular Ca2+ signaling pathways may be mechanisms by which EGF modulates the growth and migration of tumor cells.
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PMID:EGF activates intracellular and intercellular calcium signaling by distinct pathways in tumor cells. 1561 21

Primary glial tumors of the central nervous system, most commonly glioblastoma multiforme (GBM), are aggressive lesions with a dismal prognosis. Despite identification and isolation of human brain tumor stem cells (BTSCs), characteristics that distinguish BTSCs from neural stem cells remain to be elucidated. We cultured cells isolated from gliomas, using the neurosphere culture system, to understand their growth requirements. Both CD133(+) and CD133(-) adult GBM BTSCs proliferated in the absence of exogenous mitogenic stimulation and gave rise to multipotent GBM spheres that were capable of self-renewal. Epidermal growth factor (EGF) and fibroblast growth factor-2 enhanced GBM BTSC survival, proliferation, and subsequent sphere size. Blockade of EGF receptor (EGFR) signaling reduced exogenous mitogen-independent GBM sphere growth. Implantation of as few as 10 exogenous mitogen-independent GBM BTSCs led to the formation of highly invasive intracranial tumors, which closely resembled human GBMs, in immunocompromised mice. These results demonstrate that exogenous mitogen independence, mediated in part through EGFR signaling, is one characteristic that distinguishes CD133(+) and CD133(-) GBM BTSCs from neural stem cells. This novel experimental system will permit the elucidation of additional constitutively activated mechanisms that promote GBM BTSC survival, self-renewal, and proliferation.
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PMID:Proliferation of human glioblastoma stem cells occurs independently of exogenous mitogens. 1954 33


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