UMLS:C0017638 - FACTA Search

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Query: UMLS:C0017638 (glioma)
30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Brain tumors are a diverse group of malignancies that remain refractory to conventional treatment approaches, including radiotherapy and cytotoxic chemotherapy. Molecular neuro-oncology has now begun to clarify the transformed phenotype of brain tumors and identify oncogenic pathways that may be amenable to targeted therapy. Growth factor signaling pathways are often upregulated in brain tumors and may contribute to oncogenesis through autocrine and paracrine mechanisms. Excessive growth factor receptor stimulation can also lead to overactivity of the Ras signaling pathway, which is frequently aberrant in brain tumors. Receptor tyrosine kinase inhibitors, antireceptor monoclonal antibodies and antisense oligonucleotides are targeted approaches under investigation as methods to regulate aberrant growth factor signaling pathways in brain tumors. Several receptor tyrosine kinase inhibitors, including imatinib mesylate (Gleevec), gefitinib (Iressa) and erlotinib (Tarceva), have entered clinical trials for high-grade glioma patients. Farnesyl transferase inhibitors, such as tipifarnib (Zarnestra), which impair processing of proRas and inhibit the Ras signaling pathway, have also entered clinical trials for patients with malignant gliomas. Further development of targeted therapies and evaluation of these new agents in clinical trials will be needed to improve survival and quality of life of patients with brain tumors.
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PMID:Molecular neuro-oncology and development of targeted therapeutic strategies for brain tumors. Part 1: Growth factor and Ras signaling pathways. 1459 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

Gefitinib (ZD1839, Iressa), a member of the 4-anilinoquinazoline class of compounds, has the chemical name 4-quinazolinamine, N-(3-chloro-4-flurophenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy]. Gefitinib often is referred to as a "specific" or "selective" inhibitor of epidermal growth factor receptor (EGFR). EGFR expression has been noted in neuroblastoma and rhabdomyosarcoma cell lines and in tumor specimens from children with Wilms tumor, osteosarcoma, and glioma. Thus, gefitinib, the first marketed EGFR tyrosine kinase inhibitor, was chosen for study in children with refractory solid tumors and central nervous system (CNS) malignancies. This review discusses findings from 3 clinical trials of gefitinib in children with refractory solid tumors and CNS malignancies, focusing on the clinical pharmacology of the compound. To date, gefitinib has been studied in children as a single agent and in combination with irinotecan. Overall, the compound has been well tolerated in children and has a safety profile similar to that observed in adults. The clinical pharmacokinetics of gefitinib in children are similar to those observed in adults. Finally, the future for the use of gefitinib in pediatrics is similar to that of other molecularly targeted agents and awaits definition of tumors and patient populations in which it will be most advantageous.
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PMID:Evaluation of gefitinib for treatment of refractory solid tumors and central nervous system malignancies in pediatric patients. 1680 60

Amplified epidermal growth factor receptor (EGFR) signaling is supposed to contribute to clinical radiation resistance of glioblastoma multiforme (GBM). Therefore, inhibition of EGFR signaling pathways by the selective EGFR tyrosine kinase inhibitor, gefitinib (ZD1839, Iressa), may increase the therapeutic effects of radiotherapy. The effects of different schedules for administration of gefitinib on sensitivity to irradiation of the human glioma cell lines (251MG and SF-767), a rat glioma cell line (BT4C), and an immortalized rat brain endothelial cell line (RBE4) is reported. Differences in effects of the combined treatment on cell toxicity were determined by a fluorometric cytotoxicity assay, and nuclear DNA fragmentation was used for quantification of apoptosis. Pre-administration with gefitinib for 30 min prior to irradiation followed by continuous incubation with gefitinib significantly increased the cytotoxicity of SF-767, BT4C, and RBE4 cells. However, the human glioma cell line 251MG was protected against radiation-induced damage by this treatment schedule, at lower concentrations of gefitinib. Pre-administration with gefitinib for 24 h prior to irradiation without following incubation with gefitinib increased the cytotoxicity of SF-767 and BT4C cells. Post-irradiation treatment with gefitinib significantly increased the cytotoxicity in all cell lines except for 251MG. We demonstrated heterogeneity in the cytotoxic effects of gefitinib between cell lines. Response to gefitinib might be due to other mechanisms than through the EGF receptor as some of the cell lines showed sensitivity to gefitinib despite no or low expression of EGFR. This study also demonstrates the importance of timing of gefitinib administration when this agent is combined with irradiation.
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PMID:Treatment schedule is of importance when gefitinib is combined with irradiation of glioma and endothelial cells in vitro. 1791 26

Despite advances in diagnosis and treatment made over the past two decades, high-grade gliomas are still incurable neoplasms. Moreover, after failing adjuvant therapy, few active treatments are available. In this setting, novel agents, such as new chemotherapy compounds and anticancer agents against specific molecular targets, have therefore been investigated. Epidermal growth factor receptor (EGFR) is an intriguing target in high-grade gliomas because it is frequently overexpressed due to amplification of the EGFR gene. Gefitinib and erlotinib act as ATP mimetic agents, binding to the cytoplasmic ATP pocket domain and blocking receptor phosphorylations and, thereby, EGFR-mediated activation of downstream pathways. These drugs have been evaluated in several clinical trials treating recurrent high-grade gliomas with contrasting results. Retrospective correlative analyses generated a plethora of putative predictive factors of activity of EGFR tyrosine kinase inhibitors. The first generations of studies on EGFR inhibitors have not found significant activity of these agents in high-grade gliomas. Furthermore, no clear molecular or clinical predictors have been identified. As with other targeted agents, prospective trials using specific criteria and standardized methods to evaluate tissue biomarkers are required to find predictors of EGFR inhibitors activity in high-grade glioma patients.
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PMID:Epidermal growth factor receptor inhibitors in neuro-oncology: hopes and disappointments. 1828 26

Deregulated signaling through the epidermal growth factor receptor (EGFR) is involved in chemoresistance. To identify the molecular determinants of sensitivity to the EGFR inhibitor gefitinib (Iressa, ZD1839) in chemoresistance, we compared the response of matched chemosensitive and chemoresistant glioma and ovarian cancer cell lines. We found that chemoresistant cell lines were 2- to 3-fold more sensitive to gefitinib growth-inhibitory effects, because of decreased proliferation rather than survival. Sensitivity to gefitinib correlated with overexpression and constitutive phosphorylation of HER2 and HER3, but not EGFR, altered HER ligand expression, and enhanced activation of EGF-triggered EGFR pathway. No activating mutations were found in EGFR. Gefitinib fully inhibited EGF-induced and constitutive Akt activation only in chemoresistant cells. In parallel, gefitinib downregulated constitutively phosphorylated HER2 and HER3, and activated GSK3beta with a concomitant degradation of cyclin D1. Ectopically overexpressed HER2 on its own was insufficient to sensitize chemonaive cells to gefitinib. pHER3 coimmunoprecipitated with p85-PI3K in chemoresistant cells and gefitinib dissociated these complexes. siRNA-mediated inhibition of HER3 decreased constitutive activation of Akt and sensitivity to gefitinib in chemoresistant cells. Our study indicates that in chemoresistant cells gefitinib inhibits both an enhanced EGF-triggered pathway and a constitutive HER3-mediated Akt activation, indicating that inhibition of HER3 together with that of EGFR could be relevant in chemorefractory tumors. Furthermore, in combination experiments gefitinib enhanced the effects of coadministered drugs more in chemoresistant than chemosensitive ovarian cancer cells. Combined treatment might be therapeutically beneficial in chemoresistant tumors from ovary and likely from other tissues.
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PMID:Chemoresistant tumor cell lines display altered epidermal growth factor receptor and HER3 signaling and enhanced sensitivity to gefitinib. 1880 87

Glioblastoma multiforme (GBM) is the most lethal of brain tumors and is highly resistant to ionizing radiation (IR) and chemotherapy. Here, we report on a molecular mechanism by which a key glioma-specific mutation, epidermal growth factor receptor variant III (EGFRvIII), confers radiation resistance. Using Ink4a/Arf-deficient primary mouse astrocytes, primary astrocytes immortalized by p53/Rb suppression, as well as human U87 glioma cells, we show that EGFRvIII expression enhances clonogenic survival following IR. This enhanced radioresistance is due to accelerated repair of DNA double-strand breaks (DSB), the most lethal lesion inflicted by IR. The EGFR inhibitor gefitinib (Iressa) and the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 attenuate the rate of DSB repair. Importantly, expression of constitutively active, myristylated Akt-1 accelerates repair, implicating the PI3K/Akt-1 pathway in radioresistance. Most notably, EGFRvIII-expressing U87 glioma cells show elevated activation of a key DSB repair enzyme, DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Enhanced radioresistance is abrogated by the DNA-PKcs-specific inhibitor NU7026, and EGFRvIII fails to confer radioresistance in DNA-PKcs-deficient cells. In vivo, orthotopic U87-EGFRvIII-derived tumors display faster rates of DSB repair following whole-brain radiotherapy compared with U87-derived tumors. Consequently, EGFRvIII-expressing tumors are radioresistant and continue to grow following whole-brain radiotherapy with little effect on overall survival. These in vitro and in vivo data support our hypothesis that EGFRvIII expression promotes DNA-PKcs activation and DSB repair, perhaps as a consequence of hyperactivated PI3K/Akt-1 signaling. Taken together, our results raise the possibility that EGFR and/or DNA-PKcs inhibition concurrent with radiation may be an effective therapeutic strategy for radiosensitizing high-grade gliomas.
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PMID:EGFRvIII and DNA double-strand break repair: a molecular mechanism for radioresistance in glioblastoma. 1943 98

Gefitinib is an orally active inhibitor of the epidermal growth factor receptor approved for use in patients with locally advanced or metastatic non-small cell lung cancer. It has also been evaluated in several clinical trials for treatment of brain tumors such as high-grade glioma. In this study, we investigated the influence of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) on distribution of gefitinib to the central nervous system. In vitro studies conducted in Madin-Darby canine kidney II cells indicate that both P-gp and BCRP effectively transport gefitinib, limiting its intracellular accumulation. In vivo studies demonstrated that transport of gefitinib across the blood-brain barrier (BBB) is significantly limited. Steady-state brain-to-plasma (B/P) concentration ratios were 70-fold higher in the Mdr1a/b(-/-) Bcrp1(-/-) mice (ratio of approximately 7) compared with wild-type mice (ratio of approximately 0.1). The B/P ratio after oral administration increased significantly when gefitinib was coadministered with the dual P-gp and BCRP inhibitor elacridar. We investigated the integrity of tight junctions in the Mdr1a/b(-/-) Bcrp1(-/-) mice and found no difference in the brain inulin and sucrose space between the wild-type and Mdr1a/b(-/-) Bcrp1(-/-) mice. This suggested that the dramatic enhancement in the brain distribution of gefitinib is not due to a leakier BBB in these mice. These results show that brain distribution of gefitinib is restricted due to active efflux by P-gp and BCRP. This finding is of clinical significance for therapy in brain tumors such as glioma, where concurrent administration of a dual inhibitor such as elacridar can increase delivery and thus enhance efficacy of gefitinib.
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PMID:Distribution of gefitinib to the brain is limited by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2)-mediated active efflux. 2042 31

The antiproliferative effect of tandem somatostatin receptor (SSTR) activation, epidermal growth factor receptor (EGFR) inhibition, and induction of DNA damage was analyzed using octreotide (OCT), a SSTR agonist, the clinical DNA methylating agent temozolomide (TMZ), Iressa, an EGFR inhibitor, and dual EGFR-DNA targeting agents termed "combi-molecules". Using SSTR-expressing glioma cells harbouring low levels of EGFR (U87MG) or transfected to overexpress EGFR (U87/EGFR) or a variant (U87/EGFRvIII), we showed that Iressa, alone or in combination with the DNA damaging agent TMZ, and combi-molecules RA2 and RA5 inhibited EGF-induced phosphorylation of EGFR in U87MG and more moderately in U87/EGFR and U87/EGFRvIII transfected cells. This translated into equivalent levels of Erk 1/2 inhibition. Activation of SSTRs with OCT did not modulate the effects of the various treatments on Erk 1/2 phosphorylation. Likewise, SSTR activation did not alter TMZ- or DNA-damaging combi-molecules, RA2 and RA5, induced p53 activation nor upregulation. However, SSTR activation significantly shifted TMZ-, RA2- and RA5-induced cell-cycle arrest to earlier phases (i.e., G2/M to late S, late S to S, S to G1). Further analysis showed that apoptosis was not induced. This was in agreement with the fact that p53 activation did not induce Bax upregulation nor did EGFR inhibition promote Bad dephosphorylation. Moreover, enhancement of survivin, an anti-apoptotic protein, expression was observed. The results in toto suggest that the combination of SSTR activation with EGFR inhibition and DNA damage affects cell-cycle progression but a disconnection between the targeted signalling pathways in these brain tumour cells precludes synergistic cell-killing by the triple growth inhibitory events.
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PMID:Receptor activation and inhibition in cellular response to chemotherapeutic combinational mimicries: the concept of divergent targeting. 2046 86

Gefitinib, a selective epidermal growth factor receptor tyrosine kinase inhibitor, is under clinical testing and use in cancer patients, including glioma. However, the molecular mechanisms involved in gefitinib-mediated anticancer effects against glioma remain largely uncharacterized. Gefitinib inhibits cell growth and induces apoptosis in human glioma cells. Gefitinib also induces death of H4 cells with characteristics of the intrinsic apoptotic pathway, including Bax mitochondrial translocation, mitochondrial outer membrane permeabilization, cytochrome c cytosolic release, and caspase-9/caspase-3 activation. The importance of Bax in mediating gefitinib-induced apoptosis was confirmed by the attenuation of apoptosis by Bax siRNA and Bax channel blocker. Gefitinib caused Bad dephosphorylation, particularly in serine-112, and increased its binding preference to Bcl-2 and Bcl-xL. The dephosphorylation of Bad in gefitinib-treated cells was accompanied by reduced intracellular cyclic AMP content and protein kinase A (PKA) activity. Adenylyl cyclase activator forskolin attenuated, but PKA inhibitor H89 augmented, gefitinib-induced Bad dephosphorylation, Bax mitochondrial translocation, caspase-9/caspase-3 activation, and viability loss. Intriguingly, a nonselective protein phosphatase inhibitor okadaic acid alleviated gefitinib-induced alterations, except Bad dephosphorylation. In parallel with the higher basal PKA activity, response of U87 cells to gefitinib treatment was delayed and relatively resistant compared with that of H4 and T98G cells. Inactivation of PKA sensitized H4, T98G, and U87 cells to gefitinib cytotoxicity, Bad dephosphorylation in serine-112, and caspase-9/caspase-3 activation. Our findings suggest the involvement of the Bad/Bax signaling pathway in gefitinib-induced glioma apoptosis. Furthermore, the inactivation of PKA was shown to play a role in triggering the proapoptotic function of Bad.
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PMID:Gefitinib induces apoptosis in human glioma cells by targeting Bad phosphorylation. 2174 78

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