Treatment of cultured glioma cells with the EGFR-TKI gefitinib ("Iressa", ZD1839) increases the uptake of astatinated EGF despite the absence of gefitinib-mediated growth inhibition

Sundberg, Aasa Liljegren; Almqvist, Ylva; Tolmachev, Vladimir; Carlsson, Johanna

doi:10.1007/s00259-003-1129-x

Cited by 13 publications

(9 citation statements)

References 9 publications

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“…Little more literature is available on the use of Gefitinib in glioma. While apoptosis was enhanced at simultaneous Gefitinib treatment and radiation (48), no inhibitory effect on proliferation was seen with Gefitinib alone (49). In a phase II clinical study, no objective response to Gefitinib in patients with recurrent glioblastoma multiforme could be demonstrated (50).…”

Section: Mas) -------------------------------------------------------mentioning

confidence: 99%

Effective silencing of EGFR with RNAi demonstrates non-EGFR dependent proliferation of glioma cells

Vollmann

Vornlocher²,

Stempfl³

et al. 2006

Int J Oncol

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Abstract. The epidermal growth factor receptor (EGFR, ErbB1) is frequently dysregulated in a variety of solid human tumors, including malignant glioma. EGFR expression has been associated with disease progression, resistance to standard therapies and poor survival. The application of small interfering RNAs (siRNAs) has become an effective and highly specific tool to modulate gene expression, and a wide range of oncogenes have been silenced successfully. Here we show the siRNA-mediated down-regulation of EGFR in two established glioma cell lines with different EGFR expression levels (U373 MG, LN18). The expression of EGFR mRNA and protein was down-regulated by 70-90%. However, siRNA treatment had no inhibitory effect on cell proliferation, migration and activation status of EGFR-coupled signaling cascades. In accordance with these results, gene expression analysis with microarrays revealed only small, albeit specific changes in expression patterns. In conclusion, these data indicate that the specific down-regulation of EGFR might not be sufficient for a single agent therapeutic approach in malignant glioma. IntroductionMalignant glioma represent the most common primary brain tumors in the adult. Their anatomical localization, the infiltration of the surrounding normal brain parenchyma and the suppression of a tumor-directed immune response contribute to their highly aggressive phenotype. Despite extensive efforts to improve surgery, radiotherapy and chemotherapy, the median survival for patients with glioblastoma multiforme (GBM) averages only 14 months (1). One of the most frequently altered genes in glioblastoma is the epidermal growth factor receptor (EGFR, ErbB1, HER-1). EGFR gene amplification occurs in 40-50% of GBM, and tumors without amplification might also display an overexpression of this receptor (2-4). A common mutation (EGFRvIII), occurring in about half of the glioma with receptor amplification, confers enhanced tumorigenicity by rendering the receptor constitutively active (5). EGFR represents the prototype of class I receptor tyrosine kinases (RTKs). Besides EGFR, the ErbB family of receptors comprises three more members, ErbB2 (HER-2/NEU), ErbB3 (HER-3) and ErbB4 (HER-4). Receptor activation takes place after binding of specific ligands, e.g., epidermal growth factor (EGF), transforming growth factor · (TGF·), Amphiregulin, heparin-binding EGF (6). Ligand binding induces receptor homo-or heterodimerization and activation of the tyrosine kinase domain, which in turn phosphorylates both the receptor itself and downstream effector molecules. This results in signaling through multiple pathways, including the activation of extracellular regulated kinases 1/2 (ERK1/2), protein kinase B (PKB) and members of the signal transducer and activator of transcription (STAT) family. Ultimately, cells respond with enhanced proliferation, migration and transcriptional activity, as well as decreased apoptosis (7-9). Several new strategies have been developed to target EGFR, including monoclonal antibodies (mAbs) (...

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Section: Mas) -------------------------------------------------------mentioning

confidence: 99%

Effective silencing of EGFR with RNAi demonstrates non-EGFR dependent proliferation of glioma cells

Vollmann

Vornlocher²,

Stempfl³

et al. 2006

Int J Oncol

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“…Rather than acting as a pure tumor antagonist then, gefitinib may convert active EGFR into an overexpressed kinase-inactive (ErbB3-like) cell-surface receptor that sequesters EGFR-specific [epidermal growth factor (EGF) and transforming growth factor-␣] and other type I receptor ligands (e.g., betacellulin and heparinbinding-EGF; Ref. 26), thus triggering secondary dimerization (27) associated with prolonged activation of other recep-tors (28). These complexities caution against framing clinical predictions on the basis of simplistic mechanistic assumptions.…”

Section: Introductionmentioning

confidence: 99%

Selective Tyrosine Hyperphosphorylation of Cytoskeletal and Stress Proteins in Primary Human Breast Cancers

Lim¹,

Wong

Ooi

et al. 2004

Clinical Cancer Research

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Purpose: Small-molecule growth factor receptor inhibitors block cell growth in vitro and downstream signaling in vivo, but controlled trials in patients with advanced solid tumors have yielded disappointing response rates. To clarify this discrepancy, we compared the patterns of tyrosine phosphoprotein expression in human cancer cells and primary tumors.Experimental Design: Immunoaffinity chromatography, two-dimensional electrophoresis, and antiphosphotyrosine immunoblotting were combined with mass spectrometry to determine the phosphoproteomic signatures of 40 matched normal and malignant tissues from patients with breast or liver cancer. The identities and abundance of the detected tyrosine phosphoproteins were compared with those of ligand-responsive A431 cells.Results: Patterns of tyrosine-phosphorylated proteins are similar among normal tissues of the same origin but vary markedly between different tissues. Primary breast tumors exhibit a strikingly homogeneous tyrosine phosphorylation profile, whereas liver cancers display greater phosphoproteomic diversity. The main breast-tumor-specific tyrosine phosphoproteins are cytoskeletal molecules (actin, tubulin, and vimentin) and molecular chaperones (Hsp70, Hsc71, and Grp75). In contrast, control studies in ligand-stimulated A431 human cancer cells revealed an additional phosphorylated subset of promitogenic phosphoproteins (Grb2, Shc, Jnk2, phospholipase C-␥, and phosphatidylinositol 3-kinase).Conclusions: Identification of cytoskeletal and stress proteins as the most abundant tyrosine phosphoproteins in breast tumors implicates these molecules, rather than promitogenic effectors, as the prime stoichiometric substrates for kinase-inhibitory anticancer drugs in vivo. Because phosphorylated cytoskeletal proteins and chaperones mediate cell motility and apoptotic resistance, respectively, these data raise the intriguing possibility that small-molecule tyrosine kinase inhibitors may be of greatest value either as adjuvant antimetastatic/-invasive drugs or as chemo-/radiosensitizers.

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“…131 I-TM-601 (TransMolecular Inc., Birmingham, AL) is a hybrid of a synthetic chlorotoxin (from scorpions) that targets MMP-2, which is overexpressed on the surface of glioma cells, thus delivering local radiation as well as inhibiting and downregulating metalloprotease function. 170 Other strategies, which are not strictly targeted therapies but utilise molecular knowledge of cancer cells are in development (e.g. oncolytic viruses that only replicate in and lyse cells that have upregulation of Ras or loss of p53).…”

Section: Discussionmentioning

confidence: 99%

Targeted therapy for malignant gliomas

Morokoff¹,

Novak²

2004

Journal of Clinical Neuroscience

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Treatment of cultured glioma cells with the EGFR-TKI gefitinib ("Iressa", ZD1839) increases the uptake of astatinated EGF despite the absence of gefitinib-mediated growth inhibition

Cited by 13 publications

References 9 publications

Effective silencing of EGFR with RNAi demonstrates non-EGFR dependent proliferation of glioma cells

Effective silencing of EGFR with RNAi demonstrates non-EGFR dependent proliferation of glioma cells

Selective Tyrosine Hyperphosphorylation of Cytoskeletal and Stress Proteins in Primary Human Breast Cancers

Targeted therapy for malignant gliomas

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