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Marc-Eric Halatsch, Esther E. Gehrke, Vassilios I. Vougioukas, Ingolf C. Bötefür, Farhad A.- Borhani, Thomas Efferth, Erich Gebhart, Sebastian Domhof, Ursula Schmidt and Michael Buchfelder

Object

Quantitative and qualitative alterations in the epidermal growth factor receptor (EGFR) commonly occur in many cancers in humans, including malignant gliomas. The aim of the current study was to evaluate molecular and cellular effects of OSI-774, a novel EGFR tyrosine kinase inhibitor, on nine glioblastoma multiforme (GBM) cell lines.

Methods

The effects of OSI-774 on expression of EGFR messenger (m)RNA and protein, proliferation, anchorage-independent growth, and apoptosis were examined using semiquantitative reverse transcription–polymerase chain reaction, immunocytochemical analysis, Coulter counting, soft agar cloning, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling/fluorescence-activated cell sorting, respectively. All p53 genes were completely and bidirectionally sequenced.

Suppression of anchorage-independent growth by OSI-774 was inversely correlated to the induction of EGFR mRNA during relative serum starvation (r = −0.74) and was unrelated to p53 status. Overall, suppression of anchorage-independent growth was a considerably stronger effect of OSI-774 than inhibition of proliferation. The extent of OSI-774–induced apoptosis positively correlated with both proliferation and anchorage-independent growth of GBM cell lines (r = 0.75 and 0.79, respectively). In a single cell line derived from a secondary GBM, exposure to concentrations of greater than or equal to 1 μmol/L resulted in a substantial net cell loss during proliferation studies.

Conclusions

The induction of EGFR mRNA may constitute a cellular mechanism to counteract the inhibitory effect of OSI-774 on the anchorage-independent growth of GBM cells. In contrast, no considerable correlation could be established between baseline expression levels of EGFR (both mRNA and protein) in GBM cell lines and their biological response to OSI-774. The OSI-774 induced greater (p53-independent) apoptosis in more malignant GBM phenotypes and may be a promising therapeutic agent against secondary GBM.

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epidermal growth factor receptor messenger RNA induction and suppression of anchorage-independent growth by OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in glioblastoma multiforme cell lines Marc-Eric Halatsch M.D. Esther E. Gehrke M.D. Vassilios I. Vougioukas M.D. Ingolf C. Bötefür M.D. Farhad A.- Borhani M.D. Thomas Efferth Ph.D. Erich Gebhart Ph.D. Sebastian Domhof Ph.D. Ursula Schmidt M.D. Michael Buchfelder M.D. 2 2004 16 2 1 11 10.3171/foc.2004.16.2.12 FOC.2004.16.2.12 Embryology of myelomeningocele and anencephaly Mark S. Dias M

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Adam M. Sonabend, Ilya V. Ulasov, Yu Han and Maciej S. Lesniak

patients with glioblastoma multiforme . Int J Oncol 15 : 481 – 486 , 1999 25 DeMasters BK , Markham N , Lillehei KO , : Differential telomerase expression in human primary intracranial tumors . Am J Clin Pathol 107 : 548 – 554 , 1997 26 Dmitriev I , Kashentseva E , Rogers BE , : Ectodomain of coxsackievirus and adenovirus receptor genetically fused to epidermal growth factor mediates adenovirus targeting to epidermal growth factor receptor-positive cells . J Virol 74 : 6875 – 6884 , 2000 27 Eavarone DA , Yu X , Bellamkonda RV

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Marc C. Chamberlain

✓ Following the seminal trial conducted by the European Organisation for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC), concurrent temozolomide and radiotherapy has become the new standard of care for patients with newly diagnosed glioblastoma multiforme (GBM). Investigation of emerging therapies (which are now used as salvage therapy) such as small-molecule inhibitors (for example, epidermal growth factor receptor inhibitors) and convection-enhanced delivery (CED) of targeted toxins (for example, interleukin-13/pseudo-monas exotoxin) is likely to build on the EORTC/NCIC treatment platform and will, it is hoped, improve survival rates in patients with GBM. The majority of adjuvant Phase I and II trials being conducted by the brain tumor consortia are based on the EORTC/NCIC treatment platform and have added a targeted therapy in an effort to find a promising synergistic treatment. Furthermore, researchers in the consortia are continuing to explore treatments for recurrent GBM, not otherwise eligible for local therapies, such as CED. The treatments under study include novel cytotoxic chemotherapy as well as small-molecule inhibitors; these are being assessed in a variety of Phase I or II trials.

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Christina Pfister, Rainer Ritz, Heike Pfrommer, Antje Bornemann, Marcos S. Tatagiba and Florian Roser

cyclooxygenases (COX-1 and COX-2) and the lipoxygenases (5-LO, 12-LO, and 15-LO). Both classes catalyze the same enzymatic reaction that occurs in the synthesis of PG 2 and PGH 2 , which are successively metabolized to PGE 2 , PGD 2 , PGF 2 , thromboxane A 2 , and prostacyclin PGI 2 ( Fig. 1 ). 12 F ig . 1. Simplified diagram demonstrating the AA cascade and the enzymes produced. EGFR = epidermal growth factor receptor; IL = interleukin; NFκB = nuclear factor-κB; NSAIDs = nonsteroidal antiinflammatory drugs; PLA2 = phospholipase A2. The crucial role of COX enzymes

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Brian T. Ragel, Randy L. Jensen and William T. Couldwell

and induce apoptosis of colon adenocarcinoma cells . FEBS Lett 531 : 278 – 284 , 2002 47 Zhang X , Chen ZG , Choe MS , Lin Y , Sun SY , Wieand HS , : Tumor growth inhibition by simultaneously blocking epidermal growth factor receptor and cyclooxygenase-2 in a xenograft model . Clin Cancer Res 11 : 6261 – 6269 , 2005 This work was supported by a grant from the American Association of Neurological Surgeons Neurosurgery Research and Education Foundation to Brian Ragel.

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Jason Rockhill, Maciej Mrugala and Marc C. Chamberlain

(absent in ~ 50% of all meningiomas), has been identified as an important factor in meningioma tumori-genesis. 26 Aside from loss of 22q (the NF2 gene), loss of 1q, 14q, and 10q occurs in atypical and malignant meningiomas. 1 , 26 Additionally, both epidermal growth factor receptor and platelet derived growth factor receptor are overexpressed in meningioma. There are two rare familial conditions (NF2 and meningiomatosis), both inherited as autosomal-dominant traits, which predispose patients to developing meningiomas. 1 , 26 , 34 Rarely (< 1% of all meningiomas

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Andrew D. Norden, Jan Drappatz and Patrick Y. Wen

mg twice/day, depending on concurrent use of enzyme-inducing AEDs) and hydroxyurea (500 mg twice/day). 112 After a median follow up of 58 weeks, a complete response was achieved in one case, a partial response in two cases, and the disease was stable in 14 cases. The 6-month progression-free survival rate was 27%. Epidermal Growth Factor Receptor The EGFR is overexpressed in more than 60% of meningiomas. 3 , 12 , 55 , 59 , 72 , 118 , 130 Both EGF and TGF-α activate these receptors and stimulate meningioma growth in vitro, 54 , 55 , 130 supporting the

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Matthew T. Harting, James E. Baumgartner, Laura L. Worth, Linda Ewing-Cobbs, Adrian P. Gee, Mary-Clare Day and Charles S. Cox Jr.

Boockvar JA , Schouten J , Royo N , Millard M , Spangler Z , Castelbuono D , : Experimental traumatic brain injury modulates the survival, migration, and terminal phenotype of transplanted epidermal growth factor receptor-activated neural stem cells . Neurosurgery 56 : 163 – 171 , 2005 5 Borlongan CV , Hadman M , Sanberg CD , Sanberg PR : Central nervous system entry of peripherally injected umbilical cord blood cells is not required for neuroprotection in stroke . Stroke 35 : 2385 – 2389 , 2004 6 Caplan AI : Mesenchymal stem

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Eftekhar Eftekharpour, Soheila Karimi-Abdolrezaee and Michael G. Fehlings

glycosaminoglycans attached to a central protein core. The inhibitory effect of the glial scar has been reduced significantly by enzymatic separation of glycosaminoglycan side chains from the protein core. 12 The formation of CSPGs can also be inhibited by molecular degradation of the related enzymes, 42 thereby allowing axonal growth in injured spinal cord. Although no receptor has been identified for CSPGs, it has been shown that various signaling pathways are involved in CSPG-mediated inhibition including the Rho–Rock pathway 63 and activation of epidermal growth factor