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Titolo:
Radiosensitization of malignant glioma cells through overexpression of dominant-negative epidermal growth factor receptor
Autore:
Lammering, G; Valerie, K; Lin, PS; Mikkelsen, RB; Contessa, JN; Feden, JP; Farnsworth, J; Dent, P; Schmidt-Ullrich, RK;
Indirizzi:
Virginia Commonwealth Univ, Dept Radiat Oncol, Med Coll Virginia, Richmond, VA 23298 USA Virginia Commonwealth Univ Richmond VA USA 23298 , Richmond, VA 23298 USA Univ Dusseldorf, Dept Radiat Oncol, D-40225 Dusseldorf, Germany Univ Dusseldorf Dusseldorf Germany D-40225 , D-40225 Dusseldorf, Germany
Titolo Testata:
CLINICAL CANCER RESEARCH
fascicolo: 3, volume: 7, anno: 2001,
pagine: 682 - 690
SICI:
1078-0432(200103)7:3<682:ROMGCT>2.0.ZU;2-R
Fonte:
ISI
Lingua:
ENG
Soggetto:
ACTIVATED PROTEIN-KINASE; SQUAMOUS CARCINOMA-CELLS; VIRUS-THYMIDINE KINASE; SIGNAL-TRANSDUCTION; IONIZING-RADIATION; EGF RECEPTOR; CANCER-CELLS; RAT GLIOMA; INHIBITION; PROLIFERATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Citazioni:
38
Recensione:
Indirizzi per estratti:
Indirizzo: Schmidt-Ullrich, RK Virginia Commonwealth Univ, Dept Radiat Oncol, Med Coll Virginia, Med CollVirginia Campus,POB 980058,401 Coll St, Richmond, VA 23298 USA Virginia Commonwealth Univ Med Coll Virginia Campus,POB 980058,401 Coll St Richmond VA USA 23298
Citazione:
G. Lammering et al., "Radiosensitization of malignant glioma cells through overexpression of dominant-negative epidermal growth factor receptor", CLIN CANC R, 7(3), 2001, pp. 682-690

Abstract

The epidermal growth factor receptor (EGFR) plays an important role in neoplastic growth control of malignant gliomas, We have demonstrated that radiation activates EGFR Tyr-phosphorylation (EGFR Tyr-P) and the proliferationof surviving human carcinoma cells, a likely mechanism of accelerated cellular repopulation, a major cytoprotective response after radiation. We now investigate the importance of radiation-induced activation of EGFR on the radiosensitivity of the human malignant glioma cells U-87 MG and U-373 MG, The function of EGFR was inhibited through a genetic approach of transducingcells,vith an Adenovirus (Ad) vector containing dominant-negative (DN) EGFR-CD533 (Ad-EGFR-CD533) at efficiencies of 85-90%. The resulting cells are referred to as U-87-EGFR-CD533 and U-373-EGFR-CD533. After irradiation at 2Gy, both of the cell Lines exhibited a mean 3-fold increase in EGFR Tyr-P. The expression of EGFR-CD533 completely inhibited the radiation-induced activation of EGFR, In clonogenic survival assays after a single radiation exposure, the radiation dose for a survival of 37% (D-37) for U-87-EGFR-CD533cells was 1.4- to 1.5-fold lower, relative to cells transduced with AdLacZor untransduced U-87 MG cells. This effect was amplified with repeated radiation exposures (3 x 2 Gy) yielding a D-37 ratio of 1.8-2.0. In clonogenicsurvival studies with U-373 MG cells, the radiosensitizing effect of EGFR-CD533 was similar. Furthermore, irt vivo studies with U-87 MG xenografts confirmed the effect of EGFR-CD533 on tumor radiosensitization (dose enhancement ratio, 1.8). We conclude that inhibition of EGFR function via Ad-mediated gene transfer of EGFR-CD533 results in significant radiosensitization, As underlying mechanism, we suggest the disruption of a major cytoprotectiveresponse involving EGFR and its downstream effecters, such as mitogen-activated protein kinase, The experiments demonstrate for the first time that radiosensitization of malignant glioma cells through disruption of EGFR function may be achieved by genetic therapy approaches.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 06/04/20 alle ore 01:48:30