PMID- 15475464
OWN - NLM
STAT- MEDLINE
DCOM- 20050329
LR  - 20181130
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 10
IP  - 19
DP  - 2004 Oct 1
TI  - Inhibition of the type III epidermal growth factor receptor variant mutant 
      receptor by dominant-negative EGFR-CD533 enhances malignant glioma cell 
      radiosensitivity.
PG  - 6732-43
AB  - PURPOSE: The commonly expressed variant epidermal growth factor receptor (EGFR), 
      the type III EGFR variant (EGFRvIII), functions as an oncoprotein promoting 
      neoplastic transformation and tumorigenicity. The role of EGFRvIII in cellular 
      responses to genotoxic stress, such as ionizing radiation, is only minimally 
      defined. Thus, we have investigated EGFRvIII as a potential modulator of cellular 
      radiation responses and explored the feasibility of adenovirus (Ad)-mediated 
      expression of dominant-negative EGFR-CD533 as a gene therapeutic approach for 
      inhibiting EGFRvIII function in vitro and in vivo. EXPERIMENTAL DESIGN AND 
      RESULTS: EGFR-CD533 and EGFRvIII were expressed in vitro and in vivo in malignant 
      U-373 MG glioma cells through transduction with an Ad vector, Ad-EGFR-CD533 and 
      Ad-EGFRvIII, respectively. In vivo studies defined the importance of EGFRvIII as 
      a modulator of radiation responses, demonstrating a 2.6-fold activation of 
      EGFRvIII in U-373 malignant glioma tumors. Concomitant expression of EGFR-CD533 
      inhibited the radiation-induced activation of EGFRvIII in vitro and completely 
      abolished the enhanced clonogenic survival conferred by EGFRvIII. The ability of 
      EGFR-CD533 to inhibit EGFRvIII function was further confirmed in vivo through 
      complete inhibition of EGFRvIII-mediated increased tumorigenicity and 
      radiation-induced activation of EGFRvIII. Growth delay assays with U-373 
      xenograft tumors demonstrated that the expression of EGFR-CD533 significantly 
      enhanced radiosensitivity of tumor cells under conditions of intrinsic and 
      Ad-mediated EGFRvIII expression. CONCLUSIONS: We conclude that EGFRvIII confers 
      significant radioresistance to tumor cells through enhanced cytoprotective 
      responses, and we have demonstrated that dominant-negative EGFR-CD533 effectively 
      inhibits EGFRvIII function. These data affirm the broad potential of EGFR-CD533 
      to radiosensitize human malignant glioma cells.
FAU - Lammering, Guido
AU  - Lammering G
AD  - Department of Radiation Oncology, Medical College of Virginia, Virginia 
      Commonwealth University, Richmond, Virginia 23298-0058, USA.
FAU - Hewit, Theodore H
AU  - Hewit TH
FAU - Holmes, Mathew
AU  - Holmes M
FAU - Valerie, Kristoffer
AU  - Valerie K
FAU - Hawkins, William
AU  - Hawkins W
FAU - Lin, Peck-Sun
AU  - Lin PS
FAU - Mikkelsen, Ross B
AU  - Mikkelsen RB
FAU - Schmidt-Ullrich, Rupert K
AU  - Schmidt-Ullrich RK
LA  - eng
GR  - P01CA72955/CA/NCI NIH HHS/United States
GR  - R01CA65896/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (epidermal growth factor receptor VIII)
RN  - 42HK56048U (Tyrosine)
RN  - EC 2.7.10.1 (ErbB Receptors)
SB  - IM
MH  - Adenoviridae/genetics
MH  - Animals
MH  - Blotting, Western
MH  - CHO Cells
MH  - Cell Line, Tumor
MH  - Cricetinae
MH  - Cricetulus
MH  - ErbB Receptors/*genetics/metabolism
MH  - Female
MH  - Gene Expression Regulation, Neoplastic
MH  - Genes, Dominant/genetics
MH  - Genetic Vectors/genetics
MH  - Glioma/genetics/pathology/*radiotherapy
MH  - Humans
MH  - Mice
MH  - Mice, Nude
MH  - Mutation
MH  - Phosphorylation/radiation effects
MH  - Radiation, Ionizing
MH  - Time Factors
MH  - Transfection
MH  - Tyrosine/metabolism
MH  - Xenograft Model Antitumor Assays/methods
EDAT- 2004/10/12 09:00
MHDA- 2005/03/30 09:00
CRDT- 2004/10/12 09:00
PHST- 2004/10/12 09:00 [pubmed]
PHST- 2005/03/30 09:00 [medline]
PHST- 2004/10/12 09:00 [entrez]
AID - 10/19/6732 [pii]
AID - 10.1158/1078-0432.CCR-04-0393 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2004 Oct 1;10(19):6732-43. doi: 10.1158/1078-0432.CCR-04-0393.