PMID- 18056196
OWN - NLM
STAT- MEDLINE
DCOM- 20080507
LR  - 20071206
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 13
IP  - 23
DP  - 2007 Dec 1
TI  - Combination of measles virus virotherapy and radiation therapy has synergistic 
      activity in the treatment of glioblastoma multiforme.
PG  - 7155-65
AB  - PURPOSE: Glioblastoma multiforme is the most frequent primary brain tumor in 
      adults and represents one of the most lethal malignancies with a median survival 
      of 12-16 months. We have previously shown that an oncolytic measles virus 
      derivative expressing soluble human carcinoembryonic antigen (MV-CEA) has 
      significant antitumor activity against glioblastoma multiforme cell lines and 
      xenografts. Radiation therapy (RT) represents one of the mainstays of glioma 
      treatment. Here we tested the hypothesis that the combination of RT with MV-CEA 
      would have synergistic activity against gliomas. EXPERIMENTAL DESIGN: 
      3-(4,5-Dimethyl-thiazol-2yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium 
      (MTS) and clonogenic assays were used to test cytoxicity of the combination 
      treatment in vivo. To examine the mechanism of synergy, one-step viral growth 
      curves, terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling 
      (TUNEL) assays, and Western blot analyses were performed. In vivo assessment of 
      synergistic antitumor activity was conducted in a U87 glioma model. RESULTS: MTS 
      and clonogenic assays showed a strong synergistic interaction between MV-CEA and 
      RT in glioblastoma multiforme cells including both primary and established glioma 
      lines. Furthermore, significant antitumor efficacy was observed in vivo in a 
      subcuteneous U87 xenograph model. There was significant prolongation of survival 
      (P = 0.001) in the combination treatment group as compared with single modality- 
      or control-treated animals. One-step viral growth curves showed increased viral 
      burst size by up to 2 log in MV/RT combination-treated cells, as compared with 
      single agent MV-CEA-treated glioma cells. Changes in CEA levels and expression of 
      viral N and H protein were also consistent with increased viral production. 
      Furthermore, TUNEL assays and Western blot analysis showed increase in apoptosis 
      in MV/RT combination-treated cells. The pan-caspase inhibitor Z-VAD-FMK and the 
      caspase-8 inhibitor Z-IETD-FMK, but not the caspase-9 inhibitor Z-IEHD-FMK, 
      protected glioma cells from MV-CEA/RT-induced cleavage of poly(ADP-ribose) 
      polymerase (PARP), indicating that the apoptotic death in combination-treated 
      cells is mostly mediated via the extrinsic caspase pathway. The Fas/Fas ligand 
      interaction blocking antibody NOK-1 blocked MV/RT-induced PARP cleavage whereas 
      the Fas agonistic antibody CH11 increased PARP cleavage in MV/RT 
      combination-treated cells. Reverse transcription-PCR, fluorescence-activated cell 
      sorting analysis and immunohistochemistry showed up-regulation of Fas in 
      combination-treated tumor in vitro and in vivo cells. CONCLUSIONS: There is 
      synergy between MV-CEA and RT in vitro and in vivo. The synergistic effect of the 
      combination seems to be due to increase in viral burst size and increase in 
      apoptotic cell death. This latter effect is mostly mediated via the extrinsic 
      caspase-8 pathway, activated via increased signaling through the Fas death 
      receptor pathway. These results could have translational implications in glioma 
      therapy.
FAU - Liu, Chunsheng
AU  - Liu C
AD  - Molecular Medicine Program, Department of Radiation Oncology, Mayo Clinic, 
      Rochester, Minnesota 55905, USA.
FAU - Sarkaria, Jann N
AU  - Sarkaria JN
FAU - Petell, Cory A
AU  - Petell CA
FAU - Paraskevakou, Georgia
AU  - Paraskevakou G
FAU - Zollman, Paula J
AU  - Zollman PJ
FAU - Schroeder, Mark
AU  - Schroeder M
FAU - Carlson, Brett
AU  - Carlson B
FAU - Decker, Paul A
AU  - Decker PA
FAU - Wu, Wenting
AU  - Wu W
FAU - James, C David
AU  - James CD
FAU - Russell, Stephen J
AU  - Russell SJ
FAU - Galanis, Evanthia
AU  - Galanis E
LA  - eng
GR  - P50 CA 108961/CA/NCI NIH HHS/United States
GR  - R21 CA123839/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
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 (Carcinoembryonic Antigen)
RN  - 0 (Death Domain Receptor Signaling Adaptor Proteins)
RN  - EC 3.4.22.- (Caspase 8)
SB  - IM
MH  - Animals
MH  - Brain Neoplasms/*radiotherapy/*virology
MH  - Carcinoembryonic Antigen/biosynthesis/genetics
MH  - Caspase 8/metabolism
MH  - Cell Line, Tumor
MH  - Combined Modality Therapy
MH  - Death Domain Receptor Signaling Adaptor Proteins/metabolism
MH  - Glioblastoma/*radiotherapy/*virology
MH  - Humans
MH  - Measles virus/genetics/immunology/*physiology/radiation effects
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Oncolytic Virotherapy/*methods
MH  - Xenograft Model Antitumor Assays
EDAT- 2007/12/07 09:00
MHDA- 2008/05/08 09:00
CRDT- 2007/12/07 09:00
PHST- 2007/12/07 09:00 [pubmed]
PHST- 2008/05/08 09:00 [medline]
PHST- 2007/12/07 09:00 [entrez]
AID - 13/23/7155 [pii]
AID - 10.1158/1078-0432.CCR-07-1306 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2007 Dec 1;13(23):7155-65. doi: 10.1158/1078-0432.CCR-07-1306.