Radiation-induced cellular DNA damage repair response enhances viral gene therapy efficacy in the treatment of malignant pleural mesothelioma.
BACKGROUND
Malignant pleural mesothelioma (MPM) treated with radiotherapy (RT) has incomplete responses as a result of radiation-induced tumoral stress response that repairs DNA damage. Such stress response is beneficial for oncolytic viral therapy. We hypothesized that a combination of RT and NV1066, an oncolytic herpes virus, might exert an additive or synergistic effect in the treatment of MPM.


METHODS
JMN, a MPM cell line, was infected with NV1066 at multiplicities of infection of .05 to .25 in vitro with and without radiation (1 to 5 Gy). Virus replication was determined by plaque assay, cell kill by lactate dehydrogenase assay, and GADD34 (growth arrest and DNA damage repair 34, a DNA damage-repair protein) by real-time reverse transcriptase-polymerase chain reaction and Western blot test. Synergistic cytotoxicity dependence on GADD34 upregulation was confirmed by GADD34 small inhibitory RNA (siRNA).


RESULTS
Synergism was demonstrated between RT and NV1066 across a wide range of doses. As a result of such synergism, a dose-reduction for each agent (up to 5500-fold) can be accomplished over a wide range of therapeutic-effect levels without sacrificing tumor cell kill. This effect is correlated with increased GADD34 expression and inhibited by transfection of siRNA directed against GADD34.


CONCLUSIONS
RT can be combined with oncolytic herpes simplex virus therapy in the treatment of malignant pleural mesothelioma to achieve synergistic efficacy while minimizing dosage and toxicity.
Adusumilli
Prasad S
PS
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Chan
Mei-Ki
MK
Hezel
Michael
M
Yu
Zhenkun
Z
Stiles
Brendon M
BM
Chou
Ting-Chao
TC
Rusch
Valerie W
VW
Fong
Yuman
Y
D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D003131:Combined Modality Therapy; D004249:DNA Damage / Q000528:radiation effects*; D004260:DNA Repair; D006801:Humans; D008297:Male; D008654:Mesothelioma / Q000378:metabolism / Q000532:radiotherapy / Q000628:therapy* / Q000821:virology; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy; D010997:Pleural Neoplasms / Q000378:metabolism / Q000532:radiotherapy / Q000628:therapy* / Q000821:virology; D054645:Protein Phosphatase 1; D034741:RNA, Small Interfering / Q000378:metabolism; D018139:Simplexvirus; D014779:Virus Replication / Q000528:radiation effects
D000943:Antigens, Differentiation; D018797:Cell Cycle Proteins; D034741:RNA, Small Interfering; C087519:PPP1R15A protein, human; D054645:Protein Phosphatase 1