TY - JOUR
T1 - Radiation therapy potentiates effective oncolytic viral therapy in the treatment of lung cancer
AU - Adusumilli, Prasad S.
AU - Stiles, Brendon M.
AU - Chan, Mei Ki
AU - Chou, Ting Chao
AU - Wong, Richard J.
AU - Rusch, Valerie W.
AU - Fong, Yuman
N1 - Funding Information:
The authors thank Yuhong She, MD, and Wong Wai, MS, of the Anti-Tumor Core Facility, and Scott Tuorto of the Department of Surgery at Memorial Sloan-Kettering Cancer Center for their assistance with this project. We also thank Brian Horsburgh, PhD, and Medigene, Inc, for constructing and providing us with the NV1066 virus. This project is supported in part by AACR-AstraZeneca Cancer Research and Prevention Foundation fellowship (PSA), grants R01 CA76416 and R01 CA/DK80982 (YF) from the National Institutes of Health, grant MBC-99366 (YF) from the American Cancer Society, grant BC024118 from the US Army (YF), grant IMG0402501 from the Susan Komen Foundation (YF), and grant 032047 from Flight Attendant Medical Research Institute (YF).
PY - 2005/8
Y1 - 2005/8
N2 - Background. Replication-competent oncolytic herpes simplex viruses with deletion of the γ134.5 gene preferentially replicate in and kill malignant cells. The γ134.5 gene codes for ICP 34.5, a protein that enhances viral replication, and is homologous to growth arrest and DNA damage protein 34 (GADD34), a radiation-inducible DNA repair gene. We hypothesized that radiation therapy may potentiate efficacy of oncolytic viral therapy by upregulating GADD34 and promoting viral replication. Methods. The A549 and H1299 lung cancer cell lines were infected with NV1066, an oncolytic herpes simplex virus, at multiplicities of infection (number of viral particles per tumor cell) of 0.1 to 0.5 in vitro with radiation (2 to 10 Gy) or without radiation. Viral replication was determined by plaque assay, cell-to-cell spread was determined by flow cytometry, cell kill was determined by lactate dehydrogenase assay, and GADD34 induction was determined by real-time reverse transcription-polymerase chain reaction and Western blot method. Evidence of synergistic cytotoxicity dependence with GADD34 induction is further confirmed by small inhibitory RNA inhibition of GADD34 expression. Results. Using both the isobologram method and combination index method of Chou and Talalay, significant synergism was demonstrated between radiation therapy and NV1066 both in vitro and in vivo. As a result of such synergism, a dose reduction for each agent (2- to 6,000-fold) can be accomplished for 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 small inhibitory RNA directed against GADD34. Conclusions. These data provide the cellular basis for the clinical investigation of combined use of radiation therapy with oncolytic herpes simplex virus therapy in the treatment of lung cancer to achieve synergistic efficacy while minimizing dosage and toxicity.
AB - Background. Replication-competent oncolytic herpes simplex viruses with deletion of the γ134.5 gene preferentially replicate in and kill malignant cells. The γ134.5 gene codes for ICP 34.5, a protein that enhances viral replication, and is homologous to growth arrest and DNA damage protein 34 (GADD34), a radiation-inducible DNA repair gene. We hypothesized that radiation therapy may potentiate efficacy of oncolytic viral therapy by upregulating GADD34 and promoting viral replication. Methods. The A549 and H1299 lung cancer cell lines were infected with NV1066, an oncolytic herpes simplex virus, at multiplicities of infection (number of viral particles per tumor cell) of 0.1 to 0.5 in vitro with radiation (2 to 10 Gy) or without radiation. Viral replication was determined by plaque assay, cell-to-cell spread was determined by flow cytometry, cell kill was determined by lactate dehydrogenase assay, and GADD34 induction was determined by real-time reverse transcription-polymerase chain reaction and Western blot method. Evidence of synergistic cytotoxicity dependence with GADD34 induction is further confirmed by small inhibitory RNA inhibition of GADD34 expression. Results. Using both the isobologram method and combination index method of Chou and Talalay, significant synergism was demonstrated between radiation therapy and NV1066 both in vitro and in vivo. As a result of such synergism, a dose reduction for each agent (2- to 6,000-fold) can be accomplished for 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 small inhibitory RNA directed against GADD34. Conclusions. These data provide the cellular basis for the clinical investigation of combined use of radiation therapy with oncolytic herpes simplex virus therapy in the treatment of lung cancer to achieve synergistic efficacy while minimizing dosage and toxicity.
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U2 - 10.1016/j.athoracsur.2005.01.048
DO - 10.1016/j.athoracsur.2005.01.048
M3 - Article
C2 - 16039175
AN - SCOPUS:22544467233
SN - 0003-4975
VL - 80
SP - 409
EP - 417
JO - Annals of Thoracic Surgery
JF - Annals of Thoracic Surgery
IS - 2
ER -
