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10.1245/s10434-006-9127-4
Annals of Surgical Oncology 14:258-269 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Radiation-Induced Cellular DNA Damage Repair Response Enhances Viral Gene Therapy Efficacy in the Treatment of Malignant Pleural Mesothelioma

Prasad S. Adusumilli, MD, Mei-Ki Chan, BS, Michael Hezel, BS, Zhenkun Yu, MD, PhD, Brendon M. Stiles, MD, Ting-Chao Chou, PhD, Valerie W. Rusch, MD and Yuman Fong, MD

Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA

Correspondence: Address correspondence and reprint requests to: Yuman Fong, MD; E-mail: fongy{at}mskcc.org

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.

Key Words: Ionizing radiation • Gene therapy • Viruses • Herpes simplex virus • Combination therapy




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