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

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Abstract

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.

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Acknowledgments

Supported in part by AACR-Astra Zeneca Cancer Research and Prevention Foundation Fellowship (P.S.A), grants RO1 CA 75416 and RO1 CA/DK80982 (Y.F.) from the National Institutes of Health, grant MBC-99366 (Y.F.) from the American Cancer Society, grant BC024118 from the U.S. Army (Y.F.), grant IMG0402501 from the Susan G. Komen Breast Cancer Foundation (Y.F. and P.S.A.), grant 032047 from the Flight Attendant Medical Research Institute (Y.F. and P.S.A.), and William H. Goodwin and Alice Goodwin and the Commonwealth Foundation for Cancer Research grant—The Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center (Y.F).

The authors thank Medigene, Inc., for providing the NV1066 virus; Liza Marsh of the Department of Surgery at Memorial Sloan-Kettering Cancer Center for editorial assistance; and Yuhong She, MD, and Wong Wai, MS, of the Anti-Tumor Core Facility at Memorial Sloan-Kettering Cancer Center for their assistance with this project.

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Authors and Affiliations

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

    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 & Yuman Fong MD

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  1. Prasad S. Adusumilli MD
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  2. Mei-Ki Chan BS
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Correspondence to Yuman Fong MD.

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Adusumilli, P.S., Chan, MK., Hezel, M. et al. Radiation-Induced Cellular DNA Damage Repair Response Enhances Viral Gene Therapy Efficacy in the Treatment of Malignant Pleural Mesothelioma. Ann Surg Oncol 14, 258–269 (2007). https://doi.org/10.1245/s10434-006-9127-4

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