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Ann Thorac Surg 2005;80:409-417
© 2005 The Society of Thoracic Surgeons

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Thoracic Surgery Directors Association Award

Radiation Therapy Potentiates Effective Oncolytic Viral Therapy in the Treatment of Lung Cancer

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

Accepted for publication January 10, 2005.

^_* Address reprint requests to Dr Fong, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021 (Email: fongy{at}mskcc.org).

Presented at the Fortieth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 26–28, 2004.

BACKGROUND: Replication-competent oncolytic herpes simplex viruses with deletion of the ₁34.5 gene preferentially replicate in and kill malignant cells. The ₁34.5 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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