Radiation-induced cellular DNA damage repair response enhances viral gene therapy efficacy in the treatment of malignant pleural mesothelioma

Ann Surg Oncol. 2007 Jan;14(1):258-69. doi: 10.1245/s10434-006-9127-4. Epub 2006 Nov 1.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antigens, Differentiation / metabolism
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cell Survival
  • Combined Modality Therapy
  • DNA Damage / radiation effects*
  • DNA Repair*
  • Humans
  • Male
  • Mesothelioma / metabolism
  • Mesothelioma / radiotherapy
  • Mesothelioma / therapy*
  • Mesothelioma / virology
  • Mice
  • Mice, Nude
  • Oncolytic Virotherapy*
  • Pleural Neoplasms / metabolism
  • Pleural Neoplasms / radiotherapy
  • Pleural Neoplasms / therapy*
  • Pleural Neoplasms / virology
  • Protein Phosphatase 1
  • RNA, Small Interfering / metabolism
  • Simplexvirus
  • Virus Replication / radiation effects


  • Antigens, Differentiation
  • Cell Cycle Proteins
  • RNA, Small Interfering
  • PPP1R15A protein, human
  • Protein Phosphatase 1