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

  

Authors:	Adusumilli, P. S.; Chan, M. K.; Hezel, M.; Yu, Z.; Stiles, B. M.; Chou, T. C.; Rusch, V. W.; Fong, Y.
Article Title:	Radiation-induced cellular DNA damage repair response enhances viral gene therapy efficacy in the treatment of malignant pleural mesothelioma
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. © 2006 Society of Surgical Oncology.
Keywords:	human cell; combined modality therapy; animals; cell cycle proteins; mice; dna damage; cell survival; dna repair; small interfering rna; rna, small interfering; herpes simplex; cytotoxicity; in vitro study; cell line, tumor; mice, nude; tumor cell line; western blotting; gene therapy; simplexvirus; oncolytic virotherapy; pleura mesothelioma; mesothelioma; ionizing radiation; lactate dehydrogenase; real time polymerase chain reaction; upregulation; virus replication; combination therapy; herpes simplex virus; pleural neoplasms; enzyme assay; cell killing; antigens, differentiation; viruses; viral gene therapy; virus culture
Journal Title:	Annals of Surgical Oncology
Volume:	14
Issue:	1
ISSN:	1068-9265
Publisher:	Springer
Date Published:	2007-01-01
Start Page:	258
End Page:	269
Language:	English
DOI:	10.1245/s10434-006-9127-4
PUBMED:	17080237
PROVIDER:	scopus
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-33845661124&partnerID=40&md5=e559c876570cf696dca7b95d63718d85
Notes:	--- - "Cited By (since 1996): 10" - "Export Date: 17 November 2011" - "CODEN: ASONF" - "Source: Scopus"

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