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Imaging of Viral Thymidine Kinase Gene Expression by Replicating Oncolytic Adenovirus and Prediction of Therapeutic Efficacy

 Eun-Jung Kim  ;  Ji Young Yoo  ;  Young-Hwan Choi  ;  Keun-Jae Ahn  ;  Jong-Doo Lee  ;  Chae-Ok Yun  ;  Mijin Yun 
 YONSEI MEDICAL JOURNAL, Vol.49(5) : 811-818, 2008 
Journal Title
Issue Date
Adenoviridae/genetics* ; Adenoviridae/physiology ; Cell Line, Transformed ; Cell Line, Tumor ; Ganciclovir/pharmacology ; Gene Expression ; Genetic Therapy/methods ; Genetic Vectors ; Humans ; Oncolytic Virotherapy* ; Oncolytic Viruses/genetics* ; Oncolytic Viruses/physiology ; Simplexvirus/genetics ; Tetrazolium Salts/analysis ; Thiazoles/analysis ; Thymidine Kinase/genetics* ; Thymidine Kinase/metabolism ; Transgenes ; Viral Proteins/genetics* ; Viral Proteins/metabolism ; Virus Replication
Oncolysis ; adenovirus ; thymidine kinase ; gene therapy ; radiotracer
PURPOSE: We have used a genetically attenuated adenoviral vector which expresses HSVtk to assess the possible additive role of suicidal gene therapy for enhanced oncolytic effect of the virus. Expression of TK was measured using a radiotracer-based molecular counting and imaging system. MATERIALS AND METHODS: Replication-competent recombinant adenoviral vector (Ad-DeltaE1B19/55) was used in this study, whereas replication-incompetent adenovirus (Ad-DeltaE1A) was generated as a control. Both Ad-DeltaE1B19/55-TK and Ad-DeltaE1A-TK comprise the HSVtk gene inserted into the E3 region of the viruses. YCC-2 cells were infected with the viruses and incubated with 2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl-5-iodouracil (I-131 FIAU) to measure amount of radioactivity. The cytotoxicity of the viruses was determined, and gamma ray imaging of HSVtk gene was performed. MTT assay was also performed after GCV treatment. RESULTS: On gamma counter-analyses, counts/ minute (cpm)/microg of protein showed MOIs dependency with DeltaE1B19/55-TK infection. On MTT assay, Ad-DeltaE1B19/55-TK led to more efficient cell killing than Ad-DeltaE1A-TK. On plate imaging by gamma camera, both Ad-DeltaE1B19/55-TK and Ad-DeltaE1A-TK infected cells showed increased I-131 FIAU uptake in a MOI dependent pattern, and with GCV treatment, cell viability of DeltaE1B19/55-TK infection was remarkably reduced compared to that of Ad-DeltaE1A-TK infection. CONCLUSION: Replicating Ad-DeltaE1B19/55-TK showed more efficient TK expression even in the presence of higher-cancer cell killing effects compared to non-replicating Ad-DeltaE1A-TK. Therefore, GCV treatment still possessed an additive role to oncolytic effect of Ad-DeltaE1B19/55-TK. The expression of TK by oncolytic viruses could rapidly be screened using a radiotracer-based counting and imaging technique.
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1. College of Medicine (의과대학) > Dept. of Nuclear Medicine (핵의학교실) > 1. Journal Papers
Yonsei Authors
Yun, Mi Jin(윤미진) ORCID logo https://orcid.org/0000-0002-1712-163X
Lee, Jong Doo(이종두)
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