title: Persistent anti-tumor effects via recombinant adeno-associated virus encoding herpes thymidine kinase gene monitored by PET-imaging.
abstract: Despite the well-documented advantages of the recombinant adeno-associated virus (rAAV) as a gene delivery vehicle, including its non-pathogenic and long-term therapeutic gene expression, there have been very limited studies on its potential for producing persistent anti-tumor effects, particularly in vivo. To address this issue, we constructed rAAV vectors encoding herpes simplex virus 1-thymidine kinase (HSV-TK) or its mutant form (sc39TK) as therapeutic genes, and GFP as a control gene. Effective rAAV-mediated gene delivery was readily observed in human cancer cells using immunocytochemistry and Western blotting. Cell survival analysis following prodrug ganciclovir treatment implied that both preferential and superior cytotoxicity was achieved by rAAV-sc39TK introduction. Persistent anti-tumor effects in vivo were investigated in Balb/c nude mice bearing human cancer cells treated with either rAAV-sc39TK or -GFP. Severe tumor growth inhibition was clearly observed only in the case of sc39TK with ganciclovir treatment. Non-invasive micro-PET imaging using 18F-FHBG directly correlated with persistent anti-tumor effects by sc39TK. Therefore, the present study provides evidence that rAAV-mediated persistent therapeutic gene expression can occur, resulting in long-term anti-tumor activities and that these events can be readily monitored using micro-PET imaging.
authors.affiliation: Department of Microbiology, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Ji Yun
authors.initials: JY
authors.lastname: Kim
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Kim
authors.forename: Maria
authors.initials: M
authors.lastname: Khim
authors.forename: Han Saem
authors.initials: HS
authors.lastname: Lee
authors.forename: Jin Hwa
authors.initials: JH
authors.lastname: Jung
authors.forename: Dae Hyuk
authors.initials: DH
authors.lastname: Moon
authors.forename: Sunjoo
authors.initials: S
authors.lastname: Jeong
authors.forename: Heuiran
authors.initials: H
authors.lastname: Lee
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000229:Dependovirus / Q000235:genetics; D015774:Ganciclovir / Q000494:pharmacology / Q000627:therapeutic use; D023061:Gene Order; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006367:HeLa Cells; D018259:Herpesvirus 1, Human / Q000201:enzymology* / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D049268:Positron-Emission Tomography; D013937:Thymidine Kinase / Q000235:genetics* / Q000378:metabolism
chemical_list: D013937:Thymidine Kinase; D015774:Ganciclovir