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- Title
Utility of TK/GCV in the context of highly effective oncolysis mediated by a serotype 3 receptor targeted oncolytic adenovirus.
- Authors
Raki, M.; Hakkarainen, T.; Bauerschmitz, G. J.; Särkioja, M.; Desmond, R. A.; Kanerva, A.; Hemminki, A.
- Abstract
Arming oncolytic adenoviruses with therapeutic transgenes and enhancing transduction of tumor cells are useful strategies for eradication of advanced tumor masses. Herpes simplex virus thymidine kinase (TK) together with ganciclovir (GCV) has been promising when coupled with viruses featuring low oncolytic potential, but their utility is unknown in the context of highly effective infectivity-enhanced viruses. We constructed Ad5/3-Δ24-TK-GFP, a serotype 3 receptor-targeted, Rb/p16 pathway-selective oncolytic adenovirus, where a fusion gene encoding TK and green fluorescent protein (GFP) was inserted into 6.7K/gp19K-deleted E3 region. Ad5/3-Δ24-TK-GFP killed ovarian cancer cells effectively, which correlated with GFP expression. Delivery of GCV immediately after infection abrogated viral replication, which might have utility as a safety switch. Due to the bystander effect, killing of some cell lines in vitro was enhanced by GCV regardless of timing. In murine models of metastatic ovarian cancer, Ad5/3-Δ24-TK-GFP improved antitumor efficacy over the respective replication-deficient virus with GCV. However, GCV did not further enhance efficacy of Ad5/3-Δ24-TK-GFP in vivo. Simultaneous detection of tumor load and virus replication with bioluminescence and fluorescence imaging provided insight into the in vivo kinetics of oncolysis. In summary, TK/GCV may not add antitumor activity in the context of highly potent oncolysis.Gene Therapy (2007) 14, 1380–1388. doi:10.1038/sj.gt.3302992; published online 5 July 2007
- Subjects
ADENOVIRUSES; TRANSGENES; HERPES simplex virus; GANCICLOVIR; GREEN fluorescent protein; CANCER cells
- Publication
Gene Therapy, 2007, Vol 14, Issue 19, p1380
- ISSN
0969-7128
- Publication type
Article
- DOI
10.1038/sj.gt.3302992