Utility of TK GCV in the context of highly effective oncolysis mediated by a serotype 3 receptor targeted oncolytic adenovirus

• Published in: Gene therapy Vol. 14; no. 19; pp. 1380 - 1388
• Main Authors: RAKI, M, HAKKARAINEN, T, BAUERSCHMITZ, G. J, SÄRKIOJA, M, DESMOND, R. A, KANERVA, A, HEMMINKI, A
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.10.2007
• Subjects: Adenovirus; Adenoviruses; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animal models; Animals; Antitumor activity; Antiviral Agents - metabolism; Antiviral Agents - therapeutic use; Applied cell therapy and gene therapy; Biological and medical sciences; Bioluminescence; Biotechnology; Carcinoma - secondary; Carcinoma - therapy; Care and treatment; Cell Line, Tumor; Cell receptors; Cell structures and functions; Female; Fundamental and applied biological sciences. Psychology; Fusion protein; Ganciclovir; Ganciclovir - metabolism; Ganciclovir - therapeutic use; Gene Expression; Gene therapy; Genetic aspects; Genetic Engineering; Genetic Therapy - methods; Green fluorescent protein; Green Fluorescent Proteins - genetics; Health aspects; Health. Pharmaceutical industry; Herpes simplex; Herpes simplex virus; Humans; Industrial applications and implications. Economical aspects; Infectivity; Kinases; Medical imaging; Medical sciences; Metastases; Mice; Mice, Nude; Mice, SCID; Miscellaneous; Models, Animal; Molecular and cellular biology; Neoplasm Transplantation; Oncology; Oncolysis; Oncolytic Virotherapy - methods; Ovarian cancer; Ovarian Neoplasms - therapy; Peritoneal Neoplasms - secondary; Peritoneal Neoplasms - therapy; Physiological aspects; Protein kinases; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Replication; Simplexvirus - enzymology; Thymidine; Thymidine kinase; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Transgenes; Tumor cells; Virus Replication; Viruses; Finland; oncolytic adenovirus; Adenoviridae; ovarian cancer; Ovary cancer; Malignant tumor; TK/GCV; virotherapy; Female genital diseases; Virus; Ovarian diseases; Imaging; Oncolysis; noninvasive imaging; Serotype; Gene therapy; Vector; Biological receptor
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/sj.gt.3302992

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-Delta24-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-Delta24-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-Delta24-TK-GFP improved antitumor efficacy over the respective replication-deficient virus with GCV. However, GCV did not further enhance efficacy of Ad5/3-Delta24-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.