Telomerase-specific oncolytic adenoviral therapy for orthotopic hepatocellular carcinoma in HBx transgenic mice
Journal
International Journal of Cancer
Journal Volume
132
Journal Issue
6
Pages
1451-1462
Date Issued
2013
Author(s)
Abstract
The telomerase-specific replication-competent oncolytic adenovirus, Telomelysin, was developed for virus-mediated preferential lysis of tumor cells. Its selectivity is derived from a human telomerase reverse transcriptase (hTERT) promoter-driven active viral replication, which occurs in cancer cells with high telomerase activity but not in normal cells lacking such activity. Because the TERT activity is elevated in most cases of hepatocellular carcinoma (HCC), the current study aims to investigate whether Telomelysin can be used for treatment of HCC. The oncolytic effect of Telomelysin has been investigated both in vitro using cell culture and in vivo using an immunocompetent in situ orthotopic HCC model. In this model, HCC developed spontaneously in the liver of HBx transgenic mice, which is pathologically and genetically similar to human HCC. In cell culture assay, Telomelysin lyses HCC cell lines at a low multiplicity of infection (MOI), ranging 0.77-6.35 (MOI [PFU/cell]). In the orthotopic HCC model, Telomelysin showed a potent oncolytic effect on HCC but spared normal liver tissue. Dose escalation analysis identified a safety dose of 1.25 × 108 PFU for this model. The effect of multiple injections of Telomelysin was also evaluated in this immunocompetent HCC model. We found that the virus replicates in HCC after a second intratumoral injection despite an immune response induced by the previous injection. This preclinical study shows that Telomelysin can be used for treatment of human HCC at an appropriate dosage and that its tumor-killing activity persists after multiple injections. What's new? More than 95 percent of hepatocellular carcinomas (HCCs) are associated with telomerase reverse transcriptase (hTERT) activation, which promotes cell immortality. In this study, the adenovirus Telomelysin demonstrated specific oncolytic activity in HCC cells with elevated hTERT. In addition, in mice with orthotopically growing HCC xenografts, the adenovirus slowed tumor growth, despite the generation of an immune response. The results suggest that Telomelysin may be useful in the treatment of HCC. Copyright ? 2012 UICC.
SDGs
Other Subjects
antineoplastic agent; obp 301; oncolytic adenovirus; telomelysin; unclassified drug; animal cell; animal experiment; animal model; animal tissue; antineoplastic activity; article; cancer cell culture; cell culture; controlled study; drug dose escalation; drug efficacy; drug potency; drug safety; human; human cell; immunocompetent cell; in vitro study; in vivo study; liver; liver cell carcinoma; mouse; nonhuman; oncolytic virotherapy; priority journal; transgenic mouse; tumor xenograft; virus replication
Publisher
Wiley-Liss Inc.
Type
journal article