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Inclusion of the herpes simplex thymidine kinase gene in a replicating adenovirus does not augment antitumor efficacy
E S Lambright1, K Amin, R Wiewrodt
1Department of Surgery, University of Pennsylvania Medical Center, Philadelphia, PA, USA.
Abstract:
Replication-incompetent adenoviruses (Ad) carrying the herpes simplex thymidine kinase (HSVtk) gene have been used in a number of human cancer gene therapy trials, however transduction has generally been limited to a small minority of tumor cells. To solve this problem, replication-competent adenoviral vectors carrying transgenes such as HSVtk have been developed. However, contradictory evidence exists regarding the efficacy of these new vectors. Accordingly, we constructed and tested a replication-competent E3-deleted adenoviral vector containing the HSVtk suicide gene driven by the endogenous E3 promoter (Ad.wt.tk). This virus showed high level production of the HSVtk transgene and was more efficacious than a non-replicating virus in vitro, after injection into flank tumors, and against established intraperitoneal tumors. However, addition of ganciclovir (GCV) therapy to cells or tumor-bearing animals treated with the replicating vector containing the HSVtk suicide gene did not result in increased cell killing. Our results indicate that addition of HSVtk to a replicating Ad virus will not likely be useful in augmenting antitumor effects.
Insights
Replication-competent adenoviruses carrying the herpes simplex thymidine kinase (HSVtk) gene showed efficacy in cancer gene therapy. However, adding ganciclovir (GCV) did not improve tumor cell killing with this replicating vector.
Area of Science:
- Oncolytic virotherapy
- Gene therapy
- Adenovirus vectors
Background:
- Replication-incompetent adenoviruses (Ad) for cancer gene therapy have limited tumor cell transduction.
- Replication-competent adenoviral vectors offer potential for improved efficacy.
- Evidence on the efficacy of replication-competent vectors is contradictory.
Purpose of the Study:
- To construct and evaluate a replication-competent E3-deleted adenoviral vector carrying the herpes simplex thymidine kinase (HSVtk) suicide gene.
- To assess the efficacy of this vector alone and in combination with ganciclovir (GCV) therapy.
Main Methods:
- Construction of an E3-deleted replication-competent adenoviral vector (Ad.wt.tk) expressing HSVtk.
- In vitro and in vivo testing of Ad.wt.tk efficacy in flank and intraperitoneal tumor models.
- Evaluation of combined Ad.wt.tk and GCV therapy.
Main Results:
- Ad.wt.tk demonstrated high-level HSVtk production.
- The replicating vector was more efficacious than a non-replicating counterpart in vitro and in vivo.
- Combination therapy with ganciclovir (GCV) did not enhance cell killing.
Conclusions:
- Replication-competent adenoviral vectors expressing HSVtk show antitumor activity.
- The addition of HSVtk to a replicating adenovirus does not appear to augment antitumor effects when combined with GCV therapy.