140. Enhanced Cell Killing Effect of E1 Modified Adenoviruses Expressing HSV-TK Suicide Gene

To combine the advantages of the prodrug/suicide gene approach with that of replicating adenoviruses, we have developed replicating adenoviral vectors harboring HSV-TK, generating Ad-ΔE1B19-TK, Ad-ΔE1B55-TK, Ad-ΔE1B19/55-TK adenoviruses. Infection with adenoviruses expressing HSV-TK increased the sensitivity of cells to GCV. Cell killing assay was used to compare the combined therapy with the two single therapy modalities and non-treated controls in human cancer cell line. The cytotoxicity of the combination therapy with replicating adenovirus and GCV was dramatically increased compared with replicating adenoviruses alone or replication incompetent adenovirus expressing TK. In contrast, the cytotoxicity of the combination therapy with Ad-ΔE1B19-TK and GCV was reduced when compared to Ad-ΔE1B19-TK alone. This result suggests that the inhibition of viral replication and oncolysis by the HSV-TK/GCV system counterbalance the potent cytotoxicity of Ad-ΔE1B19-TK. Animals treated with Ad-ΔE1-TK with GCV had some reduction in tumor growth compared to animals injected with PBS only. All replicating adenoviral vectors were more efficacious than Ad-ΔE1-TK with GCV treatment.