Fig. 1.

Replication-defective viral vectors infect cancer cells and deliver an anticancer gene but do not replicate. Adenoviral vectors have been engineered to deliver the herpes simplex thymidine kinase gene (Hs-tk). Once inside the cell, the adenoviral DNA exists as an extrachromosomal element in the nucleus and transcribes/translates the tk gene. Thymidine kinase phosphorylates nucleoside analogs, such as valacyclovir (VCV). The phosphorylated VCV (VCP-P) molecules are then used by the cancer cell DNA polymerases to repair DNA strand break (caused by radiation), leading to DNA replication arrest and immunogenic cell death. This leads to increased recognition of tumor antigens by immune effector cells.