Tumor Cell Cytotoxicity via Prodrug Activation (Ganciclovir)

Tumor cell cytotoxicity via prodrug activation using ganciclovir is a targeted cancer therapy strategy that exploits the selective activation of a non-toxic prodrug (ganciclovir) within tumor cells, leading to their destruction. This approach is most commonly implemented through gene-directed enzyme prodrug therapy (GDEPT), where tumor cells are genetically modified to express an exogenous enzyme—most notably, herpes simplex virus thymidine kinase (HSV-tk)—which can convert ganciclovir into its active, cytotoxic form. Ganciclovir itself is not highly toxic to mammalian cells. When HSV-tk is present in tumor cells, it phosphorylates ganciclovir to its monophosphate form. Cellular kinases further phosphorylate it to the triphosphate form (ganciclovir-TP). Ganciclovir-TP inhibits DNA polymerase and incorporates into DNA during replication, causing chain termination and cell death. The process selectively kills only those cells expressing HSV-tk but also induces a "bystander effect," killing neighboring non-modified tumor cells due to diffusion of toxic metabolites or immune-mediated mechanisms. The approach has been tested in various preclinical and clinical settings for solid tumors and some hematological malignancies. The main biological outcome is targeted cytotoxicity and the stimulation of local immune responses.

Other names

Ganciclovir Prodrug TherapyHSV-tk/Ganciclovir SystemGene-Directed Enzyme Prodrug Therapy (GDEPT) with GanciclovirProdrug Activation Therapy

Ganciclovir is converted by HSV-tk to ganciclovir-TP, which inhibits DNA polymerase and incorporates into DNA, causing chain termination and cell death.