The extent of heterocellular communication mediated by gap junctions is predictive of bystander tumor cytotoxicity in vitro.
Herpes simplex virus thymidine kinase (HSV-tk)/ganciclovir (GCV) viral-directed enzyme prodrug gene therapy causes potent, tumor-selective cytotoxicity in animal models in which HSV-tk gene transduction is limited to a minority of tumor cells. The passage of toxic molecules from HSV-tk+ cells to neighboring HSV-tk- cells during GCV therapy is one mechanism that may account for this "bystander" cytotoxicity. To investigate whether gap junction-mediated intercellular coupling could mediate this bystander effect, we used a flow cytometry assay to quantitate the extent of heterocellular coupling between HSV-tk+ murine fibroblasts and both rodent and human tumor cell lines. Bystander tumor cytotoxicity during GCV treatment in a coculture assay was highly correlated (P < 0.001) with the extent of gap junction-mediated coupling. These findings show that gap junction-mediated intercellular coupling contributes to the in vitro bystander effect during HSV-tk/GCV therapy and that retroviral transduction of tumor cells is not required for bystander cytotoxicity.
D000818:Animals; D000963:Antimetabolites / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000633:toxicity*; D002450:Cell Communication; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D015774:Ganciclovir / Q000008:administration & dosage / Q000633:toxicity*; D017629:Gap Junctions / Q000502:physiology*; D006801:Humans; D051379:Mice; D011355:Prodrugs / Q000008:administration & dosage*; D051381:Rats; D018139:Simplexvirus / Q000201:enzymology*; D013937:Thymidine Kinase / Q000008:administration & dosage; D014407:Tumor Cells, Cultured
D000963:Antimetabolites; D000970:Antineoplastic Agents; D011355:Prodrugs; D013937:Thymidine Kinase; D015774:Ganciclovir