Cyclic-AMP induction of gap junctional intercellular communication increases bystander effect in suicide gene therapy

The phenomenon of the "bystander effect" (BE) observed in suicide gene ther apy studies leads to the intriguing possibility that cytotoxicity can be ac hieved even in tumor cells that have not themselves been targeted with nove l genetic material. There is considerable data suggesting the role of gap j unction-mediated intercellular communication (GJIC) in the BE. Transfer of connexin (Cx)-encoding genes, the building blocks of GJIC, has been shown b oth in vitro and in vivo to increase the EE, Since the loss of GJIC is a co mmon feature of cancer cells, we examined the consequence of GJIC up-regula tion on the BE in suicide gene therapy, We used 8-bromo-cyclic-AMP to induc e Cx43 and GJIC. In mixing assays, using various proportions of cells conta ining viral thymidine kinase delivered by an adenoviral delivery system or stably transduced by a retrovirus vector, 8-bromo-cyclic-AMP enhanced the B E of cell killing using ganciclovir, The induction in cell killing was more significant when a low percentage of the cell population was infected, whi ch is the relevant clinical situation. We have demonstrated that this is no t due to an effect on infectivity or suicide gene expression. Since decreas ed GJIC is part of the transformed phenotype, induction of Cxs provides an element of selectivity to suicide gene therapy. Our study adds strength to the rationale to develop clinically tolerable GJ inducers to potentiate the effect of suicide gene therapy via the BE.