Bystander effect in herpes simplex virus-thymidine kinase/ganciclovir cancer gene therapy: Role of gap-junctional intercellular communication

Antitumor suicide gene therapy is one of the emerging strategies against ca ncer. It consists of the introduction into cancer cells of a gene capable o f converting a nontoxic prodrug into a cytotoxic drug. Because this therape utic gene cannot be easily introduced into the whole cell population of a t umor, the successful eradication of tumors depends on a phenomenon called t he "bystander effect," by which the introduced gene can affect even cells i n which it is not itself present. From a therapeutic point of view, it may be crucial to enhance this phenomenon through various means to achieve tumo r eradication. One such suicide gene, the thymidine kinase gene from the he rpes simplex virus, in combination with the prodrug ganciclovir, has been e xtensively and successfully used in some animal models exhibiting a strong bystander effect. Among the mechanisms involved in this phenomenon, gap jun ctional intercellular communication (GJIC) is directly involved in the tran sfer of the toxic metabolites of ganciclovir, which pass directly from herp es simplex virus thymidine kinase-expressing cells to surrounding cells tha t do not express it. Because GJIC appears to be a mediator of the bystander effect both in vitro and in vivo, here we review possible molecular strate gies for enhancing the extent of tumor cell death by increasing the intratu moral GJIC capacity.