Recombinant interferon alpha 2a synergistically enhances ganciclovir-mediated tumor cell killing in the herpes simplex virus thymidine kinase system

The herpes simplex virus thymidine kinase (HSV-TK) gene is being developed in the treatment of many different types of tumors. The HSV-TK gene sensiti zes tumor cells to the antiviral drug ganciclovir (GCV) and mediates the by stander effect in which unmodified tumor cells are killed as well. Although this approach has shown a significant antitumor effect, the need to potent iate this therapy exists. The results of this study indicate that recombina nt interferon alpha 2a (IFN alpha 2a) acts synergistically with GCV to kill HSV-TK-expressing PA1 human ovarian tumor cells. Furthermore, it enhances the bystander killing of nearby unmodified tumor cells that do not express the HSV-TK gene. Previous studies have suggested that in vitro and in vivo bystander effects may be mediated by different mechanisms. However, IFN alp ha 2a enhanced bystander killing in both systems, with the survival of mice bearing preexisting tumors being significantly prolonged when they were tr eated with IFN alpha 2a and HSV-TK/GCV compared with either treatment alone . Mechanism studies have shown that treatment with IFN alpha 2a and GCV cau sed an increase in cells in S phase 24 hours after therapy in the HSV-TK-ex pressing cells, but the mechanism of action of IFN alpha 2a does not seem t o be related to an increase in DNA damage, because GCV incorporation was no t increased after treatment with IFN alpha 2a. These findings suggest that IFN alpha 2a may be a useful adjunctive therapy for the HSV-TK/GCV system.