Recombinant interferon α2a synergistically enhances ganciclovir-mediated tumor cell killing in the herpes simplex virus thymidine kinase system

Abstract

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 sensitizes tumor cells to the antiviral drug ganciclovir (GCV) and mediates the bystander effect in which unmodified tumor cells are killed as well. Although this approach has shown a significant antitumor effect, the need to potentiate this therapy exists. The results of this study indicate that recombinant interferon ␣2a (IFN␣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␣2a enhanced bystander killing in both systems, with the survival of mice bearing preexisting tumors being significantly prolonged when they were treated with IFN␣2a and HSV-TK/GCV compared with either treatment alone. Mechanism studies have shown that treatment with IFN␣2a and GCV caused an increase in cells in S phase 24 hours after therapy in the HSV-TK-expressing cells, but the mechanism of action of IFN␣2a does not seem to be related to an increase in DNA damage, because GCV incorporation was not increased after treatment with IFN␣2a. These findings suggest that IFN␣2a may be a useful adjunctive therapy for the HSV-TK/GCV system.

Herpes simplex virus thymidine kinase and granulocyte macrophage colony-stimulating factor combination gene therapy in a murine CT26 cell colon cancer model

“…27 In this study, the bystander effects were more potent in vitro, in which one tumor cell expressing the HSV-TK gene destroyed approximately two neighboring cells, compared with in vivo, in which each of two transduced cells killed only one bystander cell. Taken together with the findings on T/C ratios, this makes immunological mechanisms in the mediation of the bystander-killing effect less likely.…”

A role for MAP kinase in the antitumor activity of a nucleoside analog

“…Our previous studies showed that although IFN significantly increased the toxicity of GCV, it did not enhance the incorporation of GCV into cellular DNA, suggesting that there was no correlation between the amount incorporated and cell killing. 10 Our present studies showed that after removal of GCV from the extracellular medium, no significant amounts of GCV were excised, even in the absence of IFN exposure, suggesting that the repair enzymes did not recognize it as an illegitimate base, and DNA synthesis was not immediately stopped by its presence.…”

“…10 These assays have been validated for this system. Both types of assays were conducted for all studies related to toxicity and were confirmatory.…”

Monocyte chemoattractant protein-1 gene delivery enhances antitumor effects of herpes simplex virus thymidine kinase/ganciclovir system in a model of colon cancer

“…Some new strategies have been proposed to enhance the antitumor effects of suicide gene therapy, that is, by induction of immune responses to tumor cells via coexpression of cytokine and chemokine genes. Recent studies have demonstrated that codelivery strategies employing IL-2 and HSV-tk, 31 IL-2, GM-CSF and HSV-tk, 32 IL-12 and HSV-tk, 33 IL-4 and HSV-tk, 34 TNF-a and HSV-tk, 35 as well as IFN-a2a and HSV-tk 36 are relatively effective compared to treatment with the suicide gene alone.…”