Evaluation of ganciclovir-mediated enhancement of the antitumoral effect in oncolytic, multimutated herpes simplex virus type 1 (G207) therapy of brain tumors

Abstract

G207 is a multimutated, conditionally replicating herpes simplex virus type 1 (HSV-1) that retains an intact viral thymidine kinase (HSV-tk) gene. The virus exhibits oncolytic activity in various tumors and is being evaluated in patients with recurrent malignant glioma. In view of the potential for ganciclovir (GCV) to either enhance or inhibit the antitumoral activity of HSV-tk-retaining HSV-1 vectors, we evaluated the effect of GCV administration on the antitumoral activity of G207. In culture, addition of GCV either had no effect or inhibited the cytocidal action of G207 at replication-permissive temperatures, while it significantly increased the cell killing in three of the four cell lines studied when virus replication was inhibited at nonpermissive temperatures. Using a G207-permissive immunocompetent mouse tumor model, subcutaneous N18 neuroblastoma in syngeneic A/J mice, we found that GCV treatment did not affect G207-mediated tumor growth inhibition at a variety of viral doses (10⁵, 10⁷, and 10⁷ × 2 plaque-forming units). In A/J mice harboring intracerebral N18 tumors, GCV administration had no significant effect on the prolongation of survival by G207 inoculation. These findings suggest that GCV administration may not be beneficial to the efficacy of G207 tumor therapy under conditions that favor active viral replication, because the potential HSV-tk/GCV-mediated enhancement of G207 oncolytic activity may be balanced out by the inhibitory action of GCV on viral replication.