Herpes simplex virus delivery to orthotopic rectal carcinoma results in an efficient and selective antitumor effect

Cancer of the rectum poses a complex therapeutic challenge because of its proximity to adjacent organs and anal sphincters. The addition of radiotherapy before surgical resection has been shown to confer good survival rates while preserving sphincter function. Nevertheless, radiation is associated with significant side effects. On the basis of our previous work showing that herpes simplex virus type-1 (HSV-1) preferentially infects human colon cancer, we set out to examine the oncolytic effect of HSV-1 on orthotopic rectal tumors in mice. Two vectors were compared for oncolytic activity, HSV-1(G beta) with wild-type replication and an attenuated HSV-1 vector (HSV-G47 Delta). Intratumoral injection of HSV-1(G beta) and HSV-G47 Delta resulted in a significant reduction or disappearance of the tumors and increased survival of mice. Although the use of HSV-1(G beta) was associated with systemic toxicity, HSV-G47 Delta appears to possess a selective oncolytic activity. Moreover, infection with HSV-G47 Delta resulted in the activation of the double-stranded RNA-dependent protein kinase (PKR) pathway. A significant improvement in viral replication and the antitumor effect was observed when the PKR inhibitor 2-aminopurine was coadministered with HSV-G47 Delta to the tumor. In conclusion, the efficacy of local delivery of HSV-G47 Delta combined with a specific chemical inhibitor of antiviral activity points to a novel therapeutic modality for rectal cancer and other solid tumors. Gene Therapy (2009) 16, 905-915; doi:10.1038/gt.2009.44; published online 14 May 2009