Multi-attenuated herpes simplex virus-1 mutant G207 exerts cytotoxicity against epithelial ovarian cancer but not normal mesothelium and is suitable for intraperitoneal oncolytic therapy.

Abstract

Recombinant strains of herpes simplex virus-1 (HSV-1) harboring mutations in the infected cell product (ICP)34.5 region lose their neurovirulence and replicate more efficiently in dividing tumor cells than stationary cells, becoming replication-selective oncolytic agents. Additional mutation of the ICP6 gene, which encodes ribonucleotide reductase, further impairs the ability of HSV-1 mutants to replicate in normal cells, enhancing tumor selectivity. The present study investigated the effect of HSV-G207, a recombinant HSV-1 lacking ICP34.5 and ICP6, against epithelial ovarian cancer (EOC) in vitro and in vivo in a mouse xenograft model. To assess the selectivity of multimutated HSV-G207 against malignant cells, HSV-G207 and wild-type HSV-F were comparatively tested against normal human peritoneal mesothelial cells and EOC cells in vitro. HSV-G207 infected both EOC cells and mesothelial cells; however, unlike EOC cells, mesothelial cells provided a poor substrate for replication of HSV-G207. In contrast to wild-type HSV-F, HSV-G207 exerted a potent oncolytic effect on EOC cells but spared normal mesothelial cells in vitro. Primary EOC cells were more sensitive to the virus than established EOC cell lines. A single intraperitoneal injection of HSV-G207 resulted in a significant reduction in tumor volume and tumor spread in vivo. HSV-G207 was shown to penetrate deeply within tumor nodules and caused no apparent intraperitoneal toxicity. Oncolytic therapy with multimutated replication-restricted HSV may offer a novel approach in the treatment of EOC.

• Authors: G Coukos, A Makrigiannakis, S Montas, L R Kaiser, T Toyozumi, I Benjamin, S M Albelda, S C Rubin, K L Molnar-Kimber
• Journal: Cancer gene therapy (Cancer Gene Ther) Vol. 7 Issue 2 Pg. 275-83 (Feb 2000) ISSN: 0929-1903 [Print] England
• PMID: 10770637 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• DNA, Recombinant
• DNA, Viral

Topics

• Animals
• Carcinoma (pathology, therapy, virology)
• Cell Transformation, Viral (genetics)
• DNA, Recombinant (genetics, metabolism, therapeutic use)
• DNA, Viral (genetics, metabolism, therapeutic use)
• Epithelium (virology)
• Female
• Herpesvirus 1, Human (genetics, pathogenicity, physiology)
• Humans
• Infusions, Parenteral
• Mice
• Mice, SCID
• Mutation (genetics)
• Ovarian Neoplasms (pathology, therapy, virology)
• Tumor Cells, Cultured
• Virulence
• Virus Replication (genetics)