Article: article from journal or magazin.
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.
Cancer Gene Therapy
Publication types: Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.Publication Status: ppublish
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.
Animals, Carcinoma/pathology, Carcinoma/therapy, Cell Transformation, Viral/genetics, DNA, Recombinant/genetics, DNA, Recombinant/metabolism, DNA, Viral/genetics, DNA, Viral/metabolism, Epithelium/virology, Female, Herpesvirus 1, Human/genetics, Herpesvirus 1, Human/pathogenicity, Humans, Infusions, Parenteral, Mice, Mice, SCID, Mutation/genetics, Ovarian Neoplasms/pathology, Ovarian Neoplasms/therapy, Tumor Cells, Cultured, Virulence, Virus Replication/genetics
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