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.
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.
Coukos
G
G
Department of Obstetrics and Gynecology, University of Pennsylvania Medical Center, Philadelphia 19104, USA.
Makrigiannakis
A
A
Montas
S
S
Kaiser
L R
LR
Toyozumi
T
T
Benjamin
I
I
Albelda
S M
SM
Rubin
S C
SC
Molnar-Kimber
K L
KL
D000818:Animals; D002277:Carcinoma / Q000473:pathology / Q000628:therapy / Q000821:virology*; D002472:Cell Transformation, Viral / Q000235:genetics; D004274:DNA, Recombinant / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D004279:DNA, Viral / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D004848:Epithelium / Q000821:virology; D005260:Female; D018259:Herpesvirus 1, Human / Q000235:genetics* / Q000472:pathogenicity* / Q000502:physiology; D006801:Humans; D007263:Infusions, Parenteral; D051379:Mice; D016513:Mice, SCID; D009154:Mutation / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000473:pathology / Q000628:therapy / Q000821:virology*; D014407:Tumor Cells, Cultured; D014774:Virulence; D014779:Virus Replication / Q000235:genetics
D004274:DNA, Recombinant; D004279:DNA, Viral