title: Use of carrier cells to deliver a replication-selective herpes simplex virus-1 mutant for the intraperitoneal therapy of epithelial ovarian cancer.
abstract: Epithelial ovarian cancer (EOC) remains localized within the peritoneal cavity in a large number of patients, lending itself to i.p. approaches of therapy. In the present study, we investigated the effect of replication-selective herpes simplex virus-1 (HSV-1) used as an oncolytic agent against EOC and the use of human teratocarcinoma PA-1 as carrier cells for i.p. therapy. HSV-1716, a replication-competent attenuated strain lacking ICP34.5, caused a direct dose-dependent oncolytic effect on EOC cells in vitro. A single i.p. administration of 5 x 10(6) plaque-forming units resulted in a significant reduction of tumor volume and tumor spread and an increase in survival in a mouse xenograft model. PA-1 cells supported HSV replication in vitro and bound preferentially to human ovarian carcinoma surfaces compared with mesothelial surfaces in vitro and in vivo. In comparison with the administration of HSV-1716 alone, irradiated PA-1 cells, infected at two multiplicities of infection with HSV-1716 and injected i.p. at 5 x 10(6) cells/animal, led to a significant tumor reduction in the two models tested and the significant prolongation of mean survival in one model. Histological evaluation revealed extensive necrosis in tumor areas infected by HSV-1716. Immunohistochemistry against HSV-1 revealed areas of viral infection within tumor nodules, which persisted for several weeks after treatment. Administration of HSV-infected PA-1 carrier cells resulted in larger areas of tumor infected by the virus. Our results indicate that replication-competent attenuated HSV-1 exerts a potent oncolytic effect on EOC, which may be further enhanced by the utilization of a delivery system with carrier cells, based on amplification of the viral load and possibly on preferential binding of carrier cells to tumor surfaces.
authors.affiliation: Department of Obstetrics and Gynecology, University of Pennsylvania Medical Center, Philadelphia 19104, USA.
authors.forename: G
authors.initials: G
authors.lastname: Coukos
authors.forename: A
authors.initials: A
authors.lastname: Makrigiannakis
authors.forename: E H
authors.initials: EH
authors.lastname: Kang
authors.forename: D
authors.initials: D
authors.lastname: Caparelli
authors.forename: I
authors.initials: I
authors.lastname: Benjamin
authors.forename: L R
authors.initials: LR
authors.lastname: Kaiser
authors.forename: S C
authors.initials: SC
authors.lastname: Rubin
authors.forename: S M
authors.initials: SM
authors.lastname: Albelda
authors.forename: K L
authors.initials: KL
authors.lastname: Molnar-Kimber
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002470:Cell Survival / Q000528:radiation effects; D003588:Cytopathogenic Effect, Viral; D005260:Female; D006561:Herpes Simplex / Q000473:pathology / Q000821:virology; D006801:Humans; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000628:therapy* / Q000821:virology; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000628:therapy* / Q000821:virology; D018139:Simplexvirus / Q000235:genetics*; D015996:Survival Rate; D018243:Teratocarcinoma / Q000473:pathology / Q000821:virology*; D014407:Tumor Cells, Cultured; D014779:Virus Replication