title: Oncolytic viral therapy for human ovarian cancer using a novel replication-competent herpes simplex virus type I mutant in a mouse model.
abstract: OBJECTIVE
  Attenuated mutant strains of herpes simplex virus (HSV) have been effectively used for treatment of malignant brain tumors. As HSV-1 can infect and lyse a variety of cell types, other malignancies may also benefit from such treatment. We sought to test the feasibility of HSV-1 mutant-mediated gene therapy treatment of ovarian cancer.
  
  
  METHODS
  We prepared two attenuated mutant HSV-1 strains. An HSV-1 mutant, hrR3, has replaced the gene encoding ribonucleotide reductase (RR) with the lacZ reporter gene. We also developed a new replication-competent HSV-1 mutant, HR522; this virus, expressing the lacZ reporter gene, induces syncytium formation in infected cells. We compared the efficacy of HR522 with, paclitaxel (Taxol) and hrR3 in the treatment of nude mice harboring human ovarian cancer cells. We also examined the effect of the prodrug ganciclovir (GCV) on the treatment mediated by these HSVs. Survival was evaluated by Kaplan-Meier method and log-rank test.
  
  
  RESULTS
  The survival of mice treated with a high-titer hrR3 (5 x 10(7) plaque-forming units [PFU]) was significantly prolonged as compared with the group given paclitaxel (P < 0.0001, log-rank test). Although the survival of mice treated with high-titer HR522 (5 x 10(7) PFU) was not significantly prolonged compared with paclitaxel-treated group (P = 0.212, log-rank test), GCV markedly enhanced the efficacy of HR522 administration (P < 0.005, vs paclitaxel, log-rank test). The lacZ gene product, visualized using 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside (X-gal) histochemistry, was detected in HR522-treated tumors in areas also exhibiting apoptotic changes.
  
  
  CONCLUSIONS
  These findings indicate that the combination of HR522 and GCV possesses significant therapeutic potential for treatment of ovarian cancer. Such viral therapy offers a novel approach to reductions in the dissemination of ovarian cancer.
authors.affiliation: Department of Gynecology, Aichi Cancer Center Hospital, 1-1 kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan. nawa2000@aichi-cc.jp
authors.forename: Akihiro
authors.initials: A
authors.lastname: Nawa
authors.forename: Naoki
authors.initials: N
authors.lastname: Nozawa
authors.forename: Fumi
authors.initials: F
authors.lastname: Goshima
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Nagasaka
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Kikkawa
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Niwa
authors.forename: Toru
authors.initials: T
authors.lastname: Nakanishi
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kuzuya
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Nishiyama
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic; D002522:Chlorocebus aethiops; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy / Q000235:genetics / Q000628:therapy* / Q000821:virology*; D003588:Cytopathogenic Effect, Viral; D005260:Female; D015774:Ganciclovir / Q000494:pharmacology; D015316:Genetic Therapy / Q000379:methods*; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000628:therapy* / Q000821:virology*; D017239:Paclitaxel / Q000494:pharmacology; D014709:Vero Cells; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel; D015774:Ganciclovir