title: Effects of tumor selective replication-competent herpes viruses in combination with gemcitabine on pancreatic cancer.
abstract: OBJECTIVE
  Pancreatic cancer still has a poor prognosis, even if aggressive therapy is pursued. Currently, new modalities of oncolytic virus therapy are being tested against this cancer. The combination of one of two representative mutant herpes simplex viruses (R3616: gamma(1)34.5 inactivated, hrR3: UL39 inactivated) with a standard anti-pancreatic cancer chemotherapy drug (gemcitabine), was investigated in this study.
  
  
  METHODS
  The intracellular concentration of ribonucleotide reductase was estimated by Western blotting. The effect of gemcitabine on viral replication and the total cytotoxic effect of the combination therapy were investigated on pancreatic cancer cell lines. We compared the results of two oncolytic viruses, R3616 and hrR3. A mouse model of pancreatic cancer with peritoneal dissemination was used to evaluate the in vivo effect of the combination therapy.
  
  
  RESULTS
  Although the replication of both viruses was inhibited by gemcitabine, the combination caused more tumor cell cytotoxicity than did virus alone in vitro. The results with R3616 were more striking. Although the difference was not statistically significant, R3616 with gemcitabine had a greater effect than did R3616 alone, while hrR3 with gemcitabine had a weaker effect than did hrR3 alone in vivo experiments.
  
  
  CONCLUSIONS
  The combination of oncolytic virus with gemcitabine is a promising new strategy against advanced pancreatic cancer. Each virus has different functional characteristics, and can affect the results of the combination of viruses and chemotherapy drugs. The results indicate that there is a complicated interaction among viruses, cells, and chemotherapy drugs and that the best combination of oncolytic virus and chemotherapeutic agents should be studied more extensively before embarking on a clinical trial.
authors.affiliation: Department of Surgery II, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Izuru
authors.initials: I
authors.lastname: Watanabe
authors.forename: Hideki
authors.initials: H
authors.lastname: Kasuya
authors.forename: Naohiro
authors.initials: N
authors.lastname: Nomura
authors.forename: Toshio
authors.initials: T
authors.lastname: Shikano
authors.forename: Takashi
authors.initials: T
authors.lastname: Shirota
authors.forename: Naohito
authors.initials: N
authors.lastname: Kanazumi
authors.forename: Shin
authors.initials: S
authors.lastname: Takeda
authors.forename: Shuji
authors.initials: S
authors.lastname: Nomoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sugimoto
authors.forename: Akimasa
authors.initials: A
authors.lastname: Nakao
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D050504:Oncolytic Viruses; D010190:Pancreatic Neoplasms / Q000628:therapy*; D018139:Simplexvirus / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000093542:Gemcitabine