title: Combination treatment of human pancreatic cancer xenograft models with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib and oncolytic herpes simplex virus HF10.
abstract: BACKGROUND
  There is the potential to use replication-competent oncolytic viruses to treat cancer. We evaluated the efficacy of HF10, a herpes simplex virus type 1 (HSV-1) mutant, in combination with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in human pancreatic cancer xenograft models.
  
  
  METHODS
  The viability of human pancreatic cancer cell lines (BxPC-3 and PANC-1) treated with HF10 and erlotinib, on their own or in combination, was determined. Effects of erlotinib on HF10 entry into tumor cells were also investigated. BxPC-3 subcutaneous tumor-bearing mice were treated with HF10 and erlotinib, on their own or in combination, with effects on tumor volume determined. Immunohistochemical examination of HSV-1 and CD31 was conducted to assess virus distribution and angiogenesis within tumors. A peritoneally disseminated BxPC-3 xenograft model was evaluated for survival.
  
  
  RESULTS
  HF10 combined with erlotinib demonstrated the highest cytotoxicity against BxPC-3. A combination effect was not observed in PANC-1 cells, and erlotinib did not affect virus entry into tumor cells. In the peritoneally disseminated model, HF10 combined with erlotinib had no beneficial effect on survival. In the subcutaneous tumor model, combination therapy resulted in the inhibition of tumor growth to a greater extent than using each agent on its own. Immunohistochemistry revealed that virus distribution within the tumor persisted in the combination therapy group.
  
  
  CONCLUSIONS
  Combination therapy with HF10 and erlotinib warrants further investigation to establish a new treatment strategy against human pancreatic cancers.
authors.affiliation: Department of Surgery II, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yamamura
authors.forename: Hideki
authors.initials: H
authors.lastname: Kasuya
authors.forename: Tevfik Tolga
authors.initials: TT
authors.lastname: Sahin
authors.forename: Gewen
authors.initials: G
authors.lastname: Tan
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hotta
authors.forename: Naoko
authors.initials: N
authors.lastname: Tsurumaru
authors.forename: Saori
authors.initials: S
authors.lastname: Fukuda
authors.forename: Mitsuro
authors.initials: M
authors.lastname: Kanda
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kobayashi
authors.forename: Chie
authors.initials: C
authors.lastname: Tanaka
authors.forename: Suguru
authors.initials: S
authors.lastname: Yamada
authors.forename: Goro
authors.initials: G
authors.lastname: Nakayama
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Fujii
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sugimoto
authors.forename: Masahiko
authors.initials: M
authors.lastname: Koike
authors.forename: Shuji
authors.initials: S
authors.lastname: Nomoto
authors.forename: Michitaka
authors.initials: M
authors.lastname: Fujiwara
authors.forename: Maki
authors.initials: M
authors.lastname: Tanaka
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kodera
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D050130:Oncolytic Virotherapy; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000401:mortality / Q000628:therapy*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011799:Quinazolines / Q000627:therapeutic use*; D018139:Simplexvirus / Q000502:physiology*; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D053586:Virus Internalization; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors