title: Hyperthermia potentiates oncolytic herpes viral killing of pancreatic cancer through a heat shock protein pathway.
abstract: BACKGROUND
  Oncolytic herpes simplex virus-1 (HSV-1) is designed to specifically infect, replicate in, and lyse cancer cells. This study investigates a novel therapeutic regimen, combining the effects of NV1066 (a recombinant HSV-1) and hyperthermia in the treatment of pancreatic cancer.
  
  
  METHODS
  NV1066 is an attenuated HSV-1 that replicates in cells resistant to apoptosis. Heat shock protein 72 (Hsp72) is a member of a family of proteins that is upregulated after hyperthermic insult, lending cellular protection by inhibiting apoptosis. In these experiments, we test the hypothesis that increased Hsp72 expression in response to hyperthermia enhances anti-apoptotic mechanisms, thereby increasing viral replication and tumor cell kill. Hs 700T pancreatic cancer cells were treated with hyperthermia alone (42 degrees C), NV1066 alone, and combination therapy. Cell survival and viral growth were measured. The effect of siRNA-directed Hsp72 knockdown was also measured.
  
  
  RESULTS
  Combining hyperthermia and viral treatment produced a synergistic effect on cell kill. Viral growth increased greater than 6-fold in the presence of hyperthermia (P < .05). Hyperthermia alone showed minimal cytotoxic activity against Hs 700T cells, while NV1066 infection resulted in approximately 50% cell kill. The combination of hyperthermia and viral infection significantly increased cell kill to approximately 80% (P < .01). Hsp72 knockdown attenuated this synergistic effect.
  
  
  CONCLUSIONS
  Hyperthermia enhances NV1066 replication, thereby potentiating the viral oncolytic response against pancreatic cancer cells. This finding has potential clinical application in the use of heated perfusion or permissive hyperthermia for delivery of oncolytic viral therapies.
authors.affiliation: Division of Surgical Oncology, Hartford Hospital, Hartford, CT, USA.
authors.forename: David P
authors.initials: DP
authors.lastname: Eisenberg
authors.forename: Susanne G
authors.initials: SG
authors.lastname: Carpenter
authors.forename: Prasad S
authors.initials: PS
authors.lastname: Adusumilli
authors.forename: Mei-Ki
authors.initials: MK
authors.lastname: Chan
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Hendershott
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Yu
authors.forename: Yuman
authors.initials: Y
authors.lastname: Fong
mesh_terms: D017209:Apoptosis; D001483:Base Sequence; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D017931:DNA Primers / Q000235:genetics; D055785:Gene Knockdown Techniques; D050884:HSP72 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018259:Herpesvirus 1, Human / Q000502:physiology*; D006801:Humans; D006979:Hyperthermia, Induced; D050130:Oncolytic Virotherapy; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy* / Q000821:virology; D034741:RNA, Small Interfering / Q000235:genetics; D014779:Virus Replication
chemical_list: D017931:DNA Primers; D050884:HSP72 Heat-Shock Proteins; D034741:RNA, Small Interfering