title: Virotherapy using a novel chimeric oncolytic adenovirus prolongs survival in a human pancreatic cancer xenograft model.
abstract: BACKGROUND
  Pancreatic adenocarcinoma is an aggressive malignancy. Oncolytic adenoviruses (Ads) are modified genetically to target tumor cells while sparing normal cells. We modified the knob domain of the Ad serotype 5 with a serotype 3 knob domain and incorporated the CXCR4 promoter to regulate Ad E1A gene expression (Ad5/3-CXCR4-E1A). These modifications were made to efficiently infect and lyse pancreatic tumors.
  
  
  METHODS
  Human pancreatic cancer lines CFPAC-1, PANC-1, AsPC-1, and BxPC-3 were obtained from the American Type Culture Collection. Efficiency of Ad infection in the cells was determined by the use of an Ad construct expressing the green fluorescence protein (GFP) marker in place of the E1A gene (Ad5/3-CXCR4-GFP) and quantified by flow cytometry. Oncolytic activity in the pancreatic cancer cells was determined with the Ad5/3-CXCR4-E1A oncolytic Ad by a crystal violet staining method. To determine the oncolytic effect in vivo, pancreatic cancer cells were implanted on the flanks of 40 SCID mice (4 groups). Tumors were injected intratumorally for 3 days with Ad5/3-CXCR4-E1A, Ad5 wild-type (a positive control), or phosphate-buffered saline (a no virus control). Tumor size, overall survival, and body condition scale score were recorded. Statistical analyses included the Kaplan-Meier survival curve, the log-rank test, and one-way analysis of variance.
  
  
  RESULTS
  The serotype 3 fiber-modified Ad with the CXCR4 promoter (Ad5/3-CXCR4-E1A) was most efficient in infecting and lysing pancreatic cancer cells compared with an Ad containing an unmodified fiber knob (Ad5-CXCR4-E1A). Treatment of pancreatic tumor xenografts in vivo with Ad5/3-CXCR4-E1A group resulted in smaller tumors (P = .001), greater body condition scale score (P = .01), and greater survival time (P = .04) than the other treatment groups.
  
  
  CONCLUSIONS
  Ad5/3-CXCR4-E1A treatment significantly prolonged survival in SCID mice pancreatic tumor xenografts. This novel construct represents a potential new therapy against pancreatic cancer.
authors.affiliation: Department of Surgery and Division of Surgical Oncology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA. qchu@lsuhsc.edu
authors.forename: Quyen D
authors.initials: QD
authors.lastname: Chu
authors.forename: Guang
authors.initials: G
authors.lastname: Sun
authors.forename: Matt
authors.initials: M
authors.lastname: Pope
authors.forename: Natalia
authors.initials: N
authors.lastname: Luraguiz
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
authors.forename: Roger
authors.initials: R
authors.lastname: Kim
authors.forename: Benjamin D L
authors.initials: BD
authors.lastname: Li
authors.forename: J Michael
authors.initials: JM
authors.lastname: Mathis
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D000704:Analysis of Variance; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D016513:Mice, SCID; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000145:classification* / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D051381:Rats; D019718:Receptors, CXCR4 / Q000378:metabolism; D012703:Serotyping; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: C527276:CXCR4 protein, human; D019718:Receptors, CXCR4