title: Adenoviral therapy is more effective in gemcitabine-resistant pancreatic cancer than in gemcitabine-sensitive cells.
abstract: BACKGROUND
  Although gemcitabine is the standard treatment for pancreatic cancer, this particular type of cancer develops rapidly and has intrinsic chemoresistance. Chemoresistance plays a critical role in tumor progression, invasion and migration. Nevertheless, the effect of adenoviral therapy on chemoresistant cancer cells has not been studied. In this study, we compared the efficacy of adenoviral therapy in parental and chemoresistant pancreatic cancer cells.
  
  
  METHODS
  To establish gemcitabine-resistant cells, pancreatic cancer SUIT2 cells were exposed to increasing concentrations of gemcitabine. Both parental and chemoresistant cells were infected with adenoviruses expressing either green fluorescent protein (Ad-GFP) or the hepatocyte growth factor antagonist, NK4 (Ad-NK4). To investigate the transduction efficacy, GFP expression and NK4 concentrations were measured and an invasion assay was used to investigate the efficacy of the adenoviral therapy.
  
  
  RESULTS
  The 50% inhibitory concentration of gemcitabine was <10 nM in the parental SUIT-2 cells, while it was >1 μM in gemcitabine-resistant cells. A large number of gemcitabine-resistant cells were GFP-positive compared with only a small number of parental cells (p<0.05). The NK4 expression level was significantly higher in gemcitabine-resistant cells than in parental cells (p<0.05). The supernatant from Ad-NK4-infected gemcitabine-resistant cells significantly inhibited the invasion of cancer cells compared with that from Ad-NK4-infected parental cells (p<0.05).
  
  
  CONCLUSIONS
  Both the efficiency of transduction and the therapeutic efficacy of adenoviral therapy were higher in gemcitabine-resistant cells than in parental cells, suggesting that adenoviral gene therapy is more effective in patients with gemcitabine-resistant pancreatic cancer.
authors.affiliation: Department of Surgery and Oncology, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Takaharu
authors.initials: T
authors.lastname: Yasui
authors.forename: Kenoki
authors.initials: K
authors.lastname: Ohuchida
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Lin
authors.initials: L
authors.lastname: Cui
authors.forename: Manabu
authors.initials: M
authors.lastname: Onimaru
authors.forename: Takuya
authors.initials: T
authors.lastname: Egami
authors.forename: Hayato
authors.initials: H
authors.lastname: Fujita
authors.forename: Takao
authors.initials: T
authors.lastname: Ohtsuka
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Mizumoto
authors.forename: Kunio
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Masao
authors.initials: M
authors.lastname: Tanaka
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics; D015153:Blotting, Western; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015316:Genetic Therapy; D049452:Green Fluorescent Proteins / Q000235:genetics; D017228:Hepatocyte Growth Factor / Q000235:genetics*; D006801:Humans; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000628:therapy*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019076:Transgenes / Q000502:physiology; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; C066855:HGF protein, human; D012333:RNA, Messenger; C485184:enhanced green fluorescent protein; D003841:Deoxycytidine; D049452:Green Fluorescent Proteins; D017228:Hepatocyte Growth Factor; D000093542:Gemcitabine