title: Gene therapy based on gemcitabine chemosensitization suppresses pancreatic tumor growth.
abstract: Excepting surgical resection, there is no efficient treatment against pancreatic cancer. The chemotherapeutic agent gemcitabine improves the patient's clinical status but survival is not prolonged. The aim of this study was to design a new strategy to render gemcitabine more efficient in the treatment of pancreatic cancer using gene therapy. We have generated a fusion gene (DCK::UMK) combining deoxycytidine kinase (DCK) and uridine monophosphate kinase (UMK), which converts gemcitabine into its toxic phosphorylated metabolite. Antitumor effects of DCK::UMK gene expression were tested in vitro and in vivo in an orthotopic transplantable model of pancreatic cancer established in hamsters. DCK::UMK sensitizes pancreatic cancer cells to gemcitabine by reducing dramatically both in vitro cell viability and in vivo tumor volume. We found that in vivo expression of DCK::UMK resulted in an antitumor bystander effect due to apoptosis of untransduced cells. In vivo intratumoral gene transfer of DCK::UMK using the synthetic carrier PEI induced a potent tumor regression. Taken together, the results show that the fusion gene DCK::UMK sensitizes pancreatic cancer cells to gemcitabine treatment to induce cell death by apoptosis and tumor regression. Intratumoral delivery of the DCK::UMK gene in combination with gemcitabine might be of high interest for pancreatic cancer management.
authors.affiliation: INSERM U531, Institut Louis Bugnard IFR31, Centre Hospitalier Universitaire Rangueil, 31403 Toulouse Cedex 4, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Vernejoul
authors.forename: Laurent
authors.initials: L
authors.lastname: Ghénassia
authors.forename: Anny
authors.initials: A
authors.lastname: Souque
authors.forename: Hubert
authors.initials: H
authors.lastname: Lulka
authors.forename: Daniel
authors.initials: D
authors.lastname: Drocourt
authors.forename: Pierre
authors.initials: P
authors.lastname: Cordelier
authors.forename: Lucien
authors.initials: L
authors.lastname: Pradayrol
authors.forename: Stéphane
authors.initials: S
authors.lastname: Pyronnet
authors.forename: Louis
authors.initials: L
authors.lastname: Buscail
authors.forename: Gérard
authors.initials: G
authors.lastname: Tiraby
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D003842:Deoxycytidine Kinase / Q000235:genetics* / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D008297:Male; D008647:Mesocricetus; D009374:Neoplasms, Experimental / Q000628:therapy; D009703:Nucleoside-Phosphate Kinase / Q000235:genetics* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000473:pathology / Q000628:therapy*; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D003842:Deoxycytidine Kinase; C023276:uridine monophosphate kinase; D009703:Nucleoside-Phosphate Kinase; D000093542:Gemcitabine