title: A Novel CDC25B Promoter-Based Oncolytic Adenovirus Inhibited Growth of Orthotopic Human Pancreatic Tumors in Different Preclinical Models.
abstract: OBJECTIVE
  We decided to construct a novel oncolytic adenovirus whose replication was driven by the CDC25B promoter for its use in preclinical models of pancreatic cancer.
  
  
  METHODS
  We placed the essential E1A gene under control of the CDC25B promoter. Based on preliminary data, we pseudotyped the adenovirus with a chimeric fiber of serotypes 5/3. We investigated the in vitro lytic effect and the in vivo therapeutic efficacy in combination with gemcitabine on human pancreatic tumor xenografts orthotopically growing in nude mice and in tumors growing in Syrian hamsters. We also assessed biochemical markers of hepatic toxicity and CA19.9 levels.
  
  
  RESULTS
  AV25CDC exhibited a strong in vitro lytic effect on pancreatic cancer cells. In vivo administration of AV25CDC combined with gemcitabine in mice harboring subcutaneously growing SW1990 pancreatic tumors almost abrogated tumor growth. Nude mice harboring 15-day-old orthotopic tumors, treated intratumorally or systemically with AV25CDC combined with gemcitabine, exhibited 70% to 80% reduction in tumor size compared with control mice that lasted for at least 60 days. Chemovirotherapy treatment induced a return to normal levels of biochemical parameters of hepatic toxicity; these mice exhibited more than 90% reduction in CA19.9 serum levels compared with control. Chemovirotherapy efficacy was confirmed in mice harboring Mia PaCa-2 tumors and in Syrian hamster harboring HaP-T1 tumors. We observed that viral treatment disrupted tumor architecture and induced an increase in MMP-9 activity that might facilitate gemcitabine penetrability.
  
  
  CONCLUSIONS
  These data demonstrate that AV25CDC is an effective oncolytic agent candidate for pancreatic cancer chemovirotherapy combination.
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Fundación Instituto Leloir, IIBBA-CONICET, Argentina. Universidad de La Frontera, Temuco, Chile.
authors.forename: Helga L
authors.initials: HL
authors.lastname: Weber
authors.affiliation: Universidad de La Frontera, Temuco, Chile. Universidad Autónoma de Chile, Santiago, Chile.
authors.forename: Manuel
authors.initials: M
authors.lastname: Gidekel
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Fundación Instituto Leloir, IIBBA-CONICET, Argentina.
authors.forename: Santiago
authors.initials: S
authors.lastname: Werbajh
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Fundación Instituto Leloir, IIBBA-CONICET, Argentina.
authors.forename: Edgardo
authors.initials: E
authors.lastname: Salvatierra
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Fundación Instituto Leloir, IIBBA-CONICET, Argentina.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Rotondaro
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Fundación Instituto Leloir, IIBBA-CONICET, Argentina.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Sganga
authors.affiliation: Laboratory of Pathology, Hospital de Oncología Marie Curie, Buenos Aires, Argentina.
authors.forename: Gabriela Acosta
authors.initials: GA
authors.lastname: Haab
authors.affiliation: Division of Cancer Biology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Fundación Instituto Leloir, IIBBA-CONICET, Argentina.
authors.forename: Eduardo G
authors.initials: EG
authors.lastname: Cafferata
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Fundación Instituto Leloir, IIBBA-CONICET, Argentina. opodhajcer@leloir.org.ar.
authors.forename: Osvaldo L
authors.initials: OL
authors.lastname: Podhajcer
mesh_terms: D000256:Adenoviridae; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D006224:Cricetinae; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D008647:Mesocricetus; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods*; D010190:Pancreatic Neoplasms / Q000628:therapy*; D011401:Promoter Regions, Genetic; D023041:Xenograft Model Antitumor Assays; D020687:cdc25 Phosphatases / Q000235:genetics*; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D020687:cdc25 Phosphatases; D000093542:Gemcitabine