title: Terminally modified oligodeoxynucleotides directed against p53 in an orthotopic xenograft model: a novel adjuvant treatment strategy for pancreatic ductal carcinoma.
abstract: OBJECTIVE
  Investigation of a terminally modified oligodeoxynucleotide (ODN) directed against p53 mRNA (p53-3' polyethylene glycol-5' tocopherol ODN as a novel drug for pancreatic ductal carcinoma therapy in vitro and in vivo.
  
  
  METHODS
  The impact of lipophilic modifications at the 5' end of p53-directed ODNs on cellular uptake was analyzed in vitro using proliferation assays, fluorescence-activated cell sorting analysis, and confocal laser scanning microscopy. The in vivo effects of p53-PT-ODN on the growth of orthotopically xenografted human pancreatic ductal carcinoma cells (PancTuI) were studied in SCID beige mice. Distribution was examined in vitro and in vivo using Cy3-labeled ODNs.
  
  
  RESULTS
  Terminally modified p53-PT-ODN showed excellent cellular uptake without using transfection reagents. Microscopically detectable levels of p53-PT-ODN were reached in vivo within 3 hours after intraperitoneal injection, even in extraperitoneal organs. At this time, Cy3-labeled p53-PT-ODN was found in solid tumor formations. We observed a significant inhibition of tumor growth (50%) in vivo at low doses of p53-PT-ODN, whereas at high doses, 2 of 9 animals had no detectable tumors at necropsy. When p53-PT-ODN was injected on the day of tumor cell inoculation, the growth inhibition of solid tumors was significantly stronger compared with that with delayed treatment.
  
  
  CONCLUSIONS
  p53-Directed modified ODNs might be of therapeutic value in pancreatic ductal carcinoma, particularly as adjuvant therapy after pancreatic tumor resection.
authors.affiliation: Department of General Surgery, University of Kiel, Kiel, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Tepel
authors.forename: Marie-Luise
authors.initials: ML
authors.lastname: Kruse
authors.forename: Christina
authors.initials: C
authors.lastname: March
authors.forename: Alexander
authors.initials: A
authors.lastname: Fiedler
authors.forename: Matthias
authors.initials: M
authors.lastname: Kapischke
authors.forename: Thomas
authors.initials: T
authors.lastname: Ketterer
authors.forename: Bence
authors.initials: B
authors.lastname: Sipos
authors.forename: Bernd
authors.initials: B
authors.lastname: Kremer
authors.forename: Holger
authors.initials: H
authors.lastname: Kalthoff
mesh_terms: D000818:Animals; D002232:Carbocyanines / Q000737:chemistry; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D016376:Oligonucleotides, Antisense / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D014018:Tissue Distribution; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: D002232:Carbocyanines; D016376:Oligonucleotides, Antisense; D016159:Tumor Suppressor Protein p53; C089187:cyanine dye 3