title: A modified random oligonucleotide-based combination therapy for adjuvant treatment of pancreatic ductal adenocarcinoma.
abstract: Anti-cancer therapy in pancreatic ductal adenocarcinoma (PDAC) is mostly based on surgical removal or palliative therapy using antimetabolites, like 5'-fluorouracil or gemcitabine. Adjuvant treatment using these chemotherapeutics has recently proven a beneficial concept, though general survival rates are still poor. Most recently, combination therapy of gemcitabine with other targeted drugs was evaluated in clinical trials. We present here a study performed in a mouse orthotopic xenotransplant model of PDAC, using an oligo-nucleotide-based approach. We have shown previously that antisense oligonucleotides against p53 reduce the weight of orthotopic pancreatic tumours in immune-deficient mice. We further characterised terminal modifications of phosphorothioate oligonucleotides in vitro and found a random, unrelated control sequence carrying a D,L-alpha-tocopherol modification at the 5' and 3' ends to be most efficient in induction of cell death in PancTu-1 cells. Modified random oligonucleotide (MRON) were thus further tested in vivo. MRON showed a reduction of tumour weight in established primary orthotopic tumours in SCID/bg mice. In a surgically adapted pre-clinical model, where primary tumours were resected and animals received adjuvant treatment, MRON was very efficient in suppression of relapse and metastasis, when combined with gemcitabine. While the exact molecular mechanism of MRON activity still needs to be elucidated, the compound showed a remarkable preference for uptake into tumour cells in vivo.
authors.affiliation: Department of General Surgery and Thoracic Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Juergen
authors.initials: J
authors.lastname: Tepel
authors.forename: Christina
authors.initials: C
authors.lastname: March
authors.forename: Thomas
authors.initials: T
authors.lastname: Ketterer
authors.forename: Matthias
authors.initials: M
authors.lastname: Kapischke
authors.forename: Alexander
authors.initials: A
authors.lastname: Arlt
authors.forename: Bernd
authors.initials: B
authors.lastname: Kremer
authors.forename: Holger
authors.initials: H
authors.lastname: Kalthoff
authors.forename: Marie-Luise
authors.initials: ML
authors.lastname: Kruse
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics*; D053938:DNA Fragmentation; D004261:DNA Replication; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009838:Oligodeoxyribonucleotides; D010190:Pancreatic Neoplasms / Q000235:genetics*; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D009838:Oligodeoxyribonucleotides; D016159:Tumor Suppressor Protein p53