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.