OBJECTIVES: 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.
OBJECTIVES: 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 humanpancreatic 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: Karen Legler; Charlotte Hauser; Jan-Hendrik Egberts; Anna Willms; Carola Heneweer; Susann Boretius; Christoph Röcken; Claus-Christian Glüer; Thomas Becker; Michael Kluge; Oliver Hill; Christian Gieffers; Harald Fricke; Holger Kalthoff; Johannes Lemke; Anna Trauzold Journal: Cell Death Dis Date: 2018-05-01 Impact factor: 8.469
Authors: Gauri A Patwardhan; Qian-Jin Zhang; Dongmei Yin; Vineet Gupta; Jianxiong Bao; Can E Senkal; Besim Ogretmen; Myles C Cabot; Girish V Shah; Paul W Sylvester; S Michal Jazwinski; Yong-Yu Liu Journal: PLoS One Date: 2009-09-09 Impact factor: 3.240
Authors: Martin Chopra; Isabell Lang; Steffen Salzmann; Christina Pachel; Sabrina Kraus; Carina A Bäuerlein; Christian Brede; Ana-Laura Jordán Garrote; Katharina Mattenheimer; Miriam Ritz; Stefanie Schwinn; Carolin Graf; Viktoria Schäfer; Stefan Frantz; Hermann Einsele; Harald Wajant; Andreas Beilhack Journal: PLoS One Date: 2013-09-30 Impact factor: 3.240