title: Comparative studies of oxaliplatin-based platinum(iv) complexes in different in vitro and in vivo tumor models.
abstract: Using platinum(iv) prodrugs of clinically established platinum(ii) compounds is a strategy to overcome side effects and acquired resistances. We studied four oxaliplatin-derived platinum(iv) complexes with varying axial ligands in various in vitro and in vivo settings. The ability to interfere with DNA (pUC19) in the presence and absence of a reducing agent (ascorbic acid) was investigated in cell-free experiments. Cytotoxicity was compared under normoxic and hypoxic conditions in monolayer cultures and multicellular spheroids of colon carcinoma cell lines. Effects on the cell cycle were investigated by flow cytometry, and the capacity of inducing apoptosis was confirmed by flow cytometry and Western blotting. The anti-cancer activity of one complex was studied in vivo in immunodeficient and immunocompetent mice, and the platinum levels in various organs and the tumor after treatment were quantified. The results demonstrate that modification of the axial ligands can improve the cytotoxic potency. The complexes are able to interfere with plasmid DNA, which is enhanced by co-incubation with a reducing agent, and cause cell cycle perturbations. At higher concentrations, they induce apoptosis, but generate only low levels of reactive oxygen species. Two of the complexes increase the life span of leukemia (L1210) bearing mice, and one showed effects similar to oxaliplatin in a CT26 solid tumor model, despite the low platinum levels in the tumor. As in the case of oxaliplatin, activity in the latter model depends on an intact immune system. These findings show new perspectives for the development of platinum(iv) prodrugs of the anticancer agent oxaliplatin, combining bioreductive properties and immunogenic aspects.
authors.affiliation: University of Vienna, Institute of Inorganic Chemistry, Waehringer Strasse 42, 1090 Vienna, Austria. michael.jakupec@univie.ac.at.
authors.forename: Simone
authors.initials: S
authors.lastname: Göschl
authors.affiliation: University of Vienna, Institute of Inorganic Chemistry, Waehringer Strasse 42, 1090 Vienna, Austria. michael.jakupec@univie.ac.at.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Schreiber-Brynzak
authors.affiliation: University of Vienna, Institute of Inorganic Chemistry, Waehringer Strasse 42, 1090 Vienna, Austria. michael.jakupec@univie.ac.at and University of Vienna, Research Platform "Translational Cancer Therapy Research", Vienna, Austria.
authors.forename: Verena
authors.initials: V
authors.lastname: Pichler
authors.affiliation: University of Vienna, Institute of Inorganic Chemistry, Waehringer Strasse 42, 1090 Vienna, Austria. michael.jakupec@univie.ac.at.
authors.forename: Klaudia
authors.initials: K
authors.lastname: Cseh
authors.affiliation: University of Vienna, Research Platform "Translational Cancer Therapy Research", Vienna, Austria and Medical University of Vienna, Department of Medicine I, Institute of Cancer Research, Vienna, Austria and Medical University of Vienna, Comprehensive Cancer Center, Vienna, Austria.
authors.forename: Petra
authors.initials: P
authors.lastname: Heffeter
authors.affiliation: Medical University of Vienna, Department of Medicine I, Institute of Cancer Research, Vienna, Austria and The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
authors.forename: Ute
authors.initials: U
authors.lastname: Jungwirth
authors.affiliation: University of Vienna, Institute of Inorganic Chemistry, Waehringer Strasse 42, 1090 Vienna, Austria. michael.jakupec@univie.ac.at and University of Vienna, Research Platform "Translational Cancer Therapy Research", Vienna, Austria.
authors.forename: Michael A
authors.identifier: 0000-0001-7945-1426
authors.initials: MA
authors.lastname: Jakupec
authors.affiliation: University of Vienna, Research Platform "Translational Cancer Therapy Research", Vienna, Austria and Medical University of Vienna, Department of Medicine I, Institute of Cancer Research, Vienna, Austria and Medical University of Vienna, Comprehensive Cancer Center, Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
authors.affiliation: University of Vienna, Institute of Inorganic Chemistry, Waehringer Strasse 42, 1090 Vienna, Austria. michael.jakupec@univie.ac.at and University of Vienna, Research Platform "Translational Cancer Therapy Research", Vienna, Austria.
authors.forename: Bernhard K
authors.initials: BK
authors.lastname: Keppler
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D006801:Humans; D066298:In Vitro Techniques; D007939:Leukemia L1210 / Q000188:drug therapy / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D016513:Mice, SCID; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002945:Cisplatin