title: Comparative in vitro and in vivo pharmacological investigation of platinum(IV) complexes as novel anticancer drug candidates for oral application.
abstract: Platinum(IV) complexes are promising candidates as prodrugs for oral application in anticancer chemotherapy. However, only a few Pt(IV) compounds entered (pre)clinical trials, e.g. satraplatin, while most of the others were only tested in vitro. Aim of the study was investigation of the in vivo pharmacological behavior as well as the anticancer activity of two novel platinum(IV) complexes vs. satraplatin. The drugs were selected due to significantly different in vitro cytotoxicity while sharing some physicochemical properties (e.g. lipophilicity). Initial experiments indicated that the highly in vitro cytotoxic compound 1 ((OC-6-33)-dichloridobis((4-ethoxy)-4-oxobutanoato)-bis(ethylamine)platinum(IV)) was also characterized by high drug absorption and tissue platinum levels after oral application. Interestingly, analysis of serum samples using SEC-ICP-MS revealed that the administered drugs have completely been metabolized and/or bound to proteins in serum within 2 h after treatment. With regard to the activity in vivo, the outcomes were rather unexpected: although potent anticancer effect of 1 was observed in cell culture, the effects in vivo were rather minor. Nevertheless, 1 was superior to 2 ((OC-6-33)-diammine(cyclobutane-1,1-dicarboxylato)-bis((4-cyclopentylamino)-4-oxobutanoato)platinum(IV)) after i.p. administration, which was, at least to some extent, in accordance to the cell culture experiments. After oral gavage, both compounds exhibited comparable activity. This is remarkable considering the distinctly lower activity of 2 in cell culture as well as the low platinum levels detected both in serum and tissues after oral application. Consequently, our data indicate that the prediction of in vivo anticancer activity by cell culture experiments is not trivial, especially for orally applied drugs.
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090, Vienna, Austria.|Research Platform 'Translational Cancer Therapy Research', University of Vienna, Waehringer Strasse 42, 1090, Vienna, Austria.
authors.forename: Sarah
authors.initials: S
authors.lastname: Theiner
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090, Vienna, Austria.
authors.forename: Hristo P
authors.initials: HP
authors.lastname: Varbanov
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090, Vienna, Austria.
authors.forename: Mathea Sophia
authors.initials: MS
authors.lastname: Galanski
authors.affiliation: ADSI-Austrian Drug Screening Institute GmbH, Innrain 66a, 6020, Innsbruck, Austria.
authors.forename: Alexander E
authors.initials: AE
authors.lastname: Egger
authors.affiliation: Research Platform 'Translational Cancer Therapy Research', University of Vienna, Waehringer Strasse 42, 1090, Vienna, Austria.|Department of Medicine I, Comprehensive Cancer Center of the Medical University, Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, 1090, Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
authors.affiliation: Research Platform 'Translational Cancer Therapy Research', University of Vienna, Waehringer Strasse 42, 1090, Vienna, Austria. petra.heffeter@meduniwien.ac.at.|Department of Medicine I, Comprehensive Cancer Center of the Medical University, Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, 1090, Vienna, Austria. petra.heffeter@meduniwien.ac.at.
authors.forename: Petra
authors.initials: P
authors.lastname: Heffeter
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090, Vienna, Austria.|Research Platform 'Translational Cancer Therapy Research', University of Vienna, Waehringer Strasse 42, 1090, Vienna, Austria.
authors.forename: Bernhard K
authors.initials: BK
authors.lastname: Keppler
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005260:Female; D020128:Inhibitory Concentration 50; D007938:Leukemia / Q000188:drug therapy; D008297:Male; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D009368:Neoplasm Transplantation; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014018:Tissue Distribution; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C000601176:diammine(cyclobutane-1,1-dicarboxylato)bis((4-cyclopentylamino)-4-oxobutanoato)platinum(IV); C000601175:dichloridobis((4-ethoxy)-4-oxobutanoato)bis(ethylamine)platinum(IV); C081294:satraplatin