caa a22 4500 605506892 CHVBK 20210128100629.0 cr unu---uuuuu 210128e20150101xx s 000 0 eng 10.1007/s00775-014-1214-6 doi (NATIONALLICENCE)springer-10.1007/s00775-014-1214-6 Comparative in vitro and in vivo pharmacological investigation of platinum(IV) complexes as novel anticancer drug candidates for oral application [Elektronische Daten] [Sarah Theiner, Hristo Varbanov, Markus Galanski, Alexander Egger, Walter Berger, Petra Heffeter, Bernhard Keppler] 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 compound1 ((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 havecompletely been metabolized and/or bound to proteinsin serum within 2h 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. Graphical Abstract: SBIC, 2014 Platinum(IV) complexes nationallicence Anticancer activity nationallicence ICP-MS nationallicence Oral administration nationallicence Theiner Sarah Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090, Vienna, Austria aut Varbanov Hristo Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090, Vienna, Austria aut Galanski Markus Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090, Vienna, Austria aut Egger Alexander ADSI-Austrian Drug Screening Institute GmbH, Innrain 66a, 6020, Innsbruck, Austria aut Berger Walter Research Platform ‘Translational Cancer Therapy Research', University of Vienna, Waehringer Strasse 42, 1090, Vienna, Austria aut Heffeter Petra Research Platform ‘Translational Cancer Therapy Research', University of Vienna, Waehringer Strasse 42, 1090, Vienna, Austria aut Keppler Bernhard Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090, Vienna, Austria aut JBIC Journal of Biological Inorganic Chemistry Springer Berlin Heidelberg 20/1(2015-01-01), 89-99 0949-8257 20:1<89 2015 20 775 https://doi.org/10.1007/s00775-014-1214-6 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00775-014-1214-6 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Theiner Sarah Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090, Vienna, Austria aut NATIONALLICENCE 700 1- Varbanov Hristo Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090, Vienna, Austria aut NATIONALLICENCE 700 1- Galanski Markus Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090, Vienna, Austria aut NATIONALLICENCE 700 1- Egger Alexander ADSI-Austrian Drug Screening Institute GmbH, Innrain 66a, 6020, Innsbruck, Austria aut NATIONALLICENCE 700 1- Berger Walter Research Platform ‘Translational Cancer Therapy Research', University of Vienna, Waehringer Strasse 42, 1090, Vienna, Austria aut NATIONALLICENCE 700 1- Heffeter Petra Research Platform ‘Translational Cancer Therapy Research', University of Vienna, Waehringer Strasse 42, 1090, Vienna, Austria aut NATIONALLICENCE 700 1- Keppler Bernhard Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090, Vienna, Austria aut NATIONALLICENCE 773 0- JBIC Journal of Biological Inorganic Chemistry Springer Berlin Heidelberg 20/1(2015-01-01), 89-99 0949-8257 20:1<89 2015 20 775