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Comparative in vitro and in vivo pharmacological investigation of platinum(IV) complexes as novel anticancer drug candidates for oral application

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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.

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Acknowledgments

Matthias Klose and Ricarda Bugl are acknowledged for their assistance in sample preparation and ICP-MS measurements. In addition, we are thankful to G. Zeitler and S. Van Schoonhoven for animal care. This work was supported by the Austrian Science Fond grant P26603 (to P.H.). This work was performed in the surrounding of COST action CM1105.

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Authors and Affiliations

  1. Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090, Vienna, Austria

    Sarah Theiner, Hristo P. Varbanov, Mathea Sophia Galanski & Bernhard K. Keppler

  2. Research Platform ‘Translational Cancer Therapy Research’, University of Vienna, Waehringer Strasse 42, 1090, Vienna, Austria

    Sarah Theiner, Walter Berger, Petra Heffeter & Bernhard K. Keppler

  3. Department of Medicine I, Comprehensive Cancer Center of the Medical University, Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, 1090, Vienna, Austria

    Walter Berger & Petra Heffeter

  4. ADSI-Austrian Drug Screening Institute GmbH, Innrain 66a, 6020, Innsbruck, Austria

    Alexander E. Egger

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  1. Sarah Theiner
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  2. Hristo P. Varbanov
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  3. Mathea Sophia Galanski
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  4. Alexander E. Egger
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  5. Walter Berger
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Correspondence to Petra Heffeter.

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Theiner, S., Varbanov, H.P., Galanski, M. et al. Comparative in vitro and in vivo pharmacological investigation of platinum(IV) complexes as novel anticancer drug candidates for oral application. J Biol Inorg Chem 20, 89–99 (2015). https://doi.org/10.1007/s00775-014-1214-6

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  • DOI: https://doi.org/10.1007/s00775-014-1214-6

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