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

  • Sarah Theiner
  • Hristo P. Varbanov
  • Markus Galanski
  • Alexander E. Egger
  • Walter Berger
  • Petra Heffeter
  • Bernhard K. Keppler
Original Paper

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.

Graphical Abstract

Keywords

Platinum(IV) complexes Anticancer activity ICP-MS Oral administration 

Notes

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.

Supplementary material

775_2014_1214_MOESM1_ESM.pdf (197 kb)
Supplementary material 1 (PDF 197 kb)

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Copyright information

© SBIC 2014

Authors and Affiliations

  • Sarah Theiner
    • 1
    • 2
  • Hristo P. Varbanov
    • 1
  • Markus Galanski
    • 1
  • Alexander E. Egger
    • 4
  • Walter Berger
    • 2
    • 3
  • Petra Heffeter
    • 2
    • 3
  • Bernhard K. Keppler
    • 1
    • 2
  1. 1.Institute of Inorganic ChemistryUniversity of ViennaViennaAustria
  2. 2.Research Platform ‘Translational Cancer Therapy Research’University of ViennaViennaAustria
  3. 3.Department of Medicine I, Comprehensive Cancer Center of the Medical University, Institute of Cancer ResearchMedical University of ViennaViennaAustria
  4. 4.ADSI-Austrian Drug Screening Institute GmbHInnsbruckAustria

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