Comparative in vitro and in vivo pharmacological investigation of platinum(IV) complexes as novel anticancer drug candidates for oral application
- Author(s)
- Sarah Theiner, Hristo P. Varbanov, Mathea Sophia Galanski, Alexander E. Egger, Walter Berger, Petra Heffeter, Bernhard K. Keppler
- 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: [Figure not available: see fulltext.]
- Organisation(s)
- Department of Inorganic Chemistry, NMR Centre
- External organisation(s)
- ADSI - Austrian Drug Screening Institute GmbH, Medizinische Universität Wien
- Journal
- Journal of Biological Inorganic Chemistry
- Volume
- 20
- Pages
- 89-99
- No. of pages
- 11
- ISSN
- 0949-8257
- DOI
- https://doi.org/10.1007/s00775-014-1214-6
- Publication date
- 01-2015
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 104003 Inorganic chemistry, 301904 Cancer research, 301306 Medical molecular biology
- Keywords
- ASJC Scopus subject areas
- Biochemistry, Inorganic Chemistry
- Sustainable Development Goals
- SDG 3 - Good Health and Well-being
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/67439761-c4ce-40b5-b7ee-79e271b1eeb1