Behavior of platinum(iv) complexes in models of tumor hypoxia: cytotoxicity, compound distribution and accumulation.

Abstract

Hypoxia in solid tumors remains a challenge for conventional cancer therapeutics. As a source for resistance, metastasis development and drug bioprocessing, it influences treatment results and disease outcome. Bioreductive platinum(iv) prodrugs might be advantageous over conventional metal-based therapeutics, as biotransformation in a reductive milieu, such as under hypoxia, is required for drug activation. This study deals with a two-step screening of experimental platinum(iv) prodrugs with different rates of reduction and lipophilicity with the aim of identifying the most appropriate compounds for further investigations. In the first step, the cytotoxicity of all compounds was compared in hypoxic multicellular spheroids and monolayer culture using a set of cancer cell lines with different sensitivities to platinum(ii) compounds. Secondly, two selected compounds were tested in hypoxic xenografts in SCID mouse models in comparison to satraplatin, and, additionally, (LA)-ICP-MS-based accumulation and distribution studies were performed for these compounds in hypoxic spheroids and xenografts. Our findings suggest that, while cellular uptake and cytotoxicity strongly correlate with lipophilicity, cytotoxicity under hypoxia compared to non-hypoxic conditions and antitumor activity of platinum(iv) prodrugs are dependent on their rate of reduction.

DOI: 10.1039/c5mt00312a

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Cite this paper

@article{SchreiberBrynzak2016BehaviorOP, title={Behavior of platinum(iv) complexes in models of tumor hypoxia: cytotoxicity, compound distribution and accumulation.}, author={Ekaterina Schreiber-Brynzak and Verena Pichler and Petra Heffeter and Buck T. Hanson and Sarah Theiner and Irene Lichtscheidl-Schultz and Christoph Kornauth and Luca Bamonti and Vineet Dhery and Diana Groza and David Berry and Walter Berger and Markus Galanski and Michael A Jakupec and Bernhard K Keppler}, journal={Metallomics : integrated biometal science}, year={2016}, volume={8 4}, pages={422-33} }