Behavior of platinum(iv) complexes in models of tumor hypoxia: cytotoxicity, compound distribution and accumulation†
| Autor: | Walter Berger, Diana Groza, Markus Galanski, David Berry, Vineet Dhery, Ekaterina Schreiber-Brynzak, Christoph Kornauth, Luca Bamonti, Sarah Theiner, Verena Pichler, Bernhard K. Keppler, Petra Heffeter, Michael A. Jakupec, Buck Hanson, Irene Lichtscheidl-Schultz |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Male
Cellular pathology Biophysics Satraplatin Mice SCID Pharmacology 010402 general chemistry 01 natural sciences Biochemistry Models Biological Article Mass Spectrometry Biomaterials 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Coordination Complexes Cell Line Tumor Spheroids Cellular medicine Animals Humans Tissue Distribution Cytotoxicity Cell Proliferation Platinum Tumor hypoxia Cell Death Cell growth Chemistry Metals and Alloys Prodrug Hypoxia (medical) 0104 chemical sciences 3. Good health Chemistry (miscellaneous) 030220 oncology & carcinogenesis Lipophilicity Tumor Hypoxia medicine.symptom |
| Zdroj: | Metallomics : integrated biometal science |
| ISSN: | 1756-591X 1756-5901 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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