title: 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.
authors: Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria. michael.jakupec@univie.ac.at.
authors: Ekaterina
authors: E
authors: Schreiber-Brynzak
authors: Verena
authors: V
authors: Pichler
authors: Petra
authors: P
authors: Heffeter
authors: Buck
authors: B
authors: Hanson
authors: Sarah
authors: S
authors: Theiner
authors: Irene
authors: I
authors: Lichtscheidl-Schultz
authors: Christoph
authors: C
authors: Kornauth
authors: Luca
authors: L
authors: Bamonti
authors: Vineet
authors: V
authors: Dhery
authors: Diana
authors: D
authors: Groza
authors: David
authors: D
authors: Berry
authors: Walter
authors: W
authors: Berger
authors: Markus
authors: M
authors: Galanski
authors: Michael A
authors: MA
authors: Jakupec
authors: Bernhard K
authors: BK
authors: Keppler
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056831:Coordination Complexes / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D016513:Mice, SCID; D008954:Models, Biological; D010984:Platinum / Q000737:chemistry / Q000494:pharmacology*; D018874:Spheroids, Cellular / Q000187:drug effects / Q000473:pathology; D014018:Tissue Distribution / Q000187:drug effects; D000072258:Tumor Hypoxia / Q000187:drug effects*
chemical_list: D056831:Coordination Complexes; D010984:Platinum