Differences in protein binding and excretion of Triapine and its Fe(III) complex.
Triapine has been investigated as anticancer drug in multiple clinical phase I/II trials. Although promising anti-leukemic activity was observed, Triapine was ineffective against solid tumors. The reasons are currently widely unknown. The biological activity of Triapine is strongly connected to its iron complex (Fe-Triapine) which is pharmacologically not investigated. Here, novel analytical tools for Triapine and Fe-Triapine were developed and applied for cell extracts and body fluids of treated mice. Triapine and its iron complex showed a completely different behavior: for Triapine, low protein binding was observed in contrast to fast protein adduct formation of Fe-Triapine. Notably, both drugs were rapidly cleared from the body (serum half-life time <1h). Remarkably, in contrast to Triapine, where (in accordance to clinical data) basically no renal excretion was found, the iron complex was effectively excreted via urine. Moreover, no Fe-Triapine was detected in serum or cytosolic extracts after Triapine treatment. Taken together, our study will help to further understand the biological behavior of Triapine and its Fe-complex and allow the development of novel thiosemicarbazones with pronounced activity against solid tumor types.
Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria.
Karla
K
Pelivan
Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria.
Walter
W
Miklos
Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria.
Sushilla
S
van Schoonhoven
Institute of Analytical Chemistry, University of Vienna, Waehringer Strasse 38, 1090 Vienna, Austria.
Gunda
G
Koellensperger
Institute of Pharmacology and Toxicology, Department of Biomedical Sciences, University of Veterinary Medicine Vienna, Veterinaerplatz 1, 1210 Vienna, Austria.
Lars
L
Gille
Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria; Research Platform "Translational Cancer Therapy Research", University of Vienna and Medical University of Vienna, Vienna, Austria.
Walter
W
Berger
Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria; Research Platform "Translational Cancer Therapy Research", University of Vienna and Medical University of Vienna, Vienna, Austria. Electronic address: petra.heffeter@meduniwien.ac.at.
Petra
P
Heffeter
Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria; Research Platform "Translational Cancer Therapy Research", University of Vienna and Medical University of Vienna, Vienna, Austria. Electronic address: christian.kowol@univie.ac.at.
Christian R
CR
Kowol
Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria; Research Platform "Translational Cancer Therapy Research", University of Vienna and Medical University of Vienna, Vienna, Austria.
Bernhard K
BK
Keppler
D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001798:Blood Proteins / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002986:Clinical Trials as Topic; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D056831:Coordination Complexes / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D005260:Female; D006207:Half-Life; D007501:Iron / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011485:Protein Binding; D011725:Pyridines / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D013882:Thiosemicarbazones / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001798:Blood Proteins; D056831:Coordination Complexes; D011725:Pyridines; D013882:Thiosemicarbazones; C078157:3-aminopyridine-2-carboxaldehyde thiosemicarbazone; D007501:Iron
Drug development; In vivo; Pharmacokinetics; Thiosemicarbazones; Triapine