Synthesis and preliminary evaluation of the new water-soluble radioactive platinum(IV) complexes.
A novel class of water-soluble Pt(IV) complexes with histamine (Hist) and radioiodinated histamine ([(125)I/(131)I]Hist) has been synthesised with the goal of potential application for concomitant anticancer radio-chemotherapy of solid tumours. The prepared complex of 1:2 metal:ligand stoichiometry ([Pt(IV)(Hist)(2)(OH)(2)]Cl(2)) was characterised by microanalysis, mass spectrometry, and chromatographic methods. Cytotoxic/cytostatic activities of the complex were examined by flow cytometry method using the MCF-7 cells line. A slightly lower cytotoxicity of the Pt(IV) complex comparing to cisplatin was found (IC(50) 59 and 48 microM, respectively). Both cisplatin and the histamine complex show a cytostatic activity by blocking MCF-7 cells in S-phase of cell cycle. Biodistribution studies in normal rats revealed the highest accumulation of the (131)I-labelled complex in liver and kidneys (41.3% and 12.4% ID after 24 h post-intravenous injection (p.i.v.)). The similar pharmacokinetics was observed in tumour-bearing C3H/W mice, however, a lower accumulation in liver was observed following an intraperitoneal comparing to an intravenous administration. A concentration of the complex in tumour increased with time post-intraperitoneal injection (1.2 and 2.5%ID/g after 2 and 24 h (p.i.), respectively). An increasing tumour/muscle ratio was also observed (2.2 and 4.5 after 2 and 24 h p.i., respectively), and that suggests a penetration of the complex into the tumour cells, and a permanent binding with some cellular components, probably with the DNA.
Department of Radiopharmaceuticals, National Institute of Public Health, 30/34 Chełmska Street, 00-725 Warsaw, Poland. pg@il.waw.pl
Piotr
P
Garnuszek
Michal
M
Maurin
Janusz S
JS
Skierski
Mirosława
M
Koronkiewicz
Janina
J
Witowska-Jarosz
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006632:Histamine / Q000031:analogs & derivatives*; D006801:Humans; D007457:Iodine Radioisotopes / Q000737:chemistry / Q000494:pharmacology*; D007553:Isotope Labeling; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D021241:Spectrometry, Mass, Electrospray Ionization; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D007457:Iodine Radioisotopes; D009944:Organoplatinum Compounds; D019275:Radiopharmaceuticals; D006632:Histamine