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Mechanistic insights into antitumor effects of new dinuclear cis PtII complexes containing aromatic linkers

2010; Elsevier BV; Volume: 80; Issue: 3 Linguagem: Inglês

10.1016/j.bcp.2010.04.013

1873-2968

Lenka Zerzánková, Hana Kostrhunová, Marie Vojtı́šková, Olga Nováková, Tereza Suchánková, Miaoxin Lin, Zijian Guo, Jana Kašpárková, Viktor Brabec,

DNA and Nucleic Acid Chemistry

The primary objective was to understand more deeply the molecular mechanism underlying different antitumor effects of dinuclear PtII complexes containing aromatic linkers of different length, {[cis-Pt(NH3)2Cl]2(4,4′-methylenedianiline)}2+ (1) and {[cis-Pt(NH3)2Cl]2(α,α′-diamino-p-xylene)}2+ (2). These complexes belong to a new generation of promising polynuclear platinum drugs resistant to decomposition by sulfur nucleophiles which hampers clinical use of bifunctional polynuclear trans PtII complexes hitherto tested. Results obtained with the aid of methods of molecular biophysics and pharmacology reveal differences and new details of DNA modifications by 1 and 2 and recognition of these modifications by cellular components. The results indicate that the unique properties of DNA interstrand cross-links of this class of polynuclear platinum complexes and recognition of these cross-links may play a prevalent role in antitumor effects of these metallodrugs. Moreover, the results show for the first time a strong specific recognition and binding of high-mobility-group-domain proteins, which are known to modulate antitumor effects of clinically used platinum drugs, to DNA modified by a polynuclear platinum complex.