DNA conformation and repair of polymeric natural DNA damaged by antitumor azolato-bridged dinuclear Pt-II complex
Design of new antitumor Pt drugs is currently also focused on those new Pt complexes which form on DNA major adducts that can hardly be removed by DNA repair systems. An attempt of this kind has already been done by designing and synthesizing new antitumor azolato-bridged dinuclear Pt-II complexes, such as [(cis-Pt(NH3)(2))(2)(mu-OH)(mu-pyrazolate)](2+) (AMPZ). This new Pt-II complex exhibits markedly higher toxic effects in some tumor cell lines than conventional mononuclear cisplatin. The primary objective in the present study was to further delineate differences in the interactions of AMPZ and cisplatin with natural, high-molecular-mass DNA using a combination of biochemical and molecular biophysics techniques. The results demonstrate for the first time that little conformational distortions induced by AMPZ in highly polymeric DNA with a random nucleotide sequence represent a structural motif recognizable by DNA repair systems less efficiently than distortions induced by cisplatin. Thus. DNA adducts of azolato-bridged dinuclear Pt-II complexes can escape repair mechanisms more easily than those of cisplatin, which may potentiate antitumor effects of these new metallodrugs in cancer cells. (C) 2012 Elsevier Inc. All rights reserved.