1,721,043 research outputs found
Spontaneous Translocation of Antitumor Oxaliplatin, its Enantiomeric Analogue, and Cisplatin from One Strand to Another in Double-Helical DNA
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The Thermodynamics of Translesion DNA Synthesis Past Major Adducts of Enantiomeric Analogues of Antitumor Cisplatin
No full textThe PtII-coordination complex [PtCl2(DAB)] (DAB=2,3-diaminobutane) belongs to a class of cytotoxic cisplatin analogues that contain chiral diamine ligands. Enantiomeric pairs of these compounds have attracted particular interest because they have different effects on different DNA conformations, which, in turn, influences the binding of damaged-DNA-processing enzymes that control downstream effects of the adducts, and thus exhibit different biological activities of the enantiomers. Herein, we studied the translesion synthesis across the major 1,2-d(GG) intrastrand cross-link formed by the R,R and S,S enantiomers of [Pt(DAB)]2+ in the TGGT sequence by using the enzyme that catalyzes the polymerization of deoxyribonucleotides into a DNA strand. We also employed differential scanning calorimetry (DSC) to measure the thermodynamic changes associated with replication-bypass past 1,2-d(GG) adducts of the [Pt(DAB)]2+ enantiomers. In the sequence TGGT, the 1,2-d(GG) intrastrand cross-links that were formed by the enantiomeric pairs of [Pt(DAB)]2+ inhibited DNA polymerization in a chirality-dependent manner. The thermodynamic data helped to understand the effect of the alterations in thermodynamic stability of DNA caused by the Pt-d(GG) adducts upon DNA polymerization across these lesions. Moreover, these data can possibly explain the influence of these alterations on the ability of many DNA polymerases to bypass adducts of antitumor platinum drugs. These results also highlighted the usefulness of DSC in evaluating the impact of DNA adducts of platinum-coordinated compounds on the processing of these lesions by damaged-DNA processing-enzymes
DNA-protein cross-linking by trans-[PtCl2(E-iminoether)2]. A concept for activation of the trans geometry in platinum antitumor complexes
No full textThermodynamic and mechanistic insights into translesion DNA synthesis catalyzed by Y-family DNA polymerase across a bulky double-base lesion of an antitumor platinum drug
No full textTo determine how the Yfamily translesion DNA polymerase h (Polh) processes lesions remains fundamental to understanding the molecular origins of the mutagenic translesion bypass. We utilized model systems employing a DNA double-base lesion derived from 1,2-GG intrastrand crosslinks
of a new antitumor PtII complex containing a bulky carrier ligand, namely [PtCl2(cis-1,4-dach)] (DACH= diaminocyclohexane). The catalytic efficiency of Polh for the insertion of correct dCTP, with respect to the other incorrect nucleotides, opposite the 1,2-GG cross-link was markedly reduced by the DACH carrier ligand. This reduced efficiency of Polh to incorporate the correct dCTP could be due to a more extensive DNA unstacking and deformation of the minor groove induced in the DNA by the cross-link of bulky [PtCl2(cis-1,4-dach)]. The major products of the bypass of this doublebase lesion produced by [PtCl2(cis-1,4-dach)] by Polh resulted from misincorporation of dATP opposite the platinated G residues. The results of the present work support the thesis that this misincorporation could be due to sterical effects of the bulkier 1,4-DACH ligand hindering the formation of the Polh–DNA–incoming nucleotide complex. Calorimetric analysis suggested that thermodynamic factors may
contribute to the forces that governed enhanced incorporation of the incorrect dATP by Polh as well
Recognition of major DNA adducts of enantiomeric cisplatin analogs by HMG Box Proteins and Nucleotide Excision Repair of these adducts
No full textDifferential genotoxic effects of antitumor trans-[PtCl2(E-iminoether)2] and cisplatin in Eschirichia Coli
No full textThe mechanism of antiproliferative activity of the oxaliplatin pyrophosphate derivative involves its binding to nuclear DNA in cancer cells
No full text(1R,2R-diaminocyclohexane)(dihydropyrophosphato) platinum(II), also abbreviated as RRD2, belongs to a class of potent antitumor platinum cytostatics called phosphaplatins. Curiously, several published studies have suggested significant mechanistic differences between phosphaplatins and conventional platinum antitumor drugs. Controversial findings have been published regarding the role of RRD2 binding to DNA in the mechanism of its antiproliferative activity in cancer cells. This prompted us to perform detailed studies to confirm or rule out the role of RRD2 binding to DNA in its antiproliferative effect in cancer cells. Here, we show that RRD2 exhibits excellent antiproliferative activity in various cancer cell lines, with IC50 values in the low micromolar or submicromolar range. Moreover, the results of this study demonstrate that DNA lesions caused by RRD2 contribute to killing cancer cells treated with this phosphaplatin derivative. Additionally, our data indicate that RRD2 accumulates in cancer cells but to a lesser extent than cisplatin. On the other hand, the efficiency of cisplatin and RRD2, after they accumulate in cancer cells, in binding to nuclear DNA is similar. Our results also show that RRD2 in the medium, in which the cells were cultured before RRD2 accumulated inside the cells, remained intact. This result is consistent with the view that RRD2 is activated by releasing free pyrophosphate only in the environment of cancer cells, thereby allowing RRD2 to bind to nuclear DNA. Graphical abstract: [Figure not available: see fulltext.]
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