DNA and glutathione interactions in cell-free media of asymmetric platinum(II) complexes cis- and trans-[PtCl2(isopropylamine)(1-methylimidazole)]: relations to their different antitumor effects

被引:17
|
作者
Suchankova, Tereza [1 ]
Vojtiskova, Marie [1 ]
Reedijk, Jan [2 ]
Brabec, Viktor [1 ,3 ]
Kasparkova, Jana [1 ]
机构
[1] Acad Sci Czech Republ, Inst Biophys, CS-61265 Brno, Czech Republic
[2] Leiden Univ, Leiden Inst Chem, Gorlaeus Labs, NL-2300 RA Leiden, Netherlands
[3] Palacky Univ, Fac Sci, Dept Expt Phys, Biophys Lab, Olomouc 77146, Czech Republic
来源
JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY | 2009年 / 14卷 / 01期
关键词
DNA; Conformation; Cisplatin; Transplatin; Antitumor activity; INTERSTRAND CROSS-LINKS; STRUCTURAL-CHARACTERIZATION; TRANSPLATIN ANALOGS; MOLECULAR ASPECTS; SUPERCOILED DNA; ONE PLANAR; CISPLATIN; BINDING; TRANS-DIAMMINEDICHLOROPLATINUM(II); RECOGNITION;
D O I
10.1007/s00775-008-0425-0
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The global modification of mammalian and plasmid DNAs by the novel platinum compounds cis-[PtCl2(isopropylamine)(1-methylimidazole)] and trans-[PtCl2(isopropylamine)(1-methylimidazole)] and the reactivity of these compounds with reduced glutathione (GSH) were investigated in cell-free media using various biochemical and biophysical methods. Earlier cytotoxicity studies had revealed that the replacement of the NH3 groups in cisplatin by the azole and isopropylamine ligands lowers the activity of cisplatin in both sensitive and resistant cell lines. The results of the present work show that this replacement does not considerably affect the DNA modifications by this drug, recognition of these modifications by HMGB1 protein, their repair, and reactivity of the platinum complex with GSH. These results were interpreted to mean that the reduced activity of this analog of cisplatin in tumor cell lines is due to factors that do not operate at the level of the target DNA. In contrast, earlier studies had shown that the replacement of the NH3 groups in the clinically ineffective trans isomer (transplatin) by the azole and isopropylamine ligands results in a radical enhancement of its activity in tumor cell lines. Importantly, this replacement also markedly alters the DNA binding mode of transplatin, which is distinctly different from that of cisplatin, but does not affect reactivity with GSH. Hence, the results of the present work are consistent with the view and support the hypothesis systematically tested by us and others that platinum drugs that bind to DNA in a fundamentally different manner from that of conventional cisplatin may have altered pharmacological properties.
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页码:75 / 87
页数:13
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