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 |
| |
Authors: | Tereza Suchánková Marie Vojtí?ková Jan Reedijk Viktor Brabec Jana Ka?párková |
| |
Institution: | (1) Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, 61265 Brno, Czech Republic;(2) Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands;(3) Laboratory of Biophysics, Department of Experimental Physics, Faculty of Sciences, Palacky University, tr. Svobody 26, 77146 Olomouc, Czech Republic |
| |
Abstract: | 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. |
| |
Keywords: | DNA Conformation Cisplatin Transplatin Antitumor activity |
本文献已被 SpringerLink 等数据库收录! |
|