Unique properties of DNA interstrand cross-links of antitumor oxaliplatin and the effect of chirality of the carrier ligand
Language English Country Germany Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
Grant support
Howard Hughes Medical Institute - United States
- MeSH
- Circular Dichroism MeSH
- Cisplatin metabolism pharmacology MeSH
- Cyclohexylamines chemistry pharmacology MeSH
- Nucleic Acid Denaturation drug effects MeSH
- DNA chemistry genetics MeSH
- Nucleic Acid Conformation drug effects MeSH
- Ligands MeSH
- Organoplatinum Compounds chemistry pharmacology MeSH
- Oxaliplatin MeSH
- HMGB1 Protein metabolism MeSH
- Antineoplastic Agents chemistry pharmacology MeSH
- Cross-Linking Reagents chemistry MeSH
- Base Sequence MeSH
- Stereoisomerism MeSH
- Substrate Specificity MeSH
- Transition Temperature drug effects MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 1,2-cyclohexanediamine MeSH Browser
- Cisplatin MeSH
- Cyclohexylamines MeSH
- DNA MeSH
- Ligands MeSH
- Organoplatinum Compounds MeSH
- Oxaliplatin MeSH
- HMGB1 Protein MeSH
- Antineoplastic Agents MeSH
- Cross-Linking Reagents MeSH
The different antitumor and other biological effects of the third-generation antitumor platinum drug oxaliplatin [(1R,2R-diamminocyclohexane)oxalatoplatinum(II)] in comparison with those of conventional cisplatin [cis-diamminedichloridoplatinum(II)] are often explained by the ability of oxaliplatin to form DNA adducts of different conformation and consequently to exhibit different cytotoxic effects. This work describes, for the first time, the structural and biochemical characteristics of the interstrand cross-links of oxaliplatin. We find that: 1) DNA bending, unwinding, thermal destabilization, and delocalization of the conformational alteration induced by the cross-link of oxaliplatin are greater than those observed with the cross-link of cisplatin; 2) the affinity of high-mobility-group proteins (which are known to mediate the antitumor activity of platinum complexes) for the interstrand cross-links of oxaliplatin is markedly lower than for those of cisplatin; and 3) the chirality at the carrier 1,2-diaminocyclohexane ligand can affect some important structural properties of the interstrand cross-links of cisplatin analogues. Thus, the information contained in the present work is also useful for a better understanding of how the stereochemistry of the carrier amine ligands of cisplatin analogues can modulate their anticancer and mutagenic properties. The significance of this study is also reinforced by the fact that, in general, interstrand cross-links formed by various compounds of biological significance result in greater cytotoxicity than is expected for monofunctional adducts or other intrastrand DNA lesions. Therefore, we suggest that the unique properties of the interstrand cross-links of oxaliplatin are at least partly responsible for this drug's unique antitumor effects.
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