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.

• MeSH
• Circular Dichroism MeSH
• Cisplatin pharmacology   metabolism   MeSH
• Cyclohexylamines pharmacology   chemistry   MeSH
• Nucleic Acid Denaturation drug effects   MeSH
• DNA genetics   chemistry   MeSH
• Financing, Organized MeSH
• Nucleic Acid Conformation drug effects   MeSH
• Ligands MeSH
• Organoplatinum Compounds pharmacology   chemistry   MeSH
• HMGB1 Protein metabolism   MeSH
• Antineoplastic Agents pharmacology   chemistry   MeSH
• Cross-Linking Reagents chemistry   MeSH
• Base Sequence MeSH
• Stereoisomerism MeSH
• Substrate Specificity MeSH
• Transition Temperature drug effects   MeSH