Unique properties of DNA interstrand cross-links of antitumor oxaliplatin and the effect of chirality of the carrier ligand.
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.
Kasparkova
Jana
J
Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i. Kralovopolska 135, 61265 Brno, Czech Republic.
Vojtiskova
Marie
M
Natile
Giovanni
G
Brabec
Viktor
V
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001483:Base Sequence; D002942:Circular Dichroism; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology; D003432:Cross-Linking Reagents / Q000737:chemistry*; D003514:Cyclohexylamines / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000737:chemistry* / Q000235:genetics; D024243:HMGB1 Protein / Q000378:metabolism; D008024:Ligands; D009690:Nucleic Acid Conformation / Q000187:drug effects; D009691:Nucleic Acid Denaturation / Q000187:drug effects; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000494:pharmacology; D000077150:Oxaliplatin; D013237:Stereoisomerism; D013379:Substrate Specificity; D044366:Transition Temperature / Q000187:drug effects
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D003514:Cyclohexylamines; D024243:HMGB1 Protein; D008024:Ligands; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D004247:DNA; C030435:1,2-cyclohexanediamine; D002945:Cisplatin