Unique Properties of DNA Interstrand Cross‐Links of Antitumor Oxaliplatin and the Effect of Chirality of the Carrier Ligand

Abstract

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.

Novel Role of Base Excision Repair in Mediating Cisplatin Cytotoxicity

“…The ICLs induced by platinum drugs form unique DNA structures. The transplatin ICL structure results in no extrahelical cytosines, whereas in the oxaliplatin ICL structure, the flanking cytosines are not as exposed as in cisplatin ICLs and protein recognition is altered (45)(46)(47). The ICL structure is also distinct from those formed by mitomycin C and psoralen, and down-regulation of BER proteins resulted in hypersensitivity to these cross-linking agents (48,49).…”

The status of platinum anticancer drugs in the clinic and in clinical trials

“…15 The oxalate ligand also greatly reduces the severity of the side effects of the drug compared with cisplatin. 2 Recent clinical trials have tried to extend its spectrum of activity to include the treatment of metastatic gastric and oesophagogastric adenocarcinoma, 16 and improve its effectiveness against colorectal cancers through its administration with different drugs such as irinotecan and capecitabine.…”

DNA Helix Destabilization by Alkylating Agents: From Covalent Bonding to DNA Repair

“…Binding of HMG-B1 (and HMG-B2) stabilizes the cisplatin-induced bent and supercoiling of the DNA helix, increases the sensitivity of the cells to cisplatin and shields the platinated adducts from repair by the human DNA excision machinery (J.C. Huang et al, 1994). As a consequence of the degree of kink of the DNA, HMG proteins poorly bind to oxaliplatin adducts which induce relatively small DNA-bending and DNA destabilization (Figure 3), and so poorly protects them from DNA repair (Kasparkova et al, 2008b). This difference correlates with the lower level of DNA lesions in oxaliplatin-versus cisplatin-treated cells.…”