Conformation of DNA GG Intrastrand Cross-Link of Antitumor Oxaliplatin and Its Enantiomeric Analog

Abstract

Downstream processes that discriminate between DNA adducts of a third generation platinum antitumor drug oxaliplatin and conventional cisplatin are believed to be responsible for the differences in their biological effects. These different biological effects are explained by the ability of oxaliplatin to form DNA adducts more efficient in their biological effects. In this work conformation, recognition by HMG domain protein and DNA polymerization across the major 1,2-GG intrastrand cross-link formed by cisplatin and oxaliplatin in three sequence contexts were compared with the aid of biophysical and biochemical methods. The following major differences in the properties of the cross-links of oxaliplatin and cisplatin were found: i), the formation of the cross-link by oxaliplatin is more deleterious energetically in all three sequence contexts; ii), the cross-link of oxaliplatin bends DNA slightly but systematically less in all sequence contexts tested; iii), the affinity of HMG domain protein to the cross-link of oxaliplatin is considerably lower independent of the sequence context; and iv), the Klenow fragment of DNA polymerase I pauses considerably more at the cross-link of oxaliplatin in all sequence contexts tested. We have also demonstrated that the chirality at the carrier ligand of oxaliplatin can affect its biological effects.

Energetics, Conformation, and Recognition of DNA Duplexes Modified by Methylated Analogues of [PtCl(dien)]+

“…Such thermodynamic data can reveal how the platinum adduct influences duplex stability, a property that has been shown to play a significant role in the mechanism of biological activity of platinum antitumor drugs. [22][23][24][25][26][27] In this work we studied oligodeoxyribonu- …”

Base‐Resolution Analysis of Cisplatin–DNA Adducts at the Genome Scale

“…In this study, we took advantage of the preferential binding of HMGB1 domain A to distorted DNA structures to selectively enrich cisplatin-modified DNA for high-throughput sequencing. Owing to the ability of cisplatin–DNA adducts to stall DNA synthesis, [11] cisplatin crosslinking sites could be identified at base resolution throughout the genome (Scheme 1). …”

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

“…Such destabilization was found to be enthalpic, but not entropic, in origin. Similarly, when occurring at 5'-TGGT site, cisplatin adducts decrease the melting temperature of the DNA by more than 10°C which is much higher than that induced on 5'-CGGT and 5'-AGGC sequences (~6°C) (Malina et al, 2007). Such effects are not observed with transplatin which does not change the transition entropy or enthalpy and, consequently, does not destabilize the DNA helix (Kasparkova et al, 2008a).…”