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

Jaroslav Malina ^*, Olga Novakova ^*, Marie Vojtiskova ^*, Giovanni Natile  and Viktor Brabec ^*

^* Institute of Biophysics, Academy of Sciences of the Czech Republic, CZ-61265 Brno, Czech Republic; and Department of Pharmaceutical Chemistry, University of Bari, I-70125 Bari, Italy

Correspondence: Address reprint requests to Viktor Brabec, E-mail: brabec{at}ibp.cz.

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.