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.