Conformation of DNA GG intrastrand cross-link of antitumor oxaliplatin and its enantiomeric analog
Jaroslav Malina 1, Olga Novakova 1, Marie Vojtiskova 1, Giovanni Natile 2 and Viktor Brabec 1*
1 Institute of Biophysics, Academy of Sciences of the Czech Republic, Brno
2 Department of Pharmaceutical Chemistry, University of Bari
* To whom correspondence should be addressed. E-mail: brabec{at}ibp.cz.
Submitted on July 8, 2007
Revised on August 2, 2007
Accepted on 10 August 2007
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Abstract |
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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 as for their biological effects. In the present 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 have been 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 independently of the sequence context; (iv) Klenow fragment of DNA polymerase I pauses at the cross-link of oxaliplatin in all sequence contexts tested considerably more. We have also demonstrated that the chirality at the carrier ligand of oxaliplatin can affect its biological effects.
Key Words:
DNA cross-link, DNA polymerase, calorimetry, cisplatin, oxaliplatin, recognition
