Voltammetric behavior of antileukemia drug glivec. Part III: In situ DNA oxidative damage by the glivec electrochemical metabolite

Glivec is a relatively small molecule with activity against the protein tyrosine kinase, a protein expressed by all patients with chronic myelogenous leukemia (CML). Based on its activity on CML, glivec is undergoing extensive evaluation of its activity against other types of tumor. As a result, there is an ongoing need for clarification of glivec pharmacokinetics so that issues such as drug-biomolecular complex interactions can be understood. The interaction of DNA with the antileukemia drug glivec was investigated in bulk solution and at a dsDNA-electrochemical biosensor using differential pulse voltammetry. It was found that glivec binds to dsDNA and this interaction leads to modifications in the dsDNA structure, electrochemically recognized through changes of the anodic oxidation peaks of guanosine and adenosine bases. The dsDNA-biosensor enabled the in situ electrochemical generation of glivec redox metabolites and the detection of DNA oxidative damage. Using polynucleotides of known sequence it has been proved that the interaction between glivec and DNA takes place at adenine enriched segments. The generation of glivec oxidation product inside the DNA double helix leads to oxidation of adenine residues and the electrochemical detection of 2,8-dihydroxyadenine. An interaction mechanism is proposed and the formation of 2,8-dihydroxyadenine is explained.