Book of Abstracts: Albany 2007
June 19-23 2007
A Strong Increase in DNA Destabilization Caused by Cisplatin Binding in Alkaline Medium
Binding to DNA of the antitumor compound cisplatin locally distorts the double helix structure. These distortions correlate with decrease in DNA melting temperature. However, influence of platination on DNA stability is more complex because, besides distortion, platination lowers the DNA charge density and, in this way, increases DNA stability. Therefore, lowering of the DNA melting temperature after cisplatin binding becomes weaker with decrease in concentration of sodium ions [Na+].
We have shown that, besides Na+ concentration, pH also strongly influences DNA destabilization caused by cisplatin. In alkaline medium, the shift of melting temperature (δ(Tm)) increases several times. After incubation of DNA with cisplatin (0.01M NaClO4, 37 °C, 48h), melting of DNA was carried out in 0.1M NaCl, 5·10-5M EDTA, 5·10-3M Na2CO3 at pH=7 and pH=10.5 (Figure 1). At rb=0.05 (rb is the degree of platination per nucleotide), the shift of melting temperature changes from -4.1 °C at pH=7 to -13.1 °C at pH=10.5. Strengthening of destabilization at pH=10.5 was found for the rb interval 10-4÷0.05.
Study of change in DNA stability after platination on [Na+] at pH=7 and pH=10.5 demonstrates that, in alkaline medium, a Tm decrease is higher independently of [Na+] (Figure 2). However, the influence of [Na+] on the relative change in melting temperature caused by platination is weaker at pH=10.5 than at pH=7.
The work was supported in part by the Fund of Fundamental Investigations of the Republic of Belarus (grant X06R-102).
Elena N. Galyuk
Institute of Bioorganic Chemistry