Accurate SPR methods for DNA/drug interactions

Boston University, Boston MA

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Abstract

Platinum anticancer drugs are currently the most widely used chemotherapeutic agents in medicine. The biological activity of platinum based anticancer drugs may, in part, be explained by differences in the mode of drug binding with DNA. A novel trinuclear platinum compound (BBR3464), has recently entered phase II clinical trials. This genuinely new platinum agent, not based on the cisplatin structure, represents a new class of antitumor drugs for which the mechanism of interaction with DNA, while clearly different than of cisplatin, remains poorly understood. The ain of this research is to probe, in real time, the kinetics of binding of a novel class of high-affinity polynuclear platinum compounds with un- labeled single and double stranded DNA oligomers immobilized on a surface plasmon resonance (SPR) sensor surface. This work will compare the modes of interaction for polynuclear and mononuclear platinum compounds, including cisplatin, with DNA. This work is distinguished of kinetics at interfaces. In addition, in situ temperature dependent SPR will be used for in-situ melting (dehybridization) studies with and without drug binding. The contribution of electrostatic interactions to drug binding with DNA oligomers will be determined by investigating the effect of varying solution ionic strength and by novel combination of SPR with electrochemical methods which will selectively alter the excess surface charge at the sensor interface. Finally, MALDI MS will be used to supplement our in-situ SPR kinetics measurements with addition mass spectrometric characterization of the platinated drug DNA adducts. This work provide a deeper understanding of the fundamental differences between novel multinuclear platinum drugs and the more well-studied cisplatin regarding the preferred modes of interaction with DNA. This information may offer insight on the differences in activity between mono- nuclear platinum compounds in vivo.