Title:Methods for Elucidation of DNA-Anticancer Drug Interactions and their Applications in the Development of New Drugs
VOLUME: 22 ISSUE: 44
Author(s):Majus Misiak, Francesco Mantegazza and Giovanni L. Beretta
Affiliation:Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Via Amadeo 42-20133, Milan
Keywords:Anticancer drug, atomic force microscopy, circular dichroism, DNA, fluorescence, magnetic tweezers, nuclear magnetic
resonance.
Abstract:DNA damaging agents including anthracyclines, camptothecins and platinum
drugs are among most frequently used drugs in the chemotherapeutic routine. Due to their
relatively low selectivity for cancer cells, administration of these drugs is associated with
adverse side effects, inherent genotoxicity with risk of developing secondary cancers. Development
of new drugs, which could be spared of these drawbacks and characterize by improved
antitumor efficacy, remains challenging yet vitally important task. These properties
are in large part dictated by the selectivity of interaction between the drug and DNA and in
this way the studies aimed at elucidating the complex interactions between ligand and DNA
represent a key step in the drug development. Studies of the drug-DNA interactions encompass
determination of DNA sequence specificity and mode of DNA binding as well as kinetic,
dynamic and structural parameters of binding. Here, we consider the types of interactions
between small molecule ligands and polynucleotides, how they are affected by DNA
sequence and structure, and what is their significance for the antitumor activity. Based on this knowledge, we
discuss the wide array of experimental techniques available to researchers for studying drug-DNA interactions,
which include absorption and emission spectroscopies, NMR, magnetic and optical tweezers or atomic force
microscopy. We show, using the clinical and experimental anticancer drugs as examples, how these methods
provide various types of information and at the same time complement each other to provide full picture of drug-
DNA interaction and aid in the development of new drugs.
