Modification of DNA dynamics by platinum drug binding: a time-dependent fluorescence depolarization study of the interaction of cis- and trans-diamminedichloroplatinum(II) with DNA

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Abstract
The interaction of calf thymus DNA with the antitumor drug cis-diamminedichloroplatinum(II), and with the clinically ineffective trans isomer, is studied by time-dependent fluorescence depolarization spectroscopy of intercalated ethidium. The effect of the platinum compounds on the rapid torsional motions of DNA in solution is observed via depolarization of the ethidium fluorescence. The depolarization data are successfully analyzed with an elastic model of DNA dynamics and yield a value for the product of the torsional rigidity of the DNA and the friction factor for DNA twisting. The dependence of this quantity on the degree of platination of the DNA is determined for each isomer. At low levels of platination, the cis isomer increases the solute-solvent friction acting on the DNA torsional motions, which we attribute to local kinking of the helix axis at the sites of platination. At high levels of platination, the cis isomer decreases the torsional rigidity of the DNA, indicating that disruption of DNA duplex structure occurs under these conditions. The binding of the trans isomer to DNA has no effect on the torsional rigidity of the friction. The present results are compared with other findings on the interaction of these platinum compounds with DNA.