Studies on interaction of anthracycline antibiotics and deoxyribonucleic acid: equilibrium binding studies on the interaction of daunomycin with deoxyribonucleic acid

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Abstract
Equilibrium dialysis and fluorescence and absorbance titration were used to study the interaction of [the antineoplastic drug] daunomycin with DNA [from calf thymus, Clostridium perfringens and Micrococcus luteus]. At 200 mM Na+, the data are best fit by the neighbor exclusion model, with K = 7.0 .times. 105 M-1 and an exclusion parameter of 3-4 base pairs. The binding is dependent on ionic strength, with d log K/d log [Na+] = -0.84, from which ion release may be estimated quantitatively and the binding free energy corrected for the free energy of counterion release. From the temperature dependence of the binding constant, the binding was exothermic, with a van''t Hoff enthalpy of -12.8 kcal/mol. Competition dialysis experiments show that G+C base pairs are slightly preferred as binding sites for the drug and suggest that daunomycin binds preferentially to G+C pairs at low .hivin.r. Cesium chloride density gradient sedimentation experiments provide an experimental demonstration of this preference. Daunomycin increases the Tm [melting temperature] for DNA melting by some 30.degree. C as binding approaches saturation, with biphasic melting at low drug/base pair ratios. The data from these equilibrium studies are consistent with intercalative binding of daunomycin and provide a solid foundation for further structural and kinetic studies.

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