Spectrophotometric Studies on the Thermodynamics of the ds-DNA Interaction with Irinotecan for a Better Understanding of Anticancer Drug-DNA Interactions

Reza Hajian,Tan Guan Huat

doi:10.1155/2013/380352

Reza Hajian, Tan Guan Huat

Open Access

https://doi.org/10.1155/2013/380352

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Abstract

The ds-DNA binding properties of irinotecan (CPT-11) including binding constant, thermodynamic parameter, and thermal denaturation (Tm) have been systematically studied by spectrophotometric methods. The binding of CPT-11 to ds-DNA is quite strong as indicated by its remarkable hypochromicity and equilibrium binding constant (Kb). The van't Hoff plot of 1/Tversus ln Kbsuggests that the CPT-11 binds endothermically to ct-DNA which is characterized by large positive enthalpy and entropy changes. According to the polyelectrolyte theory, the charge release (Z), when ct-DNA interacts with CPT-11, is +0.98, which corresponds very well to the one positive charge carried by CPT-11. TheKbat a low concentration of salt is dominated by electrostatic interaction (98.5%) while that at a high concentration of salt is weakly controlled by nonelectrostatic processes (19.0%). A moderate stabilization of the double helix ds-DNA occurs when CPT-11 binds to ds-DNA as indicated by the increase inTmof ct-DNA by approximately 15°C in the presence of CPT-11. The CPT-11 is stabilized by intercalation in the DNA (binding constant,K[irinotecan-DNA] = 5.8 × 104 mol−1 L) and displaces the NR dye from the NR-DNA complex (K[NR-DNA] = 2.7 × 104 mol−1 L) in a competitive reaction.

Highlights

Irinotecan (CPT-11), a semisynthetic derivative of camptothecin, has a growing clinical impact due to its effectiveness in treating malignancies of the colon, lung, pancreas, cervix, and ovaries with increased survival bene ts for patients
It has been demonstrated that the binding of CPT-11 to ds-DNA is quite strong as indicated by the remarkable hypochromicity and equilibrium binding constant depending on the temperature and salt concentration in the medium
Binding is enthalpically driven as indicated by the large positive enthalpy and entropy changes. e salt dependence of the DNA binding of CPT-11 indicates that the charge release (ZZ)

Summary

Introduction

Irinotecan (CPT-11), a semisynthetic derivative of camptothecin, has a growing clinical impact due to its effectiveness in treating malignancies of the colon, lung, pancreas, cervix, and ovaries with increased survival bene ts for patients. Irinotecan could destroy or have effects on the DNA destruction or transcription In this respect, our investigation provided a thermodynamic pro le, standard free energy (ΔGG∘), enthalpy (ΔHH∘), and entropy (ΔSS∘) changes of the DNA binding of CPT-11 using the van’t Hoff plot by determining the equilibrium. The effect of salt concentration on the binding free energy of small molecules and DNA interactions has been long known. A systematic study on the effect of salt concentration on the DNA binding of anticancer drugs is limited. E determination of the salt effect on the KKbb value of the DNA binding of drugs and analyzing the results by the polyelectrolyte theory can be used to evaluate systematically the nonelectrostatic contribution to the KKbb and separate the total ΔGG∘ into its electrostatic and non-electrostatic contributions.

Experimental

Results and Discussion

Conclusion