Comparative thermal and thermodynamic study of DNA chemically modified with antitumor drug cisplatin and its inactive analog transplatin.
Antitumor activity of cisplatin is exerted by covalent binding to DNA. For comparison, studies of cisplatin-DNA complexes often employ the very similar but inactive transplatin. In this work, thermal and thermodynamic properties of DNA complexes with these compounds were studied using differential scanning calorimetry (DSC) and computer modeling. DSC demonstrates that cisplatin decreases thermal stability (melting temperature, Tm) of long DNA, and transplatin increases it. At the same time, both compounds decrease the enthalpy and entropy of the helix-coil transition, and the impact of transplatin is much higher. From Pt/nucleotide molar ratio rb=0.001, both compounds destroy the fine structure of DSC profile and increase the temperature melting range (ΔT). For cisplatin and transplatin, the dependences δTm vs rb differ in sign, while δΔT vs rb are positive for both compounds. The change in the parameter δΔT vs rb demonstrates the GC specificity in the location of DNA distortions. Our experimental results and calculations show that 1) in contrast to [Pt(dien)Cl]Cl, monofunctional adducts formed by transplatin decrease the thermal stability of long DNA at [Na(+)]>30mM; 2) interstrand crosslinks of cisplatin and transplatin only slightly increase Tm; 3) the difference in thermal stability of DNA complexes with cisplatin vs DNA complexes with transplatin mainly arises from the different thermodynamic properties of their intrastrand crosslinks. This type of crosslink appears to be responsible for the antitumor activity of cisplatin. At any [Na(+)] from interval 10-210mM, cisplatin and transplatin intrastrand crosslinks give rise to destabilization and stabilization, respectively.
Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, 220141 Minsk, Belarus. Electronic address: lando@iboch.bas-net.
Dmitri Y
DY
Lando
Institute of Physics, Academia Sinica, Nankang, Taipei 11529, Taiwan.
Chun-Ling
CL
Chang
Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, 220141 Minsk, Belarus.
Alexander S
AS
Fridman
Department of Physics, Yerevan State University, 0025 Yerevan, Armenia.
Inessa E
IE
Grigoryan
Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, 220141 Minsk, Belarus.
Elena N
EN
Galyuk
Department of Physics, National Central University, Chungli 32001, Taiwan.
Ya-Wei
YW
Hsueh
Institute of Physics, Academia Sinica, Nankang, Taipei 11529, Taiwan. Electronic address: huck@phys.sinica.edu.tw.
Chin-Kun
CK
Hu
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D001665:Binding Sites; D002417:Cattle; D002945:Cisplatin / Q000737:chemistry*; D004247:DNA / Q000737:chemistry; D018736:DNA Adducts / Q000737:chemistry; D019277:Entropy; D006801:Humans; D009369:Neoplasms / Q000737:chemistry / Q000378:metabolism; D009690:Nucleic Acid Conformation; D013696:Temperature; D013816:Thermodynamics
D000970:Antineoplastic Agents; D018736:DNA Adducts; C034697:transplatin; D004247:DNA; C427203:calf thymus DNA; D002945:Cisplatin
DNA complexes with platinum compounds; DNA differential scanning calorimetry; DNA optical melting studies