Thermal and thermodynamic properties of duplex DNA containing site-specific interstrand cross-link of antitumor cisplatin or its clinically ineffective trans isomer

The effect of the single, site-specific interstrand crosslink formed by cis platin or transplatin on the thermal stability and energetics of a 20-base pair DNA duplex is reported. The cross-linked or unplatinated 20-base pair duplexes were investigated with the aid of differential scanning calorimetr y, temperature-dependent W absorption, and circular dichroism, The cross-li nk of both platinum isomers increases the thermal stability of the modified duplexes by changing the molecularity of denaturation. The structural pert urbation resulting from the interstrand cross-link of cisplatin increases e ntropy of the duplex and in this way entropically stabilizes the duplex. Th is entropic cross-link-induced stabilization of the duplex is partially but not completely compensated by the enthalpic destabilization of the duplex. The net result of these enthalpic and entropic effects is that the structu ral perturbation resulting from the formation of the interstrand cross-link by cisplatin induces a decrease in duplex thermodynamic stability, with th is destabilization being enthalpic in origin. By contrast, the interstrand cross-link of transplatin is enthalpically almost neutral with the cross-li nk-induced destabilization entirely entropic in origin. These differences a re consistent with distinct conformational distortions induced by the inter strand cross-links of the two isomers, Importantly, for the duplex cross-li nked by cisplatin relative to that cross-linked by transplatin, the compens ating enthalpic and entropic effects almost completely offset the differenc e in cross-link-induced energetic destabilization, It has been proposed tha t the results of the present work further support the view that the impact of the interstrand cross-links of cisplatin and transplatin on DNA is diffe rent for each and might also be associated with the distinctly different an titumor effects of these platinum compounds.