Interaction of topotecan, DNA topoisomerase I inhibitor, with double-stranded polydeoxyribonucleotides. 4. Topotecan binds preferably to the GC base pairs of DNA

Interaction of topotecan (TPT) with synthetic double-stranded polydeoxyribonucleotides has been studied in solutions of low ionic strength at pH 6.8 by linear flow dichroism (LD), circular dichroism (CD), UV-Vis absorption, and Raman spectroscopy. The complexes of TPT with poly(dG-dC) . poly(dG-dC), poly(dG) . poly(dC), poly(dA-dC) . poly(dG-dT), and poly(dA) . poly(dT), as well as complexes of TPT with calf thymus DNA and coliphage T4 DNA studied by us previously, have been shown to have negative LD in the long-wavelength absorption band of TPT, whereas the complex of TPT with poly(dA-dT) . poly(dA-dT) has positive LD in this absorption band of TPT. Thus, there are two different types of TOT complex with the polymers. TPT has been established to bind preferably to GC base pairs because its affinity to the polymers of different composition decreases in the following order: poly(dG-dC) . poly (dG-dC) > poly(dG) . poly(dC) > poly(dA-dC) . poly(dG-dT) > poly(dA) . poly(dT). The presence of DNA has been shown to shift the monomer-dimer equilibrium in TPT solutions toward dimer formation. Several duplexes of the synthetic polynucleotides bound together by bridges of TPT dimers; may participate in the formation of the studied type of TPT-polynucleotide complex. Molecular models of TPT complex with linear and circular supercoiled DNAs and with deoxyguanosine have been considered. TPT (and presumably the whole camptothecin family) proved to represent a new class of DNA-specific ligands whose biological action is associated with formation of dimeric bridges between two DNA duplexes.