[Interaction of topotecan-a DNA topoisomerase I inhibitor-with dual-stranded polydeoxyribonucleotides. V. Topotecan is able to cause single- and double-strand breaks in ring superhelical DNA in the absence of enzyme].

: Temperature, concentration, and time dependence for the emergence of breaks in the sugar-phosphate backbone in a circular supercoiled DNA (scDNA) was studied for the first time in the presence of topotecan (TPT) and in the absence of human DNA topoisomerase I (topo I). Because TPT is a comptothecin (CPT) derivative, it is the first example for the ability of molecules of CPT family to cause double-stranded breaks in scDNA in the absence of the enzyme. The experiments were carried out in low ionic strength solutions (10 mM sodium cacodylate) at neutral pH (6.8). Incubation time necessary for the appearance of double-stranded breaks in scDNA in the presence of TPT correlated with the time of formation of strong TPT-DNA complex. A model was suggested for the complex composed of two crossed DNA duplexes bound through a bridge of two dimers of TPT lactone form. According to this model, two carbonyl groups of D rings of different TPT dimers form hydrogen bonds with 2-amino groups of guanines located in the neighboring base pairs of diverse strands of one of DNA duplexes. At the same time, two other carbonyl groups of D rings of TPT dimers form hydrogen bonds with 2-amino groups of guanines spaced five bp apart in the same strand of the second DNA duplex.