Interaction of clinically important human DNA topoisomerase I poison, topotecan, with double-stranded DNA.

摘要: Topotecan (TPT), a water-soluble derivative of camptothecin, is potent antitumor poison human DNA topoisomerase I (top1) that stabilizes the cleavage complex between enzyme and DNA. The role recently discovered TPT affinity to remains be defined. aim this work clarify molecular mechanisms TPT-DNA interaction propose models complexes in solution absence top1. It shown molecules form dimers with dimerization constant (4.0 +/- 0.7) x 10(3) M(-1) presence provokes more than 400-fold increase effective constant. Flow linear dichroism spectroscopy accompanied by circular dichroism, fluorescence, surface-enhanced Raman scattering experiments provide evidence are able bind bridging different or distant structural domains. This effect may provoke modification intrinsic geometry cruciform structures, leading appearance new crossover points serve as sites top1 loading position. data presume hypothesis TPT-mediated modulation top1-DNA recognition before ternary formation.