1. Academic Validation
  2. Saintopin, a dual inhibitor of DNA topoisomerases I and II, as a probe for drug-enzyme interactions

Saintopin, a dual inhibitor of DNA topoisomerases I and II, as a probe for drug-enzyme interactions

  • J Biol Chem. 1994 Nov 18;269(46):28702-7.
F Leteurtre 1 A Fujimori A Tanizawa A Chhabra A Mazumder G Kohlhagen H Nakano Y Pommier
Affiliations

Affiliation

  • 1 Division of Cancer Treatment, NCI, National Institutes of Health, Bethesda, Maryland 20892.
PMID: 7961822
Abstract

Stabilization of the topoisomerase-cleavable complexes is the common initial event leading to the cytotoxicity of Topoisomerase I and II (top1 and top2) inhibitors. Using saintopin (STP), a poison of both topoisomerases, we studied top1- and top2-cleavable complexes (Yamashita, Y., Kawada, S.-Z., Fujii, N., and Nakano, H. (1991) Biochemistry 30, 5838-5845). top1 and top2 sites induced in the presence of STP showed the same preferences for the base located 3' to the topoisomerase-induced DNA break (position +1): preference for G and not C. A camptothecin-resistant top1 with a mutation (Asn722-->Ser) next to the catalytic tyrosine (Tyr723) was cross-resistant to STP, suggesting that both STP and camptothecin interact with the protein near the catalytic tyrosine. These results are consistent with a dual interaction of the drug with the Enzyme and the DNA and provide further evidence for the "drug-stacking" model. This model proposes that Topoisomerase inhibitors bind, possibly through hydrogen bonding and/or stacking, with one of the bases flanking the DNA termini (guanine at position +1 in the case of STP) and within the Enzyme catalytic pocket, most likely by stacking with the catalytic tyrosine.

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