Differential effects of camptothecin derivatives on topoisomerase I- mediated DNA structure modification

Xiangyang Wang, Li Kai Wang, William D. Kingsbury, Randall K. Johnson, Sidney M. Hecht

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

The effects of eleven camptothecin derivatives on calf thymus topoisomerase I-mediated cleavage of synthetic DNA duplex have revealed that the A ring of camptothecin is very important for its biochemical activity. Depending on the type, number, and location of substituents, highly active or inactive analogues were obtained. The persistence of CPT-induced topoisomerase I-DNA covalent binary complexes was investigated by using as substrates DNA containing several good topoisomerase I cleavage sites, or else a synthetic DNA duplex of defined structure with a single high- efficiency cleavage site. The ligation kinetics at a given topoisomerase I cleavage site were sometimes quite different in the presence of CPT derivatives whose structures were closely related. Even in the presence of a single CPT analogue, topoisomerase I-DNA covalent binary complexes underwent ligation with different kinetics, presumably reflecting a dependence on DNA sequences flanking the individual topoisomerase I cleavage sites. Individual camptothecin derivatives also exhibited a spectrum of inhibitory potentials in blocking the topoisomerase I-mediated rearrangement of branched, nicked, and gapped DNA duplex substrates; in some cases the potencies of inhibition observed in these assays for individual camptothecin analogues were quite different than those determined for stabilization of the unmodified DNA- topoisomerase I binary complex.

Original languageEnglish (US)
Pages (from-to)9399-9408
Number of pages10
JournalBiochemistry
Volume37
Issue number26
DOIs
StatePublished - Jun 30 1998
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry

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