Topoisomerase-I inhibitor SN-38 can induce DNA damage and chromosomal aberrations independent from DNA synthesis

Anticancer Res. Sep-Oct 1998;18(5A):3499-505.

Abstract

Background: SN-38 is the active metabolite of the topoisomerase-I (topo-I) inhibitor Irinotecan (CPT-11). Generally, topo-I inhibitors stabilize the complex between topo-I and DNA which collide with moving DNA replication forks, eventually leading to double stranded DNA damage. Therefore, topo-I inhibitors are regarded as S-phase specific. The present study investigated S-phase dependent and independent effects of SN-38.

Materials and methods: Effects of exposure of A2780 cells to SN-38 (2 hours) were studied by assessing DNA/protein crosslinks, DNA damage and cytogenetic aberrations.

Results: A close correlation (r2 = 0.97) was established between drug-induced DNA/protein crosslinks and double stranded DNA breaks. Cytogenetic analysis revealed near maximum clastogenic effects already evident immediately following 2 hours drug exposure. However, qualitatively, chromatid breaks at 24 hours were different from those at 0 hours, in that at 24 hours they were associated with radial chromosome configurations and sister chromatid exchanges.

Conclusion: The data corroborate that the S-phase dependent mechanism of action of topo-I inhibitors is also applicable to SN-38. The cytogenetic data indicate two distinct interactions of SN-38 with DNA: immediate induction of chromatid breaks independent from DNA synthesis, and induction of chromatid breaks associated with radial chromosome configurations dependent on DNA synthesis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Camptothecin / analogs & derivatives*
  • Camptothecin / pharmacology
  • Chromatids / drug effects*
  • Chromosome Aberrations
  • DNA Damage*
  • DNA Replication
  • DNA, Neoplasm / drug effects*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Irinotecan
  • S Phase
  • Sister Chromatid Exchange
  • Topoisomerase I Inhibitors*
  • Tumor Cells, Cultured / drug effects

Substances

  • DNA, Neoplasm
  • Enzyme Inhibitors
  • Topoisomerase I Inhibitors
  • Irinotecan
  • Camptothecin