F 11782, a novel catalytic inhibitor of topoisomerases I and II, induces atypical, yet cytotoxic DNA double-strand breaks in CHO-K1 cells

Anticancer Res. 2002 Jan-Feb;22(1A):187-92.

Abstract

F 11782, or 2'', 3''-bispentafluorophenoxyacetyl-4, 6'-ethylidene-beta-D glucoside of 4'-phosphate-4'-dimethylepipodopliyllotoxin 2N-methyl glucamine salt, is a novel fluorinated lipophylic epipodophylloid which has shown marked antitumour activity in vivo. In vitro studies have demonstrated a dual catalytic inhibitory activity of F 11782 against topoisomerases and I and II by an original mechanism involving interference with the DNA binding activity of these enzymes, without DNA intercalating properties. Nevertheless, the precise mechanism(s) of cytotoxicity of F 11782 remains unclear and recent studies have suggested that this cytotoxicity might result, at least in part, from an induction of DNA-strand breaks without stabilisation of cleavable complex. In this study, DNA damage induced by F 11782 and its repair by non-homologous recombination was investigated in CHO-K1 cells. The results suggest that the nature of such damage differs from that induced by etoposide, a structurally-related topoisomerase II poison and identify a high level of stability of the damage induced which may account, at least in part, for the superior preclinical anti-tumour activity of F 11782.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • CHO Cells / drug effects
  • Camptothecin / pharmacology
  • Comet Assay
  • Cricetinae
  • DNA / drug effects
  • DNA / metabolism
  • DNA Damage*
  • DNA Repair / physiology
  • Enzyme Inhibitors / pharmacology*
  • Etoposide / pharmacology
  • Inhibitory Concentration 50
  • Naphthalenes / pharmacology*
  • Pyrans / pharmacology*
  • Topoisomerase I Inhibitors*
  • Topoisomerase II Inhibitors*

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Naphthalenes
  • Pyrans
  • Topoisomerase I Inhibitors
  • Topoisomerase II Inhibitors
  • Etoposide
  • DNA
  • tafluposide
  • Camptothecin