F 11782, a novel catalytic inhibitor of topoisomerases I and II, induces atypical, yet cytotoxic DNA double-strand breaks in CHO-K1 cells.
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.
Barret
Jean-Marc
JM
Division de Cancéologie Centre de Recherche Pierre Fabre, Castres, France. jean_marc.barret@pierre-fabre.com
Etiévant
Chantal
C
Baudouin
Caroline
C
Skov
Kirsten
K
Charvéron
Marie
M
Hill
Bridget T
BT
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016466:CHO Cells / Q000187:drug effects; D002166:Camptothecin / Q000494:pharmacology; D020552:Comet Assay; D006224:Cricetinae; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D009281:Naphthalenes / Q000494:pharmacology*; D011714:Pyrans / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009281:Naphthalenes; D011714:Pyrans; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D004247:DNA; C405744:tafluposide; D002166:Camptothecin