title: F 11782, a novel epipodophylloid non-intercalating dual catalytic inhibitor of topoisomerases I and II with an original mechanism of action.
abstract: F 11782, a novel epipodophylloid, proved a potent inhibitor of the catalytic activities of both topoisomerases I and II. Unlike classical inhibitors such as camptothecin or etoposide, F 11782 did not stabilise cleavable complexes induced by either topoisomerases I or II nor did it preferentially inhibit the religation step of the catalytic cycle of either enzyme. F 11782 neither intercalated DNA nor bound in its minor groove, and showed only weak inhibition of the ATPase activity associated with topoisomerase II. F 11782 appeared to act by inhibiting the binding of topoisomerases I and II to DNA in a manner dependent both on drug and enzyme concentrations, via a mechanism not previously described or shared by other known topoisomerase 'poisons' or inhibitors. In contrast, F 11782 had only a weak effect or none at all on various other DNA-interacting enzymes. In conclusion, F 11782, as a non-intercalating, specific catalytic inhibitor of both topoisomerases I and II with an original mechanism of action, may be considered to represent the first of a new class of topoisomerase-interacting agents.
authors.affiliation: Division of Experimental Cancerology I, Centre de Recherche Pierre Fabre, Castres, France. dominique.perrin@pierre-fabre.com
authors.forename: D
authors.initials: D
authors.lastname: Perrin
authors.forename: B
authors.initials: B
authors.lastname: van Hille
authors.forename: J M
authors.initials: JM
authors.lastname: Barret
authors.forename: A
authors.initials: A
authors.lastname: Kruczynski
authors.forename: C
authors.initials: C
authors.lastname: Etiévant
authors.forename: T
authors.initials: T
authors.lastname: Imbert
authors.forename: B T
authors.initials: BT
authors.lastname: Hill
mesh_terms: D000251:Adenosine Triphosphatases / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002166:Camptothecin / Q000494:pharmacology; D002384:Catalysis; D002417:Cattle; D002467:Cell Nucleus / Q000201:enzymology; D004247:DNA / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004795:Enzyme Stability; D005047:Etoposide / Q000494:pharmacology; D005069:Evaluation Studies as Topic; D006801:Humans; D009281:Naphthalenes / Q000494:pharmacology*; D011714:Pyrans / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D009281:Naphthalenes; D011714:Pyrans; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D004247:DNA; D000251:Adenosine Triphosphatases; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; C405744:tafluposide; D002166:Camptothecin