F 11782, a dual inhibitor of topoisomerases I and II with an original mechanism of action in vitro, and markedly superior in vivo antitumour activity, relative to three other dual topoisomerase inhibitors, intoplicin, aclarubicin and TAS-103

Purpose: F 11782 (2",3"-bis pentafluorophenoxyacetyl-4",6"-ethylidene-beta- D-gluocoside of 4'-phosphate-4'-dimethylepipodophyllotoxin di-N-methyl gluc amine salt) is a newly synthesized dual catalytic inhibitor of topoisomeras es I and II with major in vivo antitumour activity. In this study, we compa red and contrasted F 11782 with three other known inhibitors of both these nuclear enzymes, namely aclarubicin, intoplicin and TAS-103, and establishe d its novel mechanism of action, Methods: In vitro growth-inhibitory effect s against a. panel of murine and tumour cell lines were measured by cell co unting, clonogenicity or tetrazolium metabolic dye (MTT assays. In vivo ant itumour. activities were evaluated against two murine tumour models (i.v. P 388 leukaemia and s.c. BIG melanoma). Finally, interactions with either DNA ol DNA-topoisomerases were determined using various methodologies: DNA-int ercalator displacement, pBR322 DNA relaxation, kDNA decatenation, topoisome rase II extractability measurements, stabilization of topoisomerase-induced cleavable complexes (CC) in vitro and in cells, and gel retardation assays . Results: F 11782 had a different profile of sensitivities and proved gene rally less cytotoxic than the other dual inhibitors tested in vitro, while showing significantly superior antitumour activity in vivo. F 11782, which did not stabilize CC either in vitro or in cells, was the only compound of this series capable of inhibiting the catalytic activity of both DNA-topois omerases without interacting with. DNA, and of completely impairing the bin ding of these nuclear proteins to DNA. Moreover, only cotreatment of cells in vitro with F 11782 enhanced the cytotoxic activity of etoposide. Conclus ion: These results emphasize the novel mechanism of action of F 11782 vis-a -vis the other dual inhibitors of topoisomerases I and II and so augur well for its future clinical development.