title: Preclinical antitumour activity of F 11782, a novel dual catalytic inhibitor of topoisomerases.
abstract: F 11782 is a novel inhibitor of topoisomerases I and II, with an original mechanism of action (Perrin et al, 2000). This study, aimed to define its anticancer efficacy against a series of murine and human tumour models, has provided evidence of major antitumour activity for F 11782. This was demonstrated as a high level of activity against the P388 leukaemia, as reflected by increased survival of 143-457%, when administered i.p., p.o. or i.v. as single or multiple doses, and proved consistently superior to etoposide or camptothecin tested concurrently. Single or multiple i.p. doses of F 11782 also proved highly active against the s.c. grafted B16 melanoma, significantly increasing survival (P < 0.001) and inhibiting tumour growth (T/C of 0.3%), again superior to etoposide tested concurrently. Furthermore, F 11782 inhibited the number of pulmonary metastatic foci of the B16F10 melanoma by 99%. In human tumour xenograft studies, multiple i.p. doses of F 11782 resulted in major inhibitory activity against MX-1 (breast) tumours (T/C of 0.1%), as well as causing definite tumour regressions, whereas none resulted from similar experimental treatments with etoposide. Significant activity was also recorded with F 11782 against the relatively refractory LX-1 (lung) xenografts, with an optimal T/C value of 19%. It was notable that the antitumour activity of F 11782 was consistently demonstrated over a wide range of 2-6 dose levels, providing evidence of its good overall tolerance. In conclusion, these results emphasize the preclinical interest of this novel molecule and support its further preclinical development.
authors.affiliation: Division of Experimental Cancer Research, Centre de Recherche Pierre Fabre, 17 avenue Jean Moulin, Castres, 81106 Cedex 06, France.
authors.forename: A
authors.initials: A
authors.lastname: Kruczynski
authors.forename: C
authors.initials: C
authors.lastname: Etiévant
authors.forename: D
authors.initials: D
authors.lastname: Perrin
authors.forename: T
authors.initials: T
authors.lastname: Imbert
authors.forename: F
authors.initials: F
authors.lastname: Colpaert
authors.forename: B T
authors.initials: BT
authors.lastname: Hill
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy / Q000201:enzymology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000556:secondary; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009281:Naphthalenes / Q000494:pharmacology*; D009368:Neoplasm Transplantation; D011714:Pyrans / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009281:Naphthalenes; D011714:Pyrans; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; C405744:tafluposide