An Integrated Drosophila Model System Reveals Unique Properties for F14512, a Novel Polyamine-Containing Anticancer Drug That Targets Topoisomerase II 英文参考文献.docVIP

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An Integrated Drosophila Model System Reveals Unique Properties for F14512, a Novel Polyamine-Containing Anticancer Drug That Targets Topoisomerase II 英文参考文献.doc

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An Integrated Drosophila Model System Reveals Unique Properties for F14512, a Novel Polyamine-Containing Anticancer Drug That Targets Topoisomerase II 英文参考文献

AnIntegratedDrosophilaModelSystemRevealsUnique PropertiesforF14512,aNovelPolyamine-Containing AnticancerDrugThatTargetsTopoisomeraseII SoniaChelouah1,2¤a,CarolineMonod-Wissler1,2¤b,ChristianBailly3,Jean-MarcBarret3 ,Nicolas Guilbaud3,Ste′phaneVispe′3*,EmmanuelKa¨s1,2* 1Universite′ de Toulouse, UPS, Universite′ Paul Sabatier, Laboratoire de Biologie Mole′culaire Eucaryote; Toulouse; France, 2CNRS, Centre National de la Recherche Scientifique,UMR5099,LaboratoiredeBiologieMole′culaireEucaryote,Toulouse,France,3CentredeRechercheenOncologieExpe′rimentale,InstitutdeRecherchePierre Fabre,Toulouse,France Abstract F14512isanovelanti-tumormoleculebasedonanepipodophyllotoxincorecoupledtoacancer-cellvectoringspermine moiety.ThispolyaminelinkageisassumedtoensurethepreferentialuptakeofF14512bycancercells,stronginteraction withDNAandpotentinhibitionoftopoisomeraseII(TopoII).TheantitumoractivityofF14512inhumantumormodelsis significantly higher than that of other epipodophyllotoxins in spite of a lower induction of DNA breakage. Hence, the demonstrated superiority of F14512 over other Topo II poisons might not result solely from its preferential uptake by cancercells,butcouldalsobeduetouniqueeffectsonTopoIIinteractionswithDNA.Tofurtherdissectthemechanismof action of F14512, we used Drosophila melanogaster mutants whose genetic background leads to an easily scored phenotype that is sensitive to changes in Topo II activity and/or localization. F14512 has antiproliferative properties in Drosophila cells and stabilizes ternary Topo II/DNA cleavable complexes at unique sites located in moderately repeated sequences, suggesting that the drug specifically targets a select and limited subset of genomic sequences. Feeding F14512 to developing mutant Drosophila larvae led to the recovery of flies expressing a striking phenotype, Eye wide shut,whereoneeyeisreplacedbyafirstthoracicsegment.OtherrecoveredF14512-induced gain-andloss-of-function phenotypes similarly correspond to precise g