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1、www.impactjournals.com/oncotarget/Oncotarget,AdvancePublications2015Pre-clinicalevaluationoftheMDM2-p53antagonistRG7388aloneandincombinationwithchemotherapyinneuroblastomaLindiChen1,RaphaëlF.Rousseau2,StevenA.Middleton3,GwenL.Nichols3,DavidR.Newell1,JohnLune
2、c1andDeborahA.Tweddle11NewcastleCancerCentre,NorthernInstituteforCancerResearch,NewcastleUniversity,Newcastle,UnitedKingdom2GenentechInc.,SouthSanFrancisco,CA,USA3Hoffmann-LaRocheInc.,Nutley,NJ,USACorrespondenceto:DeborahA.Tweddle,email:deborah.tweddle@ncl.a
3、c.ukKeywords:neuroblastoma,MDM2-p53antagonists,RG7388,combinationtherapy,CalcusynReceived:December17,2014Accepted:February17,2015Published:March10,2015Thisisanopen-accessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense,whichpermitsunrest
4、ricteduse,distribution,andreproductioninanymedium,providedtheoriginalauthorandsourcearecredited.ABSTRACTNeuroblastomaisapredominantlyp53wild-type(wt)tumourandMDM2-p53antagonistsofferanoveltherapeuticstrategyforneuroblastomapatients.RG7388(Roche)iscurrentlyun
5、dergoingearlyphaseclinicalevaluationinadults.ThisstudyassessedtheefficacyofRG7388asasingle-agentandincombinationwithchemotherapiescurrentlyusedtotreatneuroblastomainapanelofneuroblastomacelllines.RG7388GIconcentrationsweredeterminedin21p53-wtandmutant50neuro
6、blastomacelllinesofvaryingMYCN,MDM2andp14ARFstatus,togetherwithMYCN-regulatableTet21Ncells.Theprimarydeterminantofresponsewasthepresenceofwtp53,andoveralltherewasa>200-folddifferenceinRG7388GIconcentrations50forp53-wtversusmutantcelllines.Tet21NMYCN+cellswer
7、esignificantlymoresensitivetoRG7388comparedwithMYCN-cells.Usingmedian-effectanalysisin5p53-wtneuroblastomacelllines,selectedcombinationsofRG7388withcisplatin,doxorubicin,topotecan,temozolomideandbusulfanweresynergistic.Furthermore,combinationtreatmentsledtoi
8、ncreasedapoptosis,asevidentbyhighercaspase-3/7activitycomparedtoeitheragentalone.ThesedatashowthatRG7388ishighlypotentagainstp53-wtneuroblastomacells,andstronglysupportsitsfurtherevaluationasano
