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《Novel Phase I Study Combining G1 Phase, S Phase, and G2 M Phase Cell Cycle Inhibitors in Patients with Advanced Malignancies (1)》由会员上传分享，免费在线阅读，更多相关内容在学术论文-天天文库。
1、REPORTCellCycle14:21,3434--3440;November1,2015;©2015Taylor&FrancisGroup,LLCNovelphaseIstudycombiningG1phase,Sphase,andG2/MphasecellcycleinhibitorsinpatientswithadvancedmalignanciesRajulKJain1,*,DavidSHong1,AungNaing1,JenniferWheler1,ThorunnHelgason1,Nai-YiShi1,YashGad2,3
2、andRazelleKurzrock123DepartmentofInvestigationalCancerTherapeutics(PhaseIProgram);MDAndersonCancerCenter;Houston,TXUSA;SimVivo;Houston,TXUSA;MooresCancerCenter;UniversityofCaliforniaSanDiego;LaJolla,CAUSAKeywords:bortezomib,cellcycle,oncology,phaseI,pharmacodynamics,tems
3、irolimus,topotecanPURPOSE:Cancerisamanifestationofaberrantcellularproliferation,andthecellcycleisoneofthemostsuccessfullydruggedtargetsinoncology.Nopriorstudyhasbeenreportedthatsimultaneouslytargetsthe3principalcellcyclephasespopulatedbyproliferatingcells-G1,S,andG2/M.ME
4、THODS:Temsirolimus(G1inhibitor),topotecan(Sinhibitor),andbortezomib(G2/Minhibitor)wereadministeredincombinationtopatientswithadvancedmalignanciesusinga3+3doseescalationscheduletoassessthesafetyandestablishthemaximumtolerateddose(primaryendpoints)ofthiscellcycletargetinga
5、pproach.Aninsilicopharmacodynamicmodelusingestablishedeffectsofeachoftheseagentsonthecellcyclewasusedtovalidatetheregimenandtoguidethedosingregimen.RESULTS:Sixty-twosubjectswereenrolled.Themostcommonadverseeventsanddose-limitingtoxicitieswerecytopenias,consistentwiththec
6、ellcycletargetingapproachemployed.Allcytopeniasresolvedtobaselinevaluesuponholdingstudydrugadministration.Themaximumtolerateddosewastemsirolimus15mg/kgIVD1,8,15;topotecan222.8mg/mIVD1,8;andbortezomib0.9mg/mIVD1,4,8,11ofa21-daycycle.Insilicomodelingsuggeststheregimeninduc
7、escellpopulationshiftsfromG2/MandSphasestoG1phaseandthequiescentG0phase.Eighteenpercentofsubjects(11/62)achievedpartialresponse(nD2,serousovarianandpapillarythyroid)orstablediseasefor>6months(nD9).CONCLUSION:CombiningdrugswithinhibitoryactivityofG1phase,Sphase,andG2/Mpha
8、seissafeandwarrantsfurtherevaluation.Introductioncontrollingitscomponentmolecularprocesses.Infact,someo
