Pharmacodynamic Modeling of Anti-Cancer Activity of Tetraiodothyroacetic Acid in a Perfused Cell Culture System 英文参考文献.docVIP

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Pharmacodynamic Modeling of Anti-Cancer Activity of Tetraiodothyroacetic Acid in a Perfused Cell Culture System 英文参考文献.doc

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PharmacodynamicModelingofAnti-CancerActivityof TetraiodothyroaceticAcidinaPerfusedCellCulture System Hung-YunLin1.,CorneliaB.Landersdorfer1.*, DavidLondon1,RanMeng1,Chang-UkLim2,CassieLin1, SharonLin1,Heng-YuanTang1,DavidBrown3,BrianVanScoy3,RobertKulawy3,LurdesQueimado4, GeorgeL.Drusano3,ArnoldLouie3,FaithB.Davis1,ShakerA.Mousa5,PaulJ.Davis1,6 1Signal Transduction Laboratory, Ordway Research Institute,Albany, New York, United States of America, 2Flow Cytometry Core Facility, Ordway Research Institute, Albany,NewYork,UnitedStatesofAmerica,3EmergingInfectionsandPharmacodynamicsLaboratory,OrdwayResearchInstitute,Albany,NewYork,UnitedStatesof America,4DepartmentofOtorhinolaryngology,UniversityofOklahomaHealthSciencesCenter,OklahomaCity,Oklahoma,UnitedStatesofAmerica,5Pharmaceutical ResearchInstitute,AlbanyCollegeofPharmacyandHealthSciences,Rensselaer,NewYork,UnitedStatesofAmerica,6AlbanyMedicalCollege,Albany,NewYork,United StatesofAmerica Abstract Unmodified or as a poly[lactide-co-glycolide] nanoparticle, tetraiodothyroacetic acid (tetrac) acts at the integrin avb3 receptor on human cancer cells to inhibit tumor cell proliferation and xenograft growth. To study in vitro the pharmacodynamicsoftetracformulationsintheabsenceofandinconjunctionwithotherchemotherapeuticagents,we developed a perfusion bellows cell culture system. Cells were grown on polymer flakes and exposed to various concentrationsoftetrac,nano-tetrac,resveratrol,cetuximab,oracombinationforupto18days.Cellswereharvestedand counted every one or two days. Both NONMEM VI and the exact Monte Carlo parametric expectation maximization algorithminS-ADAPTwereutilizedformathematicalmodeling.Unmodifiedtetracinhibitedtheproliferationofcancercells anddidsowithdifferingpotencyindifferentcelllines.Thedevelopedmechanism-basedmodelincludedtwoeffectsof tetracondifferentpartsofthecellcyclewhichcouldbedistinguished.Forhumanbreastcancercells,modelingsuggesteda highersensitivity(lowerIC50)totheeffectonsuccessrateofreplic