Search Algorithms as a Framework for the Optimization of Drug Combinations 英文参考文献.docVIP

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Search Algorithms as a Framework for the Optimization of Drug Combinations 英文参考文献.doc

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Search Algorithms as a Framework for the Optimization of Drug Combinations 英文参考文献

SearchAlgorithmsasaFrameworkfortheOptimization ofDrugCombinations DiegoCalzolari1.,StefaniaBruschi1.,LaurenceCoquin1,JenniferSchofield1,JacobD.Feala2,JohnC. Reed1,AndrewD.McCulloch2,GiovanniPaternostro1,2* 1Burnham Institute for Medical Research, La Jolla, California, United States of America, 2Department of Bioengineering, University of California San Diego, La Jolla, California,UnitedStatesofAmerica Abstract Combination therapies are often needed for effective clinical outcomes in the management of complex diseases, but presently they are generally based on empirical clinical experience. Here we suggest a novel application of search algorithms—originally developed for digital communication—modified to optimize combinations of therapeutic interventions.Inbiologicalexperimentsmeasuringtherestorationofthedeclinewithageinheartfunctionandexercise capacity in Drosophila melanogaster, we found that search algorithms correctly identified optimal combinations of four drugsusingonlyone-thirdofthetestsperformedinafullyfactorialsearch.Inexperimentsidentifyingcombinationsofthree doses of up to six drugs for selective killing of human cancer cells, search algorithms resulted in a highly significant enrichmentofselectivecombinationscomparedwithrandomsearches.Insimulationsusinganetworkmodelofcelldeath, wefoundthatthesearchalgorithmsidentifiedtheoptimalcombinationsof6–9interventionsin80–90%oftests,compared with15–30%foranequivalentrandomsearch.Thesefindingssuggestthatmodifiedsearchalgorithmsfrominformation theoryhavethepotentialtoenhancethediscoveryofnoveltherapeuticdrugcombinations.Thisreportalsohelpstoframe abiomedicalproblemthatwillbenefitfromaninterdisciplinaryeffortandsuggestsageneralstrategyforitssolution. Citation:CalzolariD,BruschiS,CoquinL,SchofieldJ,FealaJD,etal.(2008)SearchAlgorithmsasaFrameworkfortheOptimizationofDrugCombinations.PLoS ComputBiol4(12):e1000249.doi:10.1371/journal.pcbi.1000249 Editor:GregTucker-Kellogg,LillySingaporeCentreforDrugDiscovery,Singapore R