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  2010;70:440-446.PublishedOnlineFirstJanuary12,2010.CancerRes Ting-ChaoChou UsingtheChou-TalalayMethodDrugCombinationStudiesandTheirSynergyQuantification    UpdatedVersion10.1158/0008-5472.CAN-09-1947doi:Accessthemostrecentversionofthisarticleat:  CitedArticles:CitingArticles:  E-mailalertsrelatedtothisarticleorjour[e-mail]printsofthisarticleortosubscribetothejournal,[e-mail]permissiontore-useallorpartofthisarticle,contacttheAACRPublicationsAmericanAssociationforCancerResearch Copyright©2010onApril15,2012cancerres.aacrjournals.orgDownloadedfromPublishedOnlineFirstJanuary12,2010;DOI:10.1158/0008-5472.CAN-09-1947PerspectiveDrugCombinationStudiesandTheirSynergyQuantificationUsingtheChou-TalalayMethodTing-ChaoChouAbstractThisbriefperspectivearticlefocusesonthemostcommonerrorsandpitfalls,aswellasthedo'sanddon'tsindrugcombinationstudies,intermsofexperimentaldesign,dataacquisition,datainterpretation,andcom-puterizedsimulation.TheChou-Talalaymethodfordrugcombinationisbasedonthemedian-effectequation,derivedfromthemass-actionlawprinciple,whichistheunifiedtheorythatprovidesthecommonlinkbe-tweensingleentityandmultipleentities,andfirstorderandhigherorderdynamics.ThisgeneralequationencompassestheMichaelis-Menten,Hill,Henderson-Hasselbalch,andScatchardequationsinbiochemistryandbiophysics.Theresultingcombinationindex(CI)theoremofChou-Talalayoffersquantitativedefinitionforadditiveeffect(CI=1),synergism(CI1),andantagonism(CI1)indrugcombinations.Thistheoryalsoprovidesalgorithmsforautomatedcomputersimulationforsynergismand/orantagonismatanyeffectanddoselevel,asshownintheCIplotandisobologram,respectively.CancerRes;70(2);440–6.©2010AACR.IntroductionDrugcombinationismostwidelyusedintreatingthemostdreadfuldiseases,suchascancerandAIDS.Themainaimsaretoachievesynergistictherapeuticeffect,doseandtoxicityreduction,andtominimizeordelaytheinductionofdrugresistance(1).Toxicityreductionandresistanceminimiza-tionbenefitscouldalsobetheoutcomesofsynergism.How-ever,inonereviewarticlebyGoldinandMantelin1957(2),sevendifferentdefinitionsforsynergismweregiven,andinamorerecentreviewbyGrecoandcolleaguesin1995(3),13differentmethodsfordeterminingsynergismwerelistedandnoneofthemsupportedtheothers(1).Themeaningofsyn-ergismhasbecomeanindividual'spreference.Faultyorun-substantiatedsynergyclaimsarepervasive.Thisisseriousbecauseitisfrequentlyreferredtoinpatienttherapy.Withoutastandardizeddefinitionforsynergism,itisar-guedthattherewillbeamessinmakingsynergyclaims,whetherinpublishingascientificarticle,submittingagrantapplication,planningdrugcombinationclinicaltrialsforFoodandDrugAdministrationapproval,orassertingdrugcombinationdiscoverytothePatentOffice(4,5).Itisalsoarguedthatintheabsenceofaclear“definitionforsyner-gism”,governmentalagencieshavenobasistoregulatethedrugcombinationsynergyclaims(4,5).Ihavedevotedoverfourdecadesonthisimportantfunda-mentalissue.Inall,morethan300mechanism-specificequa-tionshavebeenderivedandpublished(6–13).Ittookabout10yearstofigureoutwhatanadditiveeffectis(1,7,12).Thisisimportant,becausebydefinition,synergismismorethananadditiveeffectandantagonismislessthananadditiveeffect.AlongwithProfessorPaulTalalayoftheJohnsHopkinsUniversitySchoolofMedicine,in1983to1984,wejointlyin-troducedascientificterm“combinationindex”(CI)toquan-titativelydepictsynergism(CI1),additiveeffect(CI=1),andantagonism(CI1;refs.11,12).ItsapplicationsweregreatlyfacilitatedbythehelpofJosephChou,whodevelopedthefirst-generationcomputersoftwarefordose-effectanaly-sisbasedonthe“mass-actionlaw”(14).Duetofastchangesincomputerhardwareandsoftware,thesecond-generation“CalcuSyn”waswrittenbyMikeHayballofCambridge,Unit-edKingdomin1997(15),andthethird-generation“Compu-Syn”wasthenwrittenbyNickMartinofMIT,Cambridge,MAin2005(16).Theroutefromtheunifiedtheorytoalgorithms,toquan-titativepracticalapplicationsisshowninFig.1.Theessencebehindthemass-actionlaw–basedtheoryisthatthe“medi-an”istheunifiedcommonlinkofsingleentityandmultipleentities,andforthefirst-orderandhigher-orderdynamics(1).The“median”inthemedian-effectequationalsoservesastheuniversalreferencepoint,whichevolvesintotheglobalpositioningsystem(GPS)conceptforbioinformatics.Thefeaturesofthismethodologyareitssimplicityandflexibility(e.g.,mechanism-andunit-independent),itsquantitativedefinition(e.g.,numericallyindexedconclusion),anditseffi-ciencyandeconomy(e.g.,allowsforasmallnumberofdatapointsofmeasurementsandusesasmallnumberofani-mals).Moredetailshavebeendescribedinrefs.1and17.TheCommonPitfallsandErrorsinDrugCombinationStudiesToavoidpitfallsindrugcombinationstudies,thefollow-ingfundamental,scientificconcep