Resistance to chemotherapy in cancer

•ResistancetoChemotherapyinCancerJianghuaQi,PH.D.DepartmentoftheBoneandSofttissuetumorDep.oftheBoneandSofttissuetumorResistancetochemotherapyisakeyimpedimenttosuccessfulcancertreatmentthathasbeenintensivelystudiedforthelastthreedecades.Understandingthebiologicalmechanismsofdrugresistanceanddevelopingagentstotargetthosemechanismsareimportantstepsinthedesignofnewtherapies.Dep.oftheBoneandSofttissuetumorCellscanexistinthreestates:normal,sensitivecancercells,andresistantcancercells.Resistancecandevelopasasinglesteporasmultiplestepsofrandomgeneticmutationsoranyotherabnormalityoccurringingeneproducts.Dep.oftheBoneandSofttissuetumorDep.oftheBoneandSofttissuetumorFig.1includesfourscenarios:diffusionresistance,intrinsicresistance,inducedresistancebythemicro-environmentalconditions,andcompletelyresistantcancercells.Thecompletelyresistantcellsareeitherintrinsicallyresistantorhaveacquiredresistanceduetopriorchemotherapy.Dep.oftheBoneandSofttissuetumorDiffusionresistanceoccurswhencertaincellsarenotexposedtothedrugduetotheirlocationwithinthetumor.Drugsandbiologicsthatarelargemoleculesmayhavearatherlimitedperfusioncapabilityanddiffusionresistanceisexpectedtooccurincellsthatarelocatedawayfromthecapillarybed.Dep.oftheBoneandSofttissuetumorModulatingthedrugdoseisanindirectwaytochallengetheproblemofdrugdelivery,butthisstrategycanstillfailincaseswherethedrugisunabletoenterthecells(inaspecificlocationinthetumor/body).Suchlimitationsimplythatitwouldbehelpfultomodelthedrugsequencebytheirpenetrabilityandonlythenbytheirbiologicalfunctions.Dep.oftheBoneandSofttissuetumorTheoretically,abnormalitiescoulddevelopfrompointmutations,geneamplificationorothergeneticorepigeneticchangesthataffectbiologicalfunctions.Penetrationofantineoplasticagentsintothecancercellinducestheirlethalpharmacologicaleffectbyinteractionwithtargetmolecules.Alteredactivityofmembrane-embeddeddruguptakeandeffluxpumpscaninhibitthiseffectbyreducingintracellulardrugaccumulation,therebypreventingdrug-targetinteractions.Dep.oftheBoneandSofttissuetumorDep.oftheBoneandSofttissuetumorSeveralstudieshaveshownthatmost,ifnotall,chemotherapeuticagentsexerttheiranticanceractivitybyinducingapoptosis;therefore,resistancetoapoptosismaybeamajorfactorlimitingtheeffectivenessofanticancertherapy.Inthelastfewyears,efforthasbeenmadetounderstandthebiochemicalalterationsofapoptoticpathwaysincancer.Manyofthesealterationsconferamultidrugresistantphenotypetomalignantcells.Dep.oftheBoneandSofttissuetumorOnemechanismbywhichalivingcellcanachievemultipleresistancesisviatheactiveeffluxofabroadrangeofanticancerdrugsthroughthecellularmembranebyMDRproteins.SuchdrugsareexportedinbothATP-dependentand-independentmanners,andcanoccurdespiteconsiderableconcentrationgradients.Dep.oftheBoneandSofttissuetumorTotheATP-dependentgroupbelongstheATP-bindingcassette(ABC)transporterfamily,whichincludesP-gp,MRP,BCRP,etc.AnotherproteinrelatedtoMDR,thoughnotbelongingtotheABCtransporterfamily,islungresistance-relatedprotein(LRP).Alloftheseproteinsareinvolvedindiversephysiologicalprocesses,andareresponsiblefortheuptakeandeffluxofamultitudeofsubstancesfromcancercells.Dep.oftheBoneandSofttissuetumorManyinhibitorsofMDRtransportershavebeenidentifiedovertheyears.Unfortunately,theydisplayedpoorresponseinclinicalstudies.Dep.oftheBoneandSofttissuetumorRecently,newcompoundsobtainedfromdrugdevelopmentprogramsconductedbythepharmaceuticalindustryarecharacterizedbyahighaffinitytoMDRtransportersandareefficientatnanomolarconcentrations.Someofthesecompounds(e.g.,MS-209)arecurrentlyunderclinicaltrialsforspecificformsofadvancedcancers.ThankYou!