cancer chemotherapy and drug resistance

CancerchemotherapyandDrugresistanceK.TejaswiniM.pharmPh.chemRollno:170112884002GPRCPContents•Introduction•Drugresistance•Cancerchemotherapy•Conclusion•ReferencesWhatiscancer?Cancerisknownmedicallyasamalignantneoplasm,isabroadgroupofdiseasesinvolvingunregulatedcellgrowth.Incancer,cellsdivideandgrowuncontrollably,formingmalignanttumors,andinvadenearbypartsofthebody.Thecancermayalsospreadtomoredistantpartsofthebodythroughthelymphaticsystemorbloodstream.Notalltumorsarecancerous;benigntumorsdonotinvadeneighboringtissuesanddonotspreadthroughoutthebody.Drugresistancecontents•Introduction•MechanismsofresistancealterationsindrugtargetsalterationsinintracellularretentionofdrugalterationsindrugdetoxificationpathwaysIncreasedDNArepairDefectiveapoptosisEpigeneticchangesintroduction•Becauseofbaselinegeneticalterationsintumorcellsandthefactthatmalignantcellscanacquirepleiotropicchangesinthepresenceofchemotherapy.tumorsmaystillbecomerefractorytobothdrugstheyhavebeenexposedtoaswellastodrugswithwhichtheyhaveneverbeentreated.•Thelattercase,termedmultidrugresistance,caninvolvecompoundswithcompletelyunrelatedstructuresandmechanismsofaction.•Clinicalresistanceoccursastheresistantclonesarepositivelyselectedforduringacourseofchemotherapy.•Despitetheemergenceofnewclassesofchemotherapeuticagentsandthewidespreaduseofrationalprotocoldesign,thestudyofthepanoplyofmechanismsofdrugresistancecontinuestobeessentialforusingthistooleffectivelyforthemostresistantsubtypesofmalignancies.Mechanismsofresistance•Thecancercellexhibitsuniquemolecularproperties,whichrenderthecellunabletohaltreplicationinthepresenceofDNAdamage.Thus,cancercellscancontinuetosurvivedespiteDNAdamage,canrapidlyincorporatenewmolecularconfigurationsthatconferasurvivalbenefit,andcanreplicaterapidlyandefficiently,increasingthespeedatwhichmolecularmechanismsofresistancecanbeincorporatedintothepopulationofcells.•Thesechangesincludeincreasedgenecopy,mutations,alteredtranscription,andepigeneticchanges.•Theoverallphenotypeofacancercellthathasincorporatedthesechangesinitsgenomeisacellthateithernolongeraccumulatesdrug,nolongermakesthedrug'stargetprotein,oraltersthetargetproteininsuchawaythattheproteinnolongerbindsorisaffectedbythedrug.Alterationsindrugtargets•Oneofthefirstmechanismsofacquiredresistancetochemotherapybythetumorcellwasdeterminedtobeanalterationoftheproteintargetedbythedrug,eitherbylossorgainoffunction.•Additionally,sometumorcellscanamplifycopiesofthegenesencodingthedrug'stargetandtranscribeandtranslatemoreofthetargetmolecules,overwhelmingthedrug'scytotoxicability.•Finally,somepreexistingsomaticmutationsthatarepresentinthetumorcellconferresistancetotherapyandmustbeconsideredwhenchoosingactiveagentsforindividuals.Increasedexpressionofdrugtarget:TumorcellshavingincreasedlevelsofintracellularDHFRafterexposuretoantifolate,methotrexateisanexample.DHFRistargetfor4-aminofolateanalogsorantifolatedrugs.TumorswhichdevelopresistancetomethotrexatewerefoundtohaveincreasedDHFRgene&increasedlevalsofexpressedDHFRenzyme.MutationofDHFRmayalsobethecause.IncreasedExpressionOfBiologicTarget:•Amplificationofgenesencodingoncogenicfusionproteins.•Inordertoavoiddamagetonormalhosttissue,onestrategyistotargetoncogenicfusionproteins,expressedintumorcellswithchromosomaltranslocationsthatresultinexpressedprotein.Eg:BCR/ABL–Expressedproteinisatyrosinekinase:resultofunbalancetranslocationofchromosomes9&22.•Imatinibmesylateisa2-phenylaminopyrimidinederivative.MarketedbyNovartisasGleevec(U.S.)&sometimesreferredtobyitsinvestigationalnameSTI-571.Isatyrosine-kinaseinhibitorusedinthetreatmentofmultiplecancers.•cellsdevelopresistanceduetoeitheramplificationofbcr/ablafterprolongedexposuretoST1571orduetoasingleaminoacidsubstitutioninthethreonineresidueoftheAblportionofthefusionproteinthatisrequiredforhydrogenbondformationwiththedrugmolecule.•Therefore,theearlyclinicalresultsneedtobeviewedwithcaution,andadditionalinvestigationofcombinationtherapiesiscurrentlyunderway.SOMATICGENETICVARIATION:Somaticvariationsofgenesequenceaffectdrugtarget–Eg:somaticpolymorphismsintheenhancer/promoterregionofTS,involvesaVNTRs,showntoinfluencethecellularresponseto5FUexposure.•CellswhosepromoterscontainthreerepeatshavehigherTSactivitythandocellswithtworepeatsbecauseofenhancedTSexpression.•Tumorcellsderivedfromthissomaticbackground(homozygousgenotypefor2repeats)willrespondwellto5FUtherapy.•Therefore,prospectivepharmacogeneticscreeningofthehost'ssomaticTSpromoterregionmayhelppredictbothtumorresponsetoconventionaldosesof5FU,aswellasconsidereitheralternativedrugregimensorincreasing5FUdosingforpatientswithhigherTSactivity.Tumormutationsindrugtarget:MultiplemutationsintopoisomeraseIIidentifiedintumorcells,theseinducesresistanceeitherthroughreductioninenzymeactivityoralterationsinproteinstructurethatpreventsbindingofdrugtotopoisomerasemolecule.TopoisomeraseIItoremovesupercoils.Thisinvolvesadouble-strandbreak(indicatedbyashortline),Withouttopoisomerases,theDNAcannotreplicatenormally.Therefore,theinhibitorsoftopoisomerases(epipodophyllotoxins