顺铂肾毒性Word格式文档下载.docx

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anupdate

NeifeAparecidaGuinaimdosSantos•

MariaAugustaCarvalhoRodrigues•

14February2012/Publishedonline:

1March2012

NadiaMariaMartins•AntonioCardozodosSantos

Received:

26January2012/Accepted:

©

Springer-Verlag2012

AbstractCisplatinisahighlyeffectiveantitumoragentwhoseclinicalapplicationislimitedbytheinherentnephrotoxicity.Thecurrentmeasuresofnephroprotectionusedinpatientsreceivingcisplatinarenotsatisfactory,andstudieshavefocusedontheinvestigationofnewpossibleprotectivestrategies.Manypathwaysinvolvedincisplatinnephrotoxicityhavebeendelineatedandproposedastargetsfornephroprotection,andmanynewpotentiallyprotectiveagentshavebeenreported.Themultiplepathwayswhichleadtorenaldamageandrenalcelldeathhavepointsofconvergenceandsharesomecommonmodulators.Themostfrequenteventamongallthedescribedpathwaysistheoxidativestressthatactsasbothatriggerandaresult.Themostexploitedpathways,theproposedprotectivestrategies,theachievementsobtainedsofaraswellasconflictingdataaresummarizedanddiscussedinthisreview,providingageneralviewoftheknowledgeaccumulatedwithpastandrecentresearchonthissubject.

KeywordsCisplatin-Nephrotoxicity-Nephroprotection-Oxidativestress-Apoptosis-Molecularmechanisms-Mitochondria

Cisplatin

Cisplatin（cisplatinumorcis-diamminedichloroplatinum（II）,CDDP）isahighlyeffectivechemotherapeuticdrug

N.A.G.dosSantos-M.A.CarvalhoRodrigues-N.M.Martins-A.C.dosSantos（&

）

DepartmentofClinical,ToxicologicalAnalysesandFoodSciencesofSchoolofPharmaceuticalSciencesofRibeiraoPreto,UniversityofSiioPaulo,RibeiriioPreto,SP,Brazile-mail:

acsantos@fcfrp.usp.br

whoseanticanceractivitywasaccidentallydiscoveredbythephysicist-biologistBarnettRosenberg,duringhisstudiesaddressingtheeffectofaplatinumelectrode-generatedelectricfieldonthedivisionprocessesofEscherichiacoli.Heobservedthatthecellulardivisionwasinhibitedandafilamentousgrowthwasinducedbyelectrolysisproductsthatwereafterwardidentifiedasplatinumcompounds.Basedonthisobservation,heandhiscolleaguesinvestigatedtheantitumoractivityofplatinumcompoundsinleukemiaL1210-andSarcoma180-bearingmice.Theantitumorefficacyofcisplatinwasthendiscovered（Rosenbergetal.1965,1967,1969）.

TheclinicaluseofcisplatinwasapprovedbytheFDAinDecember1978（FDAdatabase）.Sincethen,theapplicationofcisplatinhasbeenbroadenedtoseveraltypesofcancerandithasbeenusedbothaloneorcombinedwithotherdrugs:

asfirst-linetreatment,asadjuvant,orevenasneoadjuvanttherapyofotherproceduressuchassurgeryorradiotherapy.Currently,theuseofcisplatinisapprovedtotreatbladdercancer,cervicalcancer,malignantmesothelioma,non-smallcelllungcancer,ovariancancer,squamouscellcarcinomaoftheheadandneck,andtesticularcancer（NationalCancerInstitutedatabase）.Additionally,cisplatinhasbeenusedtotreatothertypesofcancerwhenthefirst-linetreatmenthasfailedoryetinspecificsituationsthatprecludethestandardtreatment（Candelariaetal.2006;

HelmandStates2009;

Goffinetal.2010;

CampbellandKindler2011;

Ismailietal.2011a,b）.

Cisplatinchemotherapyislimitedbytumorcellsresistanceandseveresideeffectssuchasnephrotoxicity,neurotoxicity,ototoxicity,andemetogenicity（WangandLippard2005;

PablaandDong2008）.Amongthesefactors,nephrotoxicityhasbeenreportedasthemajorlimiterincisplatintherapy（AranyandSafirstein2003）.

Thesusceptibilityofkidneystocisplatintoxicity

Kidneysareparticularlyaffectedbycisplatin,andthishasbeenattributedmainlyto（a）highconcentrationofcisplatininthekidneysand（b）therenaltransportsystems.Cisplatiniseliminatedpredominantlybythekidneys;

thebiliaryandtheintestinalexcretionofthisdrugareminimal.Duringtheexcretionprocess,thedrugisconcentratedandevennontoxicbloodlevelsofcisplatinmightreachtoxiclevelsinkidneys.Infact,ithasbeenreportedthattheconcentrationofcisplatininepithelialtubularcellsisfivefoldhigherthaninblood（Rosenberg1985;

Bajorinetal.1986;

GordonandGattone1986;

Kuhlmannetal.1997;

Schenellmann2001）.Thenephrotoxicityinducedbycisplatinisdose-dependentandthereforelimitstheincreaseofdoses,compromisingtheefficacyofthetherapy（HaniganandDevarajan2003）.Thetoxiceffectsoccurprimarilyintherenalproximaltubules,particularlyintheepithelialtubularcellsofS-3segment（Werneretal.1995）.Glomerulianddistaltubulesarealsoaffectedafterward.Impairmentoftherenalfunctionisfoundinapproximately25-35%ofpatientstreatedwithasingledoseofcisplatin（Hanetal.2009）.Decreaseof2040%ofglomerularfiltration,increasedBUN（bloodureanitrogen）,andincreasedserumcreatinineconcentrationsaswellasreducedserummagnesiumandpotassiumlevelsarefrequentinpatientstreatedwithcisplatin（RiesandKlastersky1986;

Kintzel2001;

Hanetal.2009）.

Thehighconcentrationofcisplatininkidneysfavorsitscellularuptakebypassivediffusion（Galeetal.1973;

GatelyandHowell1993）,andthiswasonceconsideredthemainprocessthroughwhichcisplatinenteredandaccumulatedincells.Morerecently,activetransportsystemshavegainedimportanceandhavebeenassociatedwithtumorcellsresistanceaswellasthetoxicityofcisplatin（Ishidaetal.2002;

Pablaetal.2009;

Burgeretal.2011）.ThefacilitatedtransportsystemswhichhavebeenassociatedwithcisplatinnephrotoxicityarethosemediatedbytheorganiccationtransporterOCT2andmorerecently,thecoppertransporterCtr1.In2002,IshidaandcolleaguesproposedthatcisplatinuptakewasmediatedbythecoppertransporterCtr1inyeastandmammals（Ishidaetal.2002）.AlthoughCtr1ishighlyexpressedinkidney（Sharp2003）,itwasfirstassociatedwithcisplatinuptakebynon-renalcellsandonlyrecentlyastudyassociatedCtr1withcis-platinuptakeinrenalcellsandthereforenephrotoxicity（Pablaetal.2009）.OCT2ishighlyexpressedinthebasolateralmembraneofproximaltubulesandhasbeenreportedtoparticipateintherenalaccumulationofcisplatin（Ludwigetal.2004;

Ciarimbolietal.2005;

Yonezawaetal.2005）.

IthasbeenreportedthatOCT1/2double-knockoutmicetreatedwithcisplatinpresentedonlyamildnephrotoxicityaswellasreducedrenalplatinumaccumulationwhencomparedtowild-typemice（Ciarimbolietal.2005）.Additionally,itwasreportedthattheconcomitantadministrationofimatinib,acationicanticanceragent,withcis-platinpreventedcisplatin-inducednephrotoxicitybyinhibitingtheOCT2-mediatedrenalaccumulationofcis-platin（Taniharaetal.2009）.Invivoandinvitrostudieshaveshownthatcimetidineinhibitscisplatinrenaldamagewithoutaffectingitsantitumoractivity（Katsudaetal.2010）.However,inanotherstudywithcimetidineinvivo,onlyapartialprotectionagainstcisplatin-inducednephrotoxicitywasobserved.Thenephroprotectiveactionofcimetidinehasbeenattributedto（i）acompetitiveinhibitionofcisplatintransportbyOCT2,sincecimetidineisanorganiccationandthereforeanOCTsubstrate（Ciarimbolietal.2005）;

and（ii）inhibitionofcytochromeP450withblockadeofironreleaseandconsequentlyinhibitionofhydroxylradicalsgeneration（Baligaetal.1998）.Theprotectiveeffectofcimetidinehasalsobeenshowninaclinicaltrialwithninepatientstreatedwithcisplatin,verapamil,andcimetidine（Sleijferetal.1987）.AnotherstrategytoblockadecisplatinuptakeinrenalcellsistheinhibitionofCtr1.Infact,ithasbeenreportedthatCTR1-deficientcellsaccumulatelessplatinumintheirDNAandaremoreresistanttothecytotoxiceffectofcisplatinthantheCTR1-repletecells（Linetal.2002）.

Theantitumormechanismversusthenephrotoxicmechanism

Themoleculeofcisplatinisformedbyacentralplatinumionlinkedto2chlorideionsand2ammoniamolecules.Neithertheantitumoractivitynorthenephrotoxicityofcisplatinresultsfromtheheavymetalplatinumitself,sincebotheffectsarestereospecifictothecisisomer,notoccurringwiththetransisomer（GoldsteinandMayor1983）.Instead,thecytotoxicityofcisplatinisrelatedtohighlyreactiveaquatedmetabolites,whoseformationisdeterminedbytheconcentrationofchlorideions.Astheintracellularconcentrationofchloride（20mM）islowerthanthebloodconcentration（100mM）,cisplatinremainsunalteredinthebloodstream,butundergoeshydrolysisintheintracellularenvironment,originatingpositivelychargedmoleculesinwhichoneortwochlorideionshavebeenreplacedbywater.TheseaquatedformseasilyreactwiththenuclearDNA,formingcovalentbondswithpurinebases,primarilyattheN7position,resultingin1,2-intrastrandcrosslinks,whicharethemainresponsibleforthegenotoxiceffectsofcisplatin.ThesecrosslinksbetweenDNAandcisplatinleadtotheimpairmentofreplicationandtranscription,resultingincellcyclearrestandeventuallyapoptosis（JamiesonandLippard1999;

WongandGiandomenico1999;

CohenandLippard2001;

Wangand

Lippard2005）.TheapoptosistriggeredbyDNAdamageismediatedbythetumorsuppressorgenep53thatactivatespro-apoptoticgenesandrepressanti-apoptoticgenes（Jiangetal.2004;

NorburyandZhivotovsky2004;

JiangandDong2008）.ThedividingtumorcellsareparticularlysusceptibletoDNAdamage,andtheanticanceractivityofcisplatinhasbeenmainlyattributedtoDNAadducts