顺铂肾毒性Word格式文档下载.docx
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顺铂肾毒性Word格式文档下载.docx
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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
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