培美与白血病英文.docx

培美与白血病英文.docx

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培美与白血病英文

1:

Drugs.2007;67（15）:

2153-71.

RelatedArticles,Links

Treatmentofacutelymphoblasticleukaemia:

anewera.

ApostolidouE,SwordsR,AlvaradoY,GilesFJ.

DepartmentofLeukemia,TheUniversityofTexasM.D.AndersonCancerCenter,Houston,Texas,USA.

Acutelymphocyticleukaemia（ALL）isaheterogeneousgroupofdisordersthatresultfromtheclonalproliferationandexpansionofmalignantlymphoidcellsinthebonemarrow,bloodandotherorgans.DistinctclinicopathologicalALLentitieshavebeenidentified,resultingintheadoptionofrisk-orientedtreatmentapproaches.AdvancesinALLtherapyhaveledtolong-termsurvivalratesof>80%inchildren.However,onlyapproximate,equals30-40%ofadultsachievelong-termdisease-freesurvival.ContemporaryALLtreatmentprogrammesincludeinduction,intensifiedconsolidation,maintenancephasesandCNSprophylaxis.TheoptimaltreatmentofPhiladelphiachromosome-positivepatientsrequirestheadditionofBCR-ABLtyrosinekinaseinhibitors,suchasimatinib,whereasallogeneicstem-celltransplantationremainsthepreferredapproachforhigh-riskpatientsinfirstremission.Sinceonlyapproximate,equals38%ofadultALLpatientsarefreeofdisease5yearsafterdiagnosisandtheoutcomeofsalvagechemotherapyisverypoor（completeremissionratesof20-30%,mediansurvivalof3-6months）,novelagentsaredesperatelyrequired.Ofthosecurrentlyinclinicalstudies,theoutlookforsphingosomalvincristine,pegylatedasparaginase（pegaspargase）,liposomalannamycin,ABT-751,pemetrexed,talotrexin,nelarabineandthenovelBCR-ABLkinaseinhibitorsisdiscussed.

PMID:

17927282[PubMed-inprocess]

2:

AnticancerRes.2007Mar-Apr;27

（2）:

769-73.

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Antifolatepseudo-resistanceduetoelevatedlevelsofthymidineandhypoxanthineinacommercialserumpreparation.

SimonM,BlatterJ,GranzowC.

DepartmentMolekulareToxikologie（G120）,DeutschesKrebsforschungszentrum,D-69120Heidelberg,Germany.

BACKGROUND:

Batchvariabilityofserausedforcellcultureisofconsiderableexperimentalconcern.Anovelfetalcalfserumproduct,FCSGold,wasclaimedtobethefirstdefinedfetalcalfserumfreeofbatchvariation.MATERIALSANDMETHODS:

Theefficacyofmethotrexate（MTX）andLY231514（multitargetedantifolate,MTA）inCCRF-CEMcellsandKBcellswascomparedusingmediasupplementedwithFCSGoldorconventionalfetalbovineserum.RESULTS:

IC50valuesfromtestsusingconventionalserumcorrespondedtopublisheddata.FCSGoldfullyprotectedthecellsfromantifolatedrugcytotoxicity.DialysisofFCSGoldrestoredresponsivenesstoantifolatedrugs.ElevatedlevelsofhypoxanthineandthymidinewerepresentinFCSGold.Theywereapproximately10-foldgreaterthantheconcentrationsrequiredtoovercomegrowtharrestmediatedby2microMMTX.CONCLUSION:

FCSGoldoridenticalproducts,e.g.FBSGold,shouldnotbeusedinstudiesonantifolatedrugaction.

PMID:

17465201[PubMed-indexedforMEDLINE]

3:

ExpertOpinEmergDrugs.2007Mar;12

（1）:

165-79.

RelatedArticles,Links

EmergingtherapeuticoptionsforPhiladelphia-positiveacutelymphocyticleukemia.

AlvaradoY,ApostolidouE,SwordsR,GilesFJ.

DepartmentofLeukemia,UniversityofTexasMDAndersonCancerCenter,Houston,Texas77030,USA.

Acutelymphocyticleukemia（ALL）isaheterogeneousgroupofdisordersthatareassociatedwithacurerateof>80%inchildren.Theprognosisinadultsisconsiderablyinferior,withage,diseasebulk,leukemiakaryotypeandimmunephenotypebeingprognosticallyrelevant.AdultALLtreatmentprogramsincludeinduction,intensifiedconsolidationandmaintenancephaseswithCNSprophylaxis.TheadditionofimatinibinpatientswithBCR-ABL-positiveALLhasimprovedtheprognosisofthissubgroup,buttheirsurvivalisstillpoor.Initialdataonthesecond-generationBCR-ABLinhibitors,dasatinibandnilotinib,indicateapotentiallygreaterefficacythanimatinib,buttheimprovementislikelytobemodest.TheoveralleffortsintermsofdevelopmentaltherapeuticsinALLareverymodestandnotinkeepingwiththeurgentneedforimprovement.MostagentsbeinginvestigatedhavemechanismsofactionsimilartothoseofexistingagentsforALLtherapyandthusrepresentmodestopportunitiestoimproveresults.Ofsuchagents,dataonBCR-ABLinhibitors,sphingosomalvincristine,pemetrexed,talotrexin,annamycinandABT-751arereviewed.

PublicationTypes:

∙Review

PMID:

17355221[PubMed-indexedforMEDLINE]

4:

CancerMetastasisRev.2007Mar;26

（1）:

111-28.

RelatedArticles,Links

Humanreducedfolatecarrier:

translationofbasicbiologytocanceretiologyandtherapy.

MatherlyLH,HouZ,DengY.

DevelopmentalTherapeuticsProgram,BarbaraAnnKarmanosCancerInstitute,TheCancerBiologyGraduateProgram,Detroit,MI48201,USA.matherly@karmanos.org

Thisreviewattemptstoprovideacomprehensiveoverviewofthebiologyofthephysiologicallyandpharmacologicallyimportanttransportsystemtermedthe"reducedfolatecarrier"（RFC）.TheubiquitouslyexpressedRFChasunequivocallyestablisheditselfasthemajortransportsysteminmammaliancellsandtissuesforagroupofcompoundsincludingfolatecofactorsandclassicalantifolatetherapeutics.LossofRFCexpressionorfunctionmayhavepotentiallyprofoundpathophysiologicconsequencesincludingcancer.Forchemotherapeuticantifolatesusedforcancersuchasmethotrexateorpemetrexed,synthesisofmutantRFCsorlossofRFCtranscriptsandproteinsresultsinantifolateresistanceduetoincompleteinhibitionofcellularenzymetargetsandinsufficientsubstrateforpolyglutamatesynthesis.SinceRFCwasfirstclonedin1994,tremendousadvanceshavebeenmadeinunderstandingthecomplextranscriptionalandposttranscriptionalregulationofRFC,inidentifyingstructurallyandfunctionallyimportantdomainsandaminoacidsintheRFCmoleculeasapreludetoestablishingthemechanismoftransport,andincharacterizingthemoleculardefectsinRFCassociatedwithlossoftransportinantifolateresistantcelllinemodels.ManyoftheinsightsgainedfromlaboratorymodelsofRFCportendopportunitiesformodulatingcarrierexpressionindrugresistanttumors,andfordesigninganewgenerationofagentswithimprovedtransportbyRFCorsubstantiallyenhancedtransportbyotherfolatetransportersoverRFC.ManyoftheadvancesinthebasicbiologyofRFCincelllinemodelsarenowbeingdirectlyappliedtohumancancersintheclinicalsetting,mostnotablypediatricacutelymphoblasticleukemiaandosteogenicsarcoma.

PublicationTypes:

∙ResearchSupport,N.I.H.,Extramural

∙ResearchSupport,Non-U.S.Gov't

∙Review

PMID:

17334909[PubMed-indexedforMEDLINE]

5:

CancerMetastasisRev.2007Mar;26

（1）:

153-81.

RelatedArticles,Links

Molecularbasisofantifolateresistance.

AssarafYG.

TheFredWyszkowskiCancerResearchLaboratory,DepartmentofBiology,Technion-IsraelInstituteofTechnology,Haifa,32000,Israel.assaraf@tx.technion.ac.il

Folatesplayakeyroleinone-carbonmetabolismessentialforthebiosynthesisofpurines,thymidylateandhenceDNAreplication.Theantifolatemethotrexatehasbeenrationally-designednearly60yearsagotopotentlyblockthefolate-dependentenzymedihydrofolatereductase（DHFR）therebyachievingtemporaryremissionsinchildhoodacuteleukemia.Recently,thenovelantifolatesraltitrexedandpemetrexedthattargetthymidylatesynthase（TS）andglycineamideribonucleotidetransformylase（GARTF）wereintroducedforthetreatmentofcolorectalcancerandmalignantpleuralmesothelioma.（Anti）folatesaredivalentanionswhichpredominantlyusethereducedfolatecarrier（RFC）fortheircellularuptake.（Anti）folatesareretainedintracellularlyviapolyglutamylationcatalyzedbyfolylpoly-gamma-glutamatesynthetase（FPGS）.Astheintracellularconcentrationofantifolatesiscriticalfortheirpharmacologicactivity,polyglutamylationisakeydeterminantofantifolatecytotoxicity.However,anticancerdrugresistancephenomenaposemajorobstaclestowardscurativecancerchemotherapy.Pre-clinicalandclinicalstudieshaveidentifiedaplethoraofmechanismsofantifolate-resistance;thesearefrequentlyassociatedwithqualitativeand/orquantitativealterationsininfluxand/oreffluxtransportersof（anti）folatesaswellasinfolate-dependentenzymes.Theseincludeinactivatingmutationsand/ordown-regulationoftheRFCandvariousalterationsinthetargetenzymesDHFR,TSandFPGS.Furthermore,ithasbeenrecentlyshownthatmembersoftheATP-bindingcassette（ABC）superfamilyincludingmultidrugresistanceproteins（MRP/ABCC）andbreastcancerresistanceprotein（BCRP/ABCG2）arelowaffinity,highcapacityATP-driven（anti）folateeffluxtransporters.Thistransportactivityisinadditiontotheirestablishedfacilitytoextrudemultiplecytotoxicagents.Hence,byactivelyextrudingantifolates,overexpressedMRPsand/orBCRPconferantifolateresistance.Moreover,down-regulationofMRPsand/orBCRPresultsindecreasedfolateeffluxtherebyleadingtoexpansionoftheintracellularfolatepoolandantifolateresistance.Thischapterreviewsanddiscussesthepanoplyofmolecularmodalitiesofantifolate-resistanceinpre-clinicaltumorcellsystemsinvitroandinvivoaswellasincancerpatients.Currentlyemergingnovelstrategiesfortheovercomingofantifolate-resistancearepresented.Finally,experimentalevidenceisprovidedthattheidentificationandcharacterizationofthemolecularmechanismsofantifolate-resistancemayproveinstrumentalinthefuturedevelopmentofrationally-basednovelantifolatesandstrategiesthatcouldconceivablyovercomedrug-resistan