Human Leukemia Growth Inhibition by a Novel Retinoid
新型类维生素A抑制人类白血病生长
基本信息
- 批准号:7237940
- 负责人:
- 金额:$ 45.86万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2004
- 资助国家:美国
- 起止时间:2004-07-01 至 2009-04-30
- 项目状态:已结题
- 来源:
- 关键词:3-chlorophenol4-bromophenolA549AHPNAcidsAcridine OrangeAcridinesActinsAcuteAcute Lymphocytic LeukemiaAcute Myelocytic LeukemiaAcute Promyelocytic LeukemiaAcute leukemiaAdoptedAdriamycin PFSAdult Acute Lymphocytic LeukemiaAdverse effectsAffectAffinityAgarAgeAge-YearsAgonistAldehydesAlkaline PhosphataseAlkylationAlkynesAmericanAminesAnalysis of VarianceAnimalsAntibodiesAntigensAntineoplastic AgentsAntsAnusApoptosisApoptosis PromoterApoptosis RegulatorApoptoticAppendixAra-CAssesAutoradiographyAzidesB-LymphocytesBCL1 OncogeneBacteriaBaltimoreBedsBexaroteneBindingBinding SitesBiohazardous SubstanceBiologicalBiological AssayBiological MarkersBiopsyBiteBlast CellBlast PhaseBlood CirculationBody WeightBody Weight decreasedBone MarrowBone Marrow TransplantationBoranesBoronic AcidsBreastBreast CarcinomaBritishBromidesBuffersCD3 AntigensCD34 geneCDKN1A geneCanadaCarbon DioxideCarboxy-LyasesCarboxylic AcidsCell CycleCell Cycle ArrestCell DeathCell LineCell NucleusCellsCessation of lifeChemistryChemotherapy-Oncologic ProcedureChimeric ProteinsChloride IonChloridesChromosomes, Human, Pair 9ChronicChronic Lymphocytic LeukemiaChronic Myeloid LeukemiaClassClassificationClinicClinicalCodon NucleotidesCollaborationsColorCompetitive BindingComplement component C1sComplement component C4aCompomersConditionConsensusConsensus SequenceCountCouplingCp CAPCritical PathwaysCytarabineCytogeneticsCytolysisCytoplasmCytosineD CellsDNADactinomycinDataDatabasesDaunorubicinDetectionDevelopmentDiagnosisDialysis procedureDiseaseDisease ProgressionDisease remissionDisease-Free SurvivalDissociationDockingDominant-Negative MutationDoseDown-RegulationDoxorubicinDrug vehicleE2F1 geneEatingEelsElectronsElementsEmbryoEngraftmentEnvironmentEnzyme-Linked Immunosorbent AssayEpidermisEpitopesEquilibriumEthersEthyl EtherEtiologyEtoposideEventExperimental DesignsExposure toEyeFCGR3B geneFailureFamilyFamily memberFelis catusFemaleFibroblastsFicollFigs - dietaryFlow CytometryFoodFrequenciesFrightFutureGasesGelGenbankGene ExpressionGene Expression RegulationGene TargetingGenerationsGenesGenetic TranscriptionGenomicsGroupingGrowthGrowth FactorGuidelinesHL-60 CellsHamstersHarvestHelix (Snails)HematopoieticHepatocyteHeterogeneous-Nuclear RibonucleoproteinsHourHumanHuman GenomeHydrogenationHypaqueImatinib mesylateImmunophenotypingImplantIn VitroIn complete remissionInbred C3H MiceIncubatedIndividualIndolesInduction of ApoptosisInhibitory Concentration 50Injection of therapeutic agentInvestigationIodidesIonsIsomerismIsopropyl ThiogalactosideKaryotypeKetonesKnock-outLNCaPLabelLaboratoriesLasersLateralLearningLegal patentLettersLeukemic CellLifeLigand Binding DomainLigandsLightLiteratureLocationLongevityLuciferasesLyeLymphoblastic LeukemiaMAPK14 geneMCF7 cellMagnetic Resonance ImagingMalignant Epithelial CellMalignant NeoplasmsMalignant neoplasm of lungMann-Whitney U TestManuscriptsMapsMarrowMaximum Tolerated DoseMeasuresMediatingMediator of activation proteinMembraneMessenger RNAMethodologyMethodsMinorMinorityModalityModelingModificationMolecularMolecular ConformationMorphologyMountain LionMusMutateMutationMyelogenousMyeloid LeukemiaN-formylpiperidineNF-kappa BNFKB Activation PathwayNail plateNamesNaphthaleneNaphthalenesNational Cancer InstituteNeckNeuro-Oncological Ventral Antigen 2Non obeseNuclearNuclear ReceptorsNude MiceNumbersObject AttachmentOncogenesOrgan Culture TechniquesPCNA genePTPRC genePathologyPathway interactionsPatientsPeptidesPharmaceutical PreparationsPhasePhase III Clinical TrialsPhenolsPhenotypePhosphotransferasesPhysical DialysisPhysiologic pulsePlasmidsPlayPolymerase Chain ReactionPongidaePopulationPositioning AttributePost-Translational RegulationPrincipal InvestigatorProceduresProcessProductionPrognostic MarkerProliferatingProstateProteasome InhibitorProtein OverexpressionProtein Tyrosine KinaseProteinsProteolysisProtocols documentationProtonsPtosisPublicationsPulse takingPurposeQuantitative Structure-Activity RelationshipRHOA geneRXRRadioRangeRateRattusReactionReactive Oxygen SpeciesRefluxRefractoryRegulationRelapseRelative (related person)ReporterReportingRepressionResearchResearch InstituteResearch PersonnelResistanceRetinoid ReceptorRetinoidsRetroviral VectorRetroviridaeReverse Transcriptase Polymerase Chain ReactionRoleRouteRunningSCID MiceSM 22 muscle proteinSamplingScheduleSchemeScoreSecondary toSerineSerumShockSignal PathwaySignal TransductionSinusSiteSodiumSodium AzideSodium ChlorideSourceSpecimenSpleenStandards of Weights and MeasuresStem cellsSterilityStimulusStructureStructure of thyroid parafollicular cellSurfaceSurface AntigensSystemT-LymphocyteTMEDATNFRSF10A geneTNFRSF10B geneTNFRSF5 geneTailTarsTeaTechniquesTestingTheftTherapeuticTherapeutic AgentsTherapeutic IndexTimeTopoisomeraseTopoisomerase IITorsionToxic effectToxicologyTracheaTrainingTranscriptional ActivationTransgenic MiceTranslationsTransplantationTreatment EfficacyTreatment ProtocolsTretinoinTumor BankTumor Necrosis Factor-alphaTumor Necrosis FactorsTumor PromotersTyrosine Kinase InhibitorUnited States National Institutes of HealthUniversitiesUntranslated RegionsUp-RegulationUpper armVeinsVertebral columnVertebratesViralVitamin AWeekWeight GainWestern BlottingWithdrawalWorkalanine aminopeptidaseanalogbacterial lysatebasebeta Globinboronic acidc-myc Genescancer cellcell growthcell growth regulationcell killingcell typechemotherapeutic agentchemotherapychlorinationcomputer studiesconformerdaydesigndetectordiabeticdimerdosagedrug efficacyear helixelectron donorexperienceexpression vectorfallsfootfusion genegel electrophoresisgenetic regulatory proteinhelenalinhnRNP A1human TNF proteinhuman stem cellsimprovedin vivoin vivo Modelindexingindoleinhibitor/antagonistirradiationkeratinizationkillingsleukemiamalignant breast neoplasmmelanomamembermessenger ribonucleoproteinmethyl groupmolecular dynamicsmouse modelmulticatalytic endopeptidase complexmutantn-butyllithiumnext generationnitrenenovelolder patientoncologyoncoprotein p21outcome forecastoxazolidinep65peripheral bloodpharmacophorepol genespre-clinicalpreventprogramspromoterprotein Kprotein functionreceptorreceptor bindingresearch studyresponsescaffoldsizesodium sulfidestannanestemtitanium carbidetranscription factortumorvector
项目摘要
DESCRIPTION (provided by applicant): 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN/CD437) belongs to a class of adamantyl retinoids (AR) that induce apoptosis through as yet undefined mechanism(s). We have now identified an AHPN analog 4-[3-(1-adamanyly)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-CI-AHPC), which binds to, but does not activate, the retinoic acid nuclear receptors. 3-C1-AHPC displays decreased toxicity compared to AHPN but continues to display high efficacy in inhibiting human acute myelogenous leukemia (AML) cell growth in vitro and mouse AML cells in vivo. In addition, we have found that 3-C1-AHPC induces the expression of a novel protein termed CARP-1. We recently identified CARP-1 as an important regulator of apoptosis by the ARs. Hypothesis: In this proposal we hypothesize that 3-C1-AHPC and newly synthesized analogs are highly active in inhibiting the growth of human primary AML cells in NOD-SCID mice and thus represent potential therapeutic agents in the treatment of AML. In addition, we also hypothesize that 3-CL-AHPC/analog apoptosis signaling is through its activation of the important transcriptional regulator, NFkB, and CARP-l-mediated pathways. Our hypothesis is based on the following observations. 1) 3-CI-AHPC inhibits the growth of AML cells in a syngeneic mouse model, patient derived AML cells, and human AML cell lines. 2) Inhibition of NFkB activation or inhibition of CARP-1 expression blocks 3-C1-AHPC-mediated apoptosis. We will confirm our hypothesis by conducting the following specific aims. Aim 1: Synthesize new analogs of 3-C1-AHPC. Aim 2: Demonstrate that 3-C1-AHPC and its analogs inhibit in vivo growth of human primary AML cells in NOD-SCID mice and display reduced toxicity. Aim 3: Delineate the mechanism(s) by which 3-CI-AHPC enhances CARP-1 expression and CARP-l-dependent reduced topoisomerase lIa levels. Aim 4: Delineate the pathway by which 3-C1-AHPC activates NFkB and its role in apoptosis induction.
说明书(申请人提供):6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene羧酸(AHPN/CD437)属于一类金刚烷基维A酸(AR),其诱导细胞凋亡的机制尚不清楚(S)。我们现在已经鉴定出一种AHPN类似4-[3-(1-adamanyly)-4-hydroxyphenyl]-3-chlorocinnamic酸(3-CI-AHPC),它与维甲酸核受体结合,但不激活。与AHPN相比,3-C1-AHPC的毒性较低,但在体外抑制人急性髓系白血病(AML)细胞生长和体内抑制小鼠AML细胞生长方面继续表现出高效的作用。此外,我们还发现3-C1-AHPC可诱导一种名为Carp-1的新蛋白的表达。我们最近在ARS中发现CARP-1是一个重要的细胞凋亡调节因子。假设:在这个方案中,我们假设3-C1-AHPC和新合成的类似物在NOD-SCID小鼠体内对人原代AML细胞的生长具有高度的抑制作用,因此是治疗AML的潜在治疗药物。此外,我们还假设3-CL-AHPC/类似物的凋亡信号是通过激活重要的转录调节因子NFkB和CARP-L介导的途径来实现的。我们的假设基于以下观察结果。1)3-CI-AHPC抑制同基因小鼠模型、患者来源的AML细胞和人AML细胞系中AML细胞的生长。2)抑制NFkB激活或抑制CARP-1的表达可阻断3-C1-AHPC介导的细胞凋亡。我们将通过以下具体目标来证实我们的假设。目的1:合成3-c1-AHPC的新类似物。目的:证实3-C1-AHPC及其类似物在NOD-SCID小鼠体内抑制人原代AML细胞的生长,并显示出较低的毒性。目的:阐明3-CI-AHPC促进CARP-1表达和依赖于CARP-L的拓扑异构酶LIA水平降低的机制(S)。目的:探讨3-c1-AHPC激活NFkB的途径及其在细胞凋亡诱导中的作用。
项目成果
期刊论文数量(0)
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JOSEPH A FONTANA其他文献
JOSEPH A FONTANA的其他文献
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{{ truncateString('JOSEPH A FONTANA', 18)}}的其他基金
Human Leukemia Growth Inhibition by a Novel Retinoid
新型类维生素A抑制人类白血病生长
- 批准号:
7087066 - 财政年份:2004
- 资助金额:
$ 45.86万 - 项目类别:
Human Leukemia Growth Inhibition by a Novel Retinoid
新型类维生素A抑制人类白血病生长
- 批准号:
6815356 - 财政年份:2004
- 资助金额:
$ 45.86万 - 项目类别:
Human Leukemia Growth Inhibition by a Novel Retinoid
新型类维生素A抑制人类白血病生长
- 批准号:
7409181 - 财政年份:2004
- 资助金额:
$ 45.86万 - 项目类别:
Human Leukemia Growth Inhibition by a Novel Retinoid
新型类维生素A抑制人类白血病生长
- 批准号:
6914222 - 财政年份:2004
- 资助金额:
$ 45.86万 - 项目类别: