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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：
JOSEPH A FONTANA
金额：
$ 45.86万
依托单位：
WAYNE STATE UNIVERSITY
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：
https://reporter.nih.gov/project-details/7237940
关键词：
3-chlorophenol 4-bromophenol A549 AHPN Acids Acridine Orange Acridines Actins Acute Acute Lymphocytic Leukemia Acute Myelocytic Leukemia Acute Promyelocytic Leukemia Acute leukemia Adopted Adriamycin PFS Adult Acute Lymphocytic Leukemia Adverse effects Affect Affinity Agar Age Age-Years Agonist Aldehydes Alkaline Phosphatase Alkylation Alkynes American Amines Analysis of Variance Animals Antibodies Antigens Antineoplastic Agents Ants Anus Apoptosis Apoptosis Promoter Apoptosis Regulator Apoptotic Appendix Ara-C Asses Autoradiography Azides B-Lymphocytes BCL1 Oncogene Bacteria Baltimore Beds Bexarotene Binding Binding Sites Biohazardous Substance Biological Biological Assay Biological Markers Biopsy Bite Blast Cell Blast Phase Blood Circulation Body Weight Body Weight decreased Bone Marrow Bone Marrow Transplantation Boranes Boronic Acids Breast Breast Carcinoma British Bromides Buffers CD3 Antigens CD34 gene CDKN1A gene Canada Carbon Dioxide Carboxy-Lyases Carboxylic Acids Cell Cycle Cell Cycle Arrest Cell Death Cell Line Cell Nucleus Cells Cessation of life Chemistry Chemotherapy-Oncologic Procedure Chimeric Proteins Chloride Ion Chlorides Chromosomes, Human, Pair 9 Chronic Chronic Lymphocytic Leukemia Chronic Myeloid Leukemia Class Classification Clinic Clinical Codon Nucleotides Collaborations Color Competitive Binding Complement component C1s Complement component C4a Compomers Condition Consensus Consensus Sequence Count Coupling Cp CAP Critical Pathways Cytarabine Cytogenetics Cytolysis Cytoplasm Cytosine D Cells DNA Dactinomycin Data Databases Daunorubicin Detection Development Diagnosis Dialysis procedure Disease Disease Progression Disease remission Disease-Free Survival Dissociation Docking Dominant-Negative Mutation Dose Down-Regulation Doxorubicin Drug vehicle E2F1 gene Eating Eels Electrons Elements Embryo Engraftment Environment Enzyme-Linked Immunosorbent Assay Epidermis Epitopes Equilibrium Ethers Ethyl Ether Etiology Etoposide Event Experimental Designs Exposure to Eye FCGR3B gene Failure Family Family member Felis catus Female Fibroblasts Ficoll Figs - dietary Flow Cytometry Food Frequencies Fright Future Gases Gel Genbank Gene Expression Gene Expression Regulation Gene Targeting Generations Genes Genetic Transcription Genomics Grouping Growth Growth Factor Guidelines HL-60 Cells Hamsters Harvest Helix (Snails)Hematopoietic Hepatocyte Heterogeneous-Nuclear Ribonucleoproteins Hour Human Human Genome Hydrogenation Hypaque Imatinib mesylate Immunophenotyping Implant In Vitro In complete remission Inbred C3H Mice Incubated Individual Indoles Induction of Apoptosis Inhibitory Concentration 50 Injection of therapeutic agent Investigation Iodides Ions Isomerism Isopropyl Thiogalactoside Karyotype Ketones Knock-out LNCaP Label Laboratories Lasers Lateral Learning Legal patent Letters Leukemic Cell Life Ligand Binding Domain Ligands Light Literature Location Longevity Luciferases Lye Lymphoblastic Leukemia MAPK14 gene MCF7 cell Magnetic Resonance Imaging Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of lung Mann-Whitney U Test Manuscripts Maps Marrow Maximum Tolerated Dose Measures Mediating Mediator of activation protein Membrane Messenger RNA Methodology Methods Minor Minority Modality Modeling Modification Molecular Molecular Conformation Morphology Mountain Lion Mus Mutate Mutation Myelogenous Myeloid Leukemia N-formylpiperidine NF-kappa B NFKB Activation Pathway Nail plate Names Naphthalene Naphthalenes National Cancer Institute Neck Neuro-Oncological Ventral Antigen 2 Non obese Nuclear Nuclear Receptors Nude Mice Numbers Object Attachment Oncogenes Organ Culture Techniques PCNA gene PTPRC gene Pathology Pathway interactions Patients Peptides Pharmaceutical Preparations Phase Phase III Clinical Trials Phenols Phenotype Phosphotransferases Physical Dialysis Physiologic pulse Plasmids Play Polymerase Chain Reaction Pongidae Population Positioning Attribute Post-Translational Regulation Principal Investigator Procedures Process Production Prognostic Marker Proliferating Prostate Proteasome Inhibitor Protein Overexpression Protein Tyrosine Kinase Proteins Proteolysis Protocols documentation Protons Ptosis Publications Pulse taking Purpose Quantitative Structure-Activity Relationship RHOA gene RXR Radio Range Rate Rattus Reaction Reactive Oxygen Species Reflux Refractory Regulation Relapse Relative (related person)Reporter Reporting Repression Research Research Institute Research Personnel Resistance Retinoid Receptor Retinoids Retroviral Vector Retroviridae Reverse Transcriptase Polymerase Chain Reaction Role Route Running SCID Mice SM 22 muscle protein Sampling Schedule Scheme Score Secondary to Serine Serum Shock Signal Pathway Signal Transduction Sinus Site Sodium Sodium Azide Sodium Chloride Source Specimen Spleen Standards of Weights and Measures Stem cells Sterility Stimulus Structure Structure of thyroid parafollicular cell Surface Surface Antigens System T-Lymphocyte TMEDA TNFRSF10A gene TNFRSF10B gene TNFRSF5 gene Tail Tars Tea Techniques Testing Theft Therapeutic Therapeutic Agents Therapeutic Index Time Topoisomerase Topoisomerase II Torsion Toxic effect Toxicology Trachea Training Transcriptional Activation Transgenic Mice Translations Transplantation Treatment Efficacy Treatment Protocols Tretinoin Tumor Bank Tumor Necrosis Factor-alpha Tumor Necrosis Factors Tumor Promoters Tyrosine Kinase Inhibitor United States National Institutes of Health Universities Untranslated Regions Up-Regulation Upper arm Veins Vertebral column Vertebrates Viral Vitamin A Week Weight Gain Western Blotting Withdrawal Work alanine aminopeptidase analog bacterial lysate base beta Globin boronic acid c-myc Genes cancer cell cell growth cell growth regulation cell killing cell type chemotherapeutic agent chemotherapy chlorination computer studies conformer day design detector diabetic dimer dosage drug efficacy ear helix electron donor experience expression vector falls foot fusion gene gel electrophoresis genetic regulatory protein helenalin hnRNP A1 human TNF protein human stem cells improved in vivo in vivo Model indexing indole inhibitor/antagonist irradiation keratinization killings leukemia malignant breast neoplasm melanoma member messenger ribonucleoprotein methyl group molecular dynamics mouse model multicatalytic endopeptidase complex mutant n-butyllithium next generation nitrene novel older patient oncology oncoprotein p21 outcome forecast oxazolidine p65 peripheral blood pharmacophore pol genes pre-clinical prevent programs promoter protein K protein function receptor receptor binding research study response scaffold size sodium sulfide stannane stem titanium carbide transcription factor tumor vector

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.

性状（由申请人提供）：6-[3-（1-金刚烷基）-4-羟基苯基]-2-萘羧酸（AHPN/CD 437）属于一类金刚烷基类维生素A（AR），通过尚未明确的机制诱导细胞凋亡。我们现在已经鉴定了AHPN类似物4-[3-（1-金刚烷基）-4-羟基苯基]-3-氯肉桂酸（3-CI-AHPC），其结合但不激活视黄酸核受体。与AHPN相比，3-C1-AHPC显示出降低的毒性，但在体外抑制人急性髓性白血病（AML）细胞生长和体内抑制小鼠AML细胞方面继续显示出高效力。此外，我们发现3-C1-AHPC诱导一种新的蛋白质CARP-1的表达。我们最近发现CARP-1是AR细胞凋亡的重要调节因子。假设：在该提案中，我们假设3-C1-AHPC和新合成的类似物在抑制NOD-SCID小鼠中的人原代AML细胞的生长方面具有高度活性，因此代表了治疗AML的潜在治疗剂。此外，我们还假设3-CL-AHPC/类似物凋亡信号传导是通过其激活重要的转录调节因子NF κ B和CARP-I介导的途径。我们的假设是基于以下观察。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活化或抑制CARP-1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：合成新的3-C1-AHPC类似物。目的2：证明3-C1-AHPC及其类似物抑制NOD-SCID小鼠中人原代AML细胞的体内生长并显示出降低的毒性。目的3：描述3-CI-AHPC增强CARP-1表达和CARP-1依赖性降低拓扑异构酶IIa水平的机制。目的4：阐明3-C1-AHPC激活NF κ B的途径及其在细胞凋亡诱导中的作用。