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VITAMIN D PLANT ANTIOXIDANT SILIBININ IN LEUKEMIA TRANSLATIONAL STUDY

维生素 D 植物抗氧化剂水飞蓟宾在白血病转化研究中的应用

基本信息

批准号：
7472357
负责人：
George P Studzinski
金额：
$ 18.96万
依托单位：
UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7472357
关键词：
1,25 (OH) vitamin D 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole Acute Address Animal Model Animals Antioxidants Attention Biochemical Biological Blood Blood specimen Bone Marrow Cell Count Cell Cycle Progression Cell Line Cells Chemosensitization Chronic Myeloid Leukemia Clinical Trials Clinical Trials Design Combined Modality Therapy Condition Consent Cytology Data Deposition Development Differentiation Therapy Dominant-Negative Mutation Ectopic Expression Environment Exposure to Figs - dietary Goals HL-60 Cells Human In Vitro JUN gene Leukemic Cell Liver MAPK8 gene Malignant Neoplasms Mediating Messenger RNA Mitotic Cell Cycle Modeling Molecular Mus Myeloid Leukemia Oligonucleotides Orphan Disease Oxidation-Reduction Pathway interactions Patients Pharmaceutical Preparations Phosphorylation Pilot Projects Plants Pre-Clinical Model Proteins Public Health Range Research Research Design Response Elements Rest Role SCID Mice SP600125 Sampling Scheme Signal Transduction Small Interfering RNA Source Spleen System Testing Toxic effect Transcription Factor AP-1 Translating Treatment Protocols Vitamin D Vitamin D Analog Vitamins White Blood Cell Count procedure Xenograft procedure analog base design established cell line genetic regulatory protein in vivo inhibitor/antagonist killings leukemia novel pre-clinical preclinical study programs protein expression research study response silibinin transcription factor translational study

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this application is to identify the components and conditions for novel combination therapy of human myeloid leukemia. We will determine which combinations of silibinin, a plant-derived antioxidant, with vitamin D derivatives (VDDs) that have low cell toxicity and reduced calcemia-inducing activity, have potential as differentiation therapy for myeloid leukemia. Specifically, (i) we will optimize the conditions under which silibinin potentiates the induction of differentiation by VDDs in a range of myeloid leukemia cells. These cells will be from both established cell lines and from primary cultures of myeloid leukemia blood samples. Using these cells, we will also evaluate several promising newly synthesized analogs of vitamin D for their efficacy as differentiation-inducing agents in combination with silibinin. (ii) Secondly, we will utilize the information thus obtained to perform studies of the efficacy of these silibinin/ VDD combinations in a murine myeloid leukemia model, and in human myeloid leukemia cell xenografts. (iii) Thirdly, we will study the mechanisms of potentiation by silibinin of the action of the most effective VDDs. These experiments will address the hypothesis that the antioxidant action of silibinin amplifies the differentiation signal provided by 1,25-dihydroxyvitamin D and its low-calcemic analogs by generating a reducing intracellular environment, which then maintains transcription factors in their most active state in leukemic cells. These preclinical studies are designed to provide data that will permit the design of clinical trials of vitamin D analogs/antioxidant combinations in myeloid leukemia. Public Health Significance: Differentiation therapy, which depends on the activation of existing cellular programs rather than on toxic drugs to combat malignant tumors, is already effective as the treatment of some cancers. We propose to develop it as therapy for blood malignancy known as myeloid leukemia, which although kills approximately 15,000 people in USA every year, is unlikely to receive attention from commercial support for finding its cure. Thus, myeloid leukemia can be considered an orphan disease, and merits support from public sources for the development of novel therapy.

描述（由申请人提供）：本申请的总体目标是确定新型人类髓性白血病联合治疗的成分和条件。我们将确定水飞蓟宾（一种植物来源的抗氧化剂）与维生素D衍生物（vdd）的哪些组合具有低细胞毒性和降低钙诱导活性，有潜力作为髓性白血病的分化治疗。具体来说，(i)我们将优化水飞蓟宾在一系列髓系白血病细胞中增强vdd诱导分化的条件。这些细胞将来自已建立的细胞系和原代培养的髓性白血病血液样本。利用这些细胞，我们还将评估几种新合成的维生素D类似物与水飞蓟宾联合作为分化诱导剂的功效。（ii）其次，我们将利用由此获得的信息对这些水飞蓟宾/ VDD组合在小鼠髓性白血病模型和人类髓性白血病细胞异种移植中的功效进行研究。（iii）第三，我们将研究水飞蓟宾对最有效的vdd的增强作用机制。这些实验将验证水飞脂宾的抗氧化作用，即通过产生还原细胞内环境，放大1,25-二羟基维生素D及其低钙类似物提供的分化信号，从而使白血病细胞中的转录因子保持在最活跃的状态。这些临床前研究旨在为设计维生素D类似物/抗氧化剂联合治疗髓性白血病的临床试验提供数据。公共卫生意义：分化疗法依靠激活现有的细胞程序，而不是依靠有毒药物来对抗恶性肿瘤，已经成为一些癌症的有效治疗方法。我们建议将其作为血液恶性肿瘤骨髓性白血病的治疗方法，尽管在美国每年有大约1.5万人死于骨髓性白血病，但这种疾病不太可能得到商业支持来寻找治疗方法。因此，髓性白血病可以被认为是一种孤儿疾病，值得公共资源的支持来开发新的治疗方法。