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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：
7295294
负责人：
George P Studzinski
金额：
$ 20.36万
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 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7295294
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鉴定用于人髓性白血病的新型联合治疗的组分和条件。我们将确定水飞蓟宾（一种植物源性抗氧化剂）与具有低细胞毒性和降低钙血症诱导活性的维生素D衍生物（VDDs）的组合具有作为髓系白血病分化治疗的潜力。具体而言，（i）我们将优化水飞蓟宾在一定范围的髓性白血病细胞中增强VDD诱导分化的条件。这些细胞将来自已建立的细胞系和骨髓性白血病血液样品的原代培养物。使用这些细胞，我们还将评估几种有前途的新合成的维生素D类似物与水飞蓟宾组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来进行这些水飞蓟宾/ VDD组合在鼠髓性白血病模型和人髓性白血病细胞异种移植物中的功效的研究。(iii)第三，我们将研究水飞蓟宾增强最有效的VDDs作用的机制。这些实验将解决这一假设，即水飞蓟宾的抗氧化作用放大了分化信号提供的1，25-二羟基维生素D和其低钙类似物通过产生减少细胞内环境，然后保持转录因子在其最活跃的状态在白血病细胞。这些临床前研究旨在提供数据，允许设计维生素D类似物/抗氧化剂组合治疗髓性白血病的临床试验。公共卫生意义：分化疗法依赖于激活现有的细胞程序，而不是有毒的药物来对抗恶性肿瘤，已经有效地治疗了一些癌症。我们建议将其开发为被称为骨髓性白血病的血液恶性肿瘤的治疗方法，虽然每年在美国造成约15，000人死亡，但不太可能获得商业支持以找到其治愈方法。因此，髓性白血病可以被认为是一种孤儿病，值得公共资源支持开发新的治疗方法。