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：
7840481
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/7840481
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 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 NOD/SCID mouse Oligonucleotides Orphan Disease Oxidation-Reduction Pathway interactions Patients Pharmaceutical Preparations Phosphorylation Pilot Projects Plants Pre-Clinical Model Proteins Public Health Regimen Research Research Design Response Elements Rest Role SP600125 Sampling Scheme Signal Transduction Small Interfering RNA Source Spleen System Testing Toxic effect Transcription Factor AP-1 Translating Vitamin D Vitamin D Analog Vitamins White Blood Cell Count procedure Xenograft procedure analog base combat 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）：本应用的总体目标是确定人髓性白血病的新型组合疗法的组成部分和条件。我们将确定哪种硅质素（一种植物来源的抗氧化剂）与维生素D衍生物（VDD）的组合，具有较低的细胞毒性和降低的止刻度活性，具有髓样白血病的分化治疗。具体而言，（i）我们将优化硅酸盐素在一系列髓样白血病细胞中增强VDD诱导的诱导的条件。这些细胞将来自已建立的细胞系和髓样白血病血液样本的原发性培养物。使用这些细胞，我们还将评估几种有希望的新合成的维生素D类似物，以作为与硅脂结合使用分化的诱导剂的功效。（ii）其次，我们将利用因此获得的信息来研究这些硅蛋白/ VDD组合在鼠髓性白血病模型以及人髓髓性白血病细胞异种移植物中的功效。（iii）第三，我们将通过硅酸盐来研究最有效VDD的作用的增强机制。这些实验将解决以下假设：硅酸盐素的抗氧化作用扩增了1,25-二羟基乙他素D及其低血液类似物提供的分化信号，通过产生还原的细胞内环境，从而通过生成还原性的细胞内环境，从而在白血病细胞中保持最活跃状态的转录因子。这些临床前研究旨在提供允许设计髓样白血病中维生素D类似物/抗氧化剂组合的临床试验的数据。公共卫生的意义：依赖现有细胞计划的激活而不是有毒药物来对抗恶性肿瘤的分化疗法已经有效地是对某些癌症的治疗有效的。我们建议将其作为血液恶性肿瘤的疗法，称为髓样白血病，尽管每年在美国约有15,000人杀死15,000人，但不太可能因商业支持而受到关注以寻找其治愈方法。因此，髓样白血病可以视为一种孤儿疾病，值得公共来源的新疗法发展的支持。