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

• 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
• 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

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人类髓系白血病的新型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(VDDS)的哪些组合具有低细胞毒性和降低钙血症诱导活性，有可能作为髓系白血病的分化治疗。具体地说，(I)我们将优化水飞蓟宾在一系列髓系白血病细胞中增强VDDS诱导分化的条件。这些细胞既来自已建立的细胞系，也来自髓系白血病血液样本的原代培养。利用这些细胞，我们还将评估几种新合成的维生素D类似物作为分化诱导剂与水飞蓟宾联合使用的有效性。(Ii)其次，我们将利用所获得的信息来研究这些水飞蓟宾/VDD组合在小鼠髓系白血病模型和人髓系白血病细胞异种移植中的疗效。(Iii)第三，我们将研究水飞蓟宾对最有效的VDDS的作用机制。这些实验将解决这样的假设，即水飞蓟宾的抗氧化作用通过产生减少的细胞内环境来放大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提供数据，以允许设计维生素D类似物/抗氧化剂组合治疗髓系白血病的临床试验。公共卫生意义：分化疗法依赖于激活现有的细胞程序，而不是依赖于有毒药物来对抗恶性肿瘤，已经有效地治疗了一些癌症。我们建议将其开发用于治疗被称为髓系白血病的血液恶性肿瘤，尽管在美国每年约有15,000人死于这种疾病，但不太可能得到商业支持的关注，以寻找其治疗方法。因此，髓系白血病可以被认为是一种孤儿疾病，应该得到公共来源的支持，以开发新的治疗方法。