Vitamin D Analogs as Adjuvants in Chemotherapy

维生素 D 类似物作为化疗佐剂

• 批准号: 8018642
• 负责人: George P Studzinski
• 金额: $ 19.98万
• 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: 1987
• 资助国家: 美国
• 起止时间: 1987-06-01 至 2012-09-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8018642
• 关键词: Adjuvant; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Antisense Oligonucleotides; Attention; Blood; Blood specimen; CCAAT-Enhancer-Binding Proteins; Calcitriol; Cell Differentiation process; Cell Line; Cells; Chemosensitization; Clinical Trials; Complement; Data; Development; Differentiation Inducer; Differentiation Therapy; Environment; Enzymes; Event; Exposure to; Figs - dietary; Food Additives; Food Preservatives; Gene Expression; Generations; Genes; Goals; Growth Factor; HL-60 Cells; Health; Human; Imidazole; Immunoblotting; Immunoprecipitation; In Vitro; JUN gene; Leukemic Cell; Link; MAP Kinase Gene; MAPK14 gene; MAPK8 gene; MEKs; Malignant Neoplasms; Mammalian Cell; Molecular; Monitor; Myeloid Leukemia; Nature; Nuclear; Nuclear Localization Signal; Orphan Disease; Oxidation-Reduction; Pathway interactions; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Phenotype; Physiological; Plants; Plasmids; Protein Kinase; Proteins; RAF1 gene; Regulation; Reverse Transcriptase Polymerase Chain Reaction; Role; Rosemary; SB 203580; Sampling; Schedule; Series; Shunt Device; Signal Pathway; Signal Transduction; Source; Subgroup; Surface; Surrogate Markers; Techniques; Testing; Transcription Factor AP-1; Treatment Protocols; Vitamin D; Vitamin D Analog; analog; arm; carnosol; chemotherapy; combat; cost; inhibitor/antagonist; insight; killings; leukemia; macrophage; novel; polyphenol; programs; research study; response; rosmarinic acid; salvin; scaffold; transcription factor; translational study

DESCRIPTION (provided by applicant): The overall goal of this proposal is to develop differentiation therapy to supplement the treatment regimens for human myeloid leukemia. We will focus on the identification of the most effective analogs (deltanoids) of the physiological form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D) administered at low concentrations to leukemia cells in culture and study alterations in gene expression and other cellular changes. The deltanoids and 1,25D induce monocytic/macrophage-like differentiation and will also be administered in combination with nontoxic substances currently used as food preservatives or additives, or with potential for such use, to maximize the differentiation activity of of the deltanoids. Further enhancement of the activity of these differentiation agents will be explored by the addition of an anti-inflammatory inhibitor of an intracellular signaling pathway. Established lines of leukemia, as well as samples of leukemic cells freshly obtained from patients, will be used for studies of of cell differentiation. The rationale is provided by previous observation that antioxidants provide a reducing environment and induce expression of genes which complement the differentiation-inducing actions of deltanoid-responsive genes. Insight into differentiation control will be obtained by examination of signaling pathways with particular attention to MAPK pathways and to transcription factors. This will be accomplished by adding pharmacological agents, antisense oligonucleotides, siRNAs, transcription factor decoys, and transfected plasmid constructs to study the molecular consequences of these manipulations , which will be determined by immunoblotting, quantitative RT-PCR, immunoprecipitation, and other standard techniques. Differentiating cells will be monitored by determination of surface markers as well as the activity and the expression of various enzymes. The information obtained in basic studies will be utilized to guide development of a new generation of deltanoids and deltanoid combinations with co- inducers, while translational studies on leukemic cells ex vivo will serve to identify subgroups of myeloid leukemias most suitable for the initiation of clinical trials.

描述(由申请人提供)： 这项建议的总体目标是开发分化疗法，以补充人类髓系白血病的治疗方案。我们将集中于鉴定最有效的生理形式维生素D的类似物，1，25-二羟基维生素D3(1，25D)在培养的白血病细胞中给予低浓度的维生素D，并研究基因表达的变化和其他细胞变化。Deltanid和1，25D诱导单核/巨噬细胞样分化，也将与目前用作食品防腐剂或添加剂的无毒物质或潜在的此类用途联合使用，以最大限度地提高Deltanid的分化活性。通过添加一种细胞内信号通路的抗炎抑制剂，将进一步增强这些分化剂的活性。已建立的白血病细胞系以及从患者新鲜获得的白血病细胞样本将用于细胞分化的研究。以前的观察表明，抗氧化剂提供了还原环境并诱导了基因的表达，这些基因补充了Deltanid反应基因的分化诱导作用。通过对信号通路的研究，尤其是对MAPK通路和转录因子的研究，将获得对分化控制的深入了解。这将通过添加药理学试剂、反义寡核苷酸、siRNA、转录因子诱骗和转基因质粒构建物来研究这些操作的分子后果，这将通过免疫印迹、定量RT-PCR、免疫沉淀和其他标准技术来确定。将通过测定表面标志物以及各种酶的活性和表达来监测分化细胞。基础研究中获得的信息将被用来指导新一代Deltanid和Deltanid与共诱导剂组合的开发，而对白血病细胞的体外翻译研究将有助于确定最适合启动临床试验的髓系白血病亚群。