POLYAMINE ANALOGS IN ANTI GENE THERAPY FOR BREAST CANCER

乳腺癌抗基因疗法中的多胺类似物

• 批准号: 6633220
• 负责人: TJ THOMAS
• 金额: $ 24.73万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6633220
• 关键词: DNA replication; MCF7 cell; analog; breast neoplasms; cell cycle; cell growth regulation; chemical structure function; cyclins; drug interactions; drug screening /evaluation; enzyme activity; epidermal growth factor; genetic promoter element; growth factor receptors; neoplasm /cancer pharmacology; northern blottings; nucleic acid inhibitor; oligonucleotides; polyamines; protooncogene; triple helix; western blottings

DESCRIPTION (As Adapted From the Investigator's Abstract): The long-term goal for this project is to develop a triplex DNA-based anti-gene strategy for breast cancer treatment. The applicant's studies during the previous funding period have demonstrated a remarkable structural specificity effect of polyamine analogs in stabilizing triplex DNA, and in facilitating the uptake of a triplex forming oligonucleotide (TFO) in breast cancer cells. Their hypothesis is that the selective utilization of polyamine analogs is a viable strategy to increase the stability of triplex DNA, and enhance the therapeutic potential of TFOs. This hypothesis will be tested by: 1) Quantification of the ability of novel polyamine analogs to stabilize triplex DNA at the promoter site sequences of cmyc, her2, and cyclinD1 genes by spectroscopic techniques, fluorescence measurements, and electrophoretic mobility shift assay; 2) elucidation of the role of polyamine -induced TFO condensation in facilitating nuclear uptake of TFOs and determination of TFO accumulation and stability in breast cancer cells; 3) Evaluation of the biologic response of TFOs and polyamine analogs as single agents and in combination on breast cancer cells by Northern and Western blot analysis of target gene expression, and polyamine metabolism pathways; and 4) Elucidation of the mechanism of TFO/polyamine analog action in terms of transcription factors to targeted sites. Results of these studies will help to develop a new therapeutic modality for breast cancer, and advance our knowledge of the mechanism of triplex DNA stabilization in vitro.

描述（改编自研究者摘要）：长期目标 该项目的目标是开发一种基于三重 DNA 的反基因策略 乳腺癌治疗。申请人上一次资助期间的学习情况 时期表现出显着的结构特异性效应 多胺类似物可稳定三链 DNA，并促进吸收 乳腺癌细胞中形成三链体的寡核苷酸（TFO）。他们的 假设选择性利用多胺类似物是一种可行的方法 提高三链DNA稳定性并增强治疗效果的策略 TFO 的潜力。该假设将通过以下方式进行检验： 1) 量化 新型多胺类似物稳定启动子处三链体 DNA 的能力 通过光谱技术获得 cmyc、her2 和 cyclinD1 基因的位点序列， 荧光测量和电泳迁移率变化测定； 2） 阐明多胺诱导的 TFO 缩合在促进 TFO 的核摄取以及 TFO 积累和稳定性的测定 乳腺癌细胞； 3) TFO的生物反应评估和 多胺类似物作为单一药物和联合药物对乳腺癌细胞的作用 靶基因表达和多胺的 Northern 和 Western blot 分析 代谢途径； 4) TFO/多胺机理的阐明 转录因子对目标位点的模拟作用。结果 这些研究将有助于开发一种新的乳腺治疗方法 癌症，并增进我们对三链 DNA 稳定机制的了解 体外。