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（根据调查员的摘要改编）：长期目标 对于这个项目，是制定基于三个DNA的反基因策略 乳腺癌治疗。申请人在以前的资金中的研究 时期显示出显着的结构特异性效应 在稳定三个中的多胺类似物，并促进吸收 在乳腺癌细胞中形成寡核苷酸（TFO）的三环。他们的 假设是多胺类似物的选择性利用是一个可行的 提高三元DNA稳定性并增强治疗性的策略 TFO的潜力。该假设将通过：1）定量 新型多胺类似物在启动子上稳定三个DNA的能力 通过光谱技术的CMYC，HER2和CYCLIND1基因的位点序列， 荧光测量和电泳迁移率转移测定； 2） 阐明多胺诱导的TFO凝结在促进中的作用 TFO的核吸收以及确定TFO积累和稳定性 乳腺癌细胞； 3）评估TFO和 多胺类似物作为单一药物，并通过 靶基因表达和多胺的北部和蛋白质印迹分析 代谢途径； 4）阐明TFO/多胺的机制 类似于针对目标位点的转录因子的模拟作用。结果 这些研究将有助于为乳房开发一种新的治疗方式 癌症，并促进我们对三稳定机制的了解 体外。