USE OF SYNTHETIC OLIGODEOXYNUCLEOTIDES IN BONE MARROW PURGING

合成寡脱氧核苷酸在骨髓净化中的用途

• 批准号: 6163438
• 负责人: R BERGAN
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6163438
• 关键词: antineoplastics; antisense nucleic acid; bone marrow purging; clinical research; electroporation; human subject; laboratory mouse; lymphoma; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; neoplasm /cancer pharmacology; nonhuman therapy evaluation; nucleic acid sequence; oligonucleotides; protooncogene; synthetic nucleic acid; transfection

"DISCONTINUED This project seeks to develop the use of oligodeoxynucleotides (ODNs) in a clinically optimal manner. A prior series of investigations demonstrated that ODNs could be introduced into cells efficiently by electroporation (EP): 100% transfection rates, instantaneous delivery, more optimal intracellular ODN distribution profile, and immediate onset of action. Those studies also demonstrated that, with antisense to c-myc, U937 human lymphoma cells could be selectively purged from normal human bone marrow, with little effect upon normal CFU-GM numbers. Recent investigations have focused on how this potential bone marrow purging approach effects long term culture initiating cells (LTC-IC); LTC-IC assays provide the most accurate in vitro measure of true stem cell activity in humans. To date, no significant effects upon LTC-ICs have been detected after treatment of normal bone marrow with EP and/or c-myc antisense. Other investigations have focused upon the inhibition of p210bcr-abl associated protein-tyrosine kinase (PTK) activity by an ODN-based inhibitor, which we have developed. Increased p210bcr-abl PTK activity is involved in the initiation and propagation of chronic myelogenous leukemia (CML). After introduction by EP, ODN-1 rapidly decreases p210bcr-abl associated tyrosine phosphorylation, and leads to growth inhibition of both established and primary CML cells by CFU-GM assay. Ongoing studies demonstrate negligible effects upon LTC-IC activity. After screening multiple primary patient samples, we have been able to determine that inhibition of p210bcr-abl PTK activity in patients with CML has effects which appear to vary from patient to patient, consistent with a variable role of p210bcr-abl in different patients. These findings have led to ongoing investigations whose aim is to target multiple molecular targets simultaneously in CML."

“已停止该项目旨在开发 寡脱氧核苷酸（ODNs）在临床最佳 方式先前的一系列研究表明， 可以通过电穿孔（EP）有效地引入细胞中： 100%的转染率，瞬时输送，更优 细胞内ODN分布特征，以及 行动上这些研究还表明， c-myc、U937人淋巴瘤细胞可被选择性清除 从正常人骨髓中提取，对正常 CFU-GM数值。最近的调查集中在如何， 潜在骨髓净化方法影响长期培养 启动细胞（LTC-IC）; LTC-IC检测提供最准确的 在体外测量人体中真正干细胞活性。至今没有 在处理后已经检测到对LTC-IC的显著影响 正常骨髓与EP和/或c-myc反义。其他 研究集中在抑制p210 bcr-abl 相关的蛋白酪氨酸激酶（PTK）活性通过基于ODN的 我们开发的抑制剂。p210 bcr-abl PTK增加 活动参与慢性炎症的启动和传播， 骨髓性白血病（CML）。在EP引入后，ODN-1 迅速降低p210 bcr-abl相关的酪氨酸磷酸化， 并导致既有的CML和原发性CML的生长抑制 通过CFU-GM测定法测定细胞。正在进行的研究表明， 对LTC-IC活性的影响在筛选多个主要 患者样本，我们已经能够确定， p210 bcr-abl PTK活性在CML患者中具有作用， 似乎因患者而异，与变量一致 p210 bcr-abl在不同患者中的作用这些发现导致 正在进行的调查，其目的是针对多个分子 在CML中同时进行。"