USE OF SYNTHETIC OLIGODEOXYNUCLEOTIDES IN BONE MARROW PURGING

“停产这一项目寻求发展 寡脱氧核苷酸(ODN)在临床上的应用 举止。先前的一系列调查表明，ODN 可通过电穿孔(EP)有效地导入细胞： 100%转染率，瞬间传递，更理想 ODN在细胞内的分布和即刻发病 行动。这些研究还表明，在反义到 C-myc、U937人淋巴瘤细胞可被选择性清除 来自正常的人骨髓，对正常的影响很小 CFU-GM编号。最近的调查集中在这一点上 潜在的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 在体外测量人类真实的干细胞活性。到目前为止，没有 治疗后对LTC-IC有显著影响 EP和/或c-myc反义的正常骨髓。其他 研究的重点是p210bcr-abl的抑制作用。 基于ODN的相关蛋白酪氨酸激酶活性的研究 抑制剂，这是我们开发的。增加p210bcr-ABL PTK 活动参与了慢性粒细胞白血病的启动和传播 髓系白血病(CML)。经EP导入后，ODN-1 迅速降低p210bcr-abl相关的酪氨酸磷酸化， 并导致已建立的和原发的CML的生长抑制 CFU-GM法检测细胞。正在进行的研究表明可以忽略不计 对LTC-IC活性的影响。在筛选多个主服务器之后 患者样本，我们已经能够确定其抑制作用 P210bcr-ABL PTK活性在慢性粒细胞白血病患者中的作用 看起来因病人而异，与一个变量一致 P210bcr-ABL在不同患者中的作用这些发现导致了 正在进行的研究，其目的是针对多个分子 在慢性粒细胞白血病中同时瞄准目标。

"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."