VAV ANTISENSE ODN--A NOVEL THERAPEUTIC FOR HUMAN LEUKEMIAS

反义寡脱氧核苷酸（AS）已被广泛应用 在实验室中干扰基因表达并阐明基因功能 设置. 最近，我的团队和其他人报告说， 以及在显示潜在治疗效用的VOVO模型中， 的ODN。 在这一系列工作的基础上， AS ODN治疗人类白血病的临床试验 宾夕法尼亚大学。 虽然这些初步结果 临床试验可能被视为令人鼓舞的，我们赞赏这一点， 抗癌疗法的方法只有在以下情况下才能实用： 发展了对“反义机制”的更基本的理解。 这个项目的长期目标是丰富我们对 AS ODN如何损害活细胞中mRNA利用， 这一知识在人类白血病的ODN疗法的发展。 为了研究ODN干扰基因功能的机制， 使用正常和肿瘤性人类造血细胞作为模型 系统 具体来说，我们将研究AS分子如何损害 在这种类型的细胞中利用Vav mRNA。 Vav蛋白是 作为重要信号的原癌基因的产物 造血细胞中的蛋白质。 我们的初步数据，下面讨论， 表明Vav mRNA代表了一个合理的治疗靶点， 某些人类白血病 因此，这些研究将同时 基本的和翻译的相关性，并有望最终在 建立一个I期临床治疗方案， 白血病 制定了三个具体目标，以帮助我们实现 这个项目的长期目标。

Antisense (AS) oligodeoxynucleotides (ODN) have been widely employed to perturb gene expression, and elucidate gene function in a laboratory setting. More recently my group, and others, have reported in vitro and in vovo models which demonstrate the potential therapeutic utility of AS ODN. Based on this body of work, we have instituted Phase I trials of AS ODN for the treatment of human leukemias at the Hospital of the University of Pennsylvania. While the results of these initial clinical trials may be viewed as encouraging, we appreciate that this approach to anti-cancer therapeutics can only be made practical if a more basic understanding of the "antisense mechanism" is developed. The long term goals of this project are to enrich our understanding of how AS ODN impair mRNA utilization in living cells, and to then use this knowledge in the development of ODN therapies for human leukemias. To study the mechanisms of ODN pertubation of gene function we will employ normal and neoplastic human hematopoietic cells as a model system. Specifically, we will examine how AS molecules impair the utilization of Vav mRNA in cells of this type. Vav protein is the product of a protooncogene which functions as an important signalling protein in hematopoietic cells. Our preliminary data, discussed below, suggests that Vav mRNA represents a rational therapeutic target in certain human leukemias. Accordingly, these studies will have both basic and translational relevance and will hopefully culminate in the institution of a Phase I clinical protocol for the treatment of human leukemia. Three specific aims have been developed to help us achieve this project's long term goals.