THIOREDOXIN IN ALL AND ITS THERAPEUTIC IMPLICATIONS

描述：（申请人摘要） 这是一项生物相关性研究，有三个主要目标：（i） 研究硫氧还蛋白在原发性儿童T细胞中的表达， B系急性淋巴细胞白血病（ALL），（ii）与 硫氧还蛋白过表达的临床特征和结果，以及 (iii)检查可能利用改变的表达， 治疗干预的未来发展。最近的研究表明 硫氧还蛋白可能是一种新发现的人类癌症癌蛋白 并支持硫氧还蛋白氧化还原系统作为 开发选择性抑制癌症的药物。通过 与一个国家基准实验室合作， 由UCSD医学中心POG的Alice Yu博士进行，申请人将分析 硫氧还蛋白在原发性T、B细胞白血病中的表达 所有患者均接受POG方案的统一治疗，包括以下内容 具体目标：具体目标1：系统分析 T-和B-谱系ALL中硫氧还蛋白的表达， 假设硫氧还蛋白表达可能与 临床特征和结局;具体目标2：确定血浆 ALL患者细胞外硫氧还蛋白水平，并检测 假设血浆中高水平硫氧还蛋白可能 临床意义和具体目标3：确定体外 原代ALL细胞对1-甲基丙基二硫化物和其他 相关化合物，并探索其抗白血病作用或 诱导细胞凋亡。为了开发未来的治疗试剂 对于白血病，这些二硫化物对白血病集落的影响 还将研究体外的正常造血作用。

DESCRIPTION: (Applicant's Abstract) This is a biological correlative study with three major objectives: (i) to investigate the expression of thioredoxin in primary childhood T- and B- lineage acute lymphoblastic leukemia (ALL), (ii) to correlate overexpression of thioredoxin with clinical features and outcome, and (iii) to examine the possible exploitation of the altered expression for future development of therapeutic interventions. Recent studies suggest that thioredoxin may be a newly identified oncoprotein for human cancer and supports the thioredoxin redox system as a rational target for the development of drugs to selectively inhibit cancer. Through collaboration with one of the national reference laboratories, headed by Dr. Alice Yu of POG, UCSD Medical Center, the applicant will analyze the expression of thioredoxin in primary T- and B-lineage leukemia from ALL patients uniformly treated by POG protocols with the following specific aims: Specific Aim 1: To carry out a systematic analysis of the expression of thioredoxin in T- and B- lineage ALL and to test the hypothesis that expression of thioredoxin may be correlated with clinical features and outcome; Specific Aim 2: To determine the plasma level of extracellular thioredoxin in ALL patients and to test the hypothesis that high level of thioredoxin in the plasma may have clinical significance and Specific Aim 3: To determine the in vitro sensitivity of primary ALL cells to 1-methylpropyldisulfide and other related compounds, and to explore for their anti-leukemic actions or induction of apoptosis. In order to develop future therapeutic reagents for leukemia, the effect of these disulfides on leukemia colony formation as well as normal hematopoiesis in vitro will also be studied.