MICRODETECTION ASSAY FOR DRUG RESISTANT TUMORS

耐药肿瘤的微量检测分析

• 批准号: 6497595
• 负责人: WILLIAM T BECK
• 金额: $ 32.93万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-04-15 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6497595
• 关键词: DNA methylation; DNA topoisomerases; P glycoprotein; acute myelogenous leukemia; antineoplastics; beta galactosidase; cell line; chromatin; complementary DNA; deoxyribonuclease I; enzyme activity; gene expression; genetic library; genetic promoter element; human tissue; luciferin monooxygenase; method development; microarray technology; multidrug resistance; neoplasm /cancer genetics; neoplasm /cancer pharmacology; neoplasm /cancer relapse /recurrence

DESCRIPTION: (Applicant's Abstract) Despite recent advances in cancer genetics and treatment, anticancer drug resistance remains a formidable problem. The long-term goal of this project has been the development of microdetection assays that will ultimately permit individualization of therapy. Through the years, the applicant has focused on understanding the mechanisms of tumor cell resistance to natural product drugs, and has defined both P-glycoprotein-associated multidrug resistance (Pgp-MDR) and altered topoisomerase II-associated MDR, with the idea that a focus on a few targets might permit exploitation for diagnosis or therapy. It is now clear that resistance, even to a single anticancer drug, is a multifactorial phenomenon with multiple genetic changes. Given this panoply of changes, the task of identifying "the" gene(s) responsible for the phenotype is very challenging. However, if these changes represent a reproducible pattern of gene expression, then it might not matter knowing which gene(s) cause the phenotype if what is desired is knowing whether an expression pattern accurately represents the phenotype. Recent advances in cDNA array technology now make it possible, after all these years; to develop a true "microdetection" assay that can theoretically detect drug resistant tumor cells. However, application of this methodology to identify a small proportion of therapy resistant cells in an otherwise sensitive tumor population remains problematic. The applicant will develop the idea in this application that marrying methods of gene array, drug action, and analysis of specific genes will be able to provide a profile of such a subpopulation of drug resistant cells. Accordingly, the hypothesis to be tested is that tumor cells from therapy-resistant patients display coordinate expression of drug-resistant genes that can be detected by their molecular and cellular signatures. The specific aims are: 1) define the basis for the apparent coordinate regulation of the MDR1, MRP, and other genes in relapsed AML through study of MRP regulation, and 2) use gene array methodology to identify patterns of gene expression associated with therapy resistance in AML.

描述：（申请人的摘要）尽管癌症遗传学最近进展 和治疗，抗癌耐药性仍然是一个巨大的问题。这 该项目的长期目标是开发微调 最终允许个性化治疗的测定法。通过 多年，申请人专注于理解肿瘤细胞的机制 对天然产品药物的抗性，并且已经定义了 P-糖蛋白相关的多药耐药性（PGP-MDR），并改变了 拓扑异构酶II相关的MDR，并认为关注一些目标 可能允许剥削诊断或治疗。现在很明显 抗药性，即使是单一抗癌药物，也是一种多因素现象 有多种遗传变化。鉴于此众多变化，任务的任务 识别负责表型的“”基因非常具有挑战性。 但是，如果这些变化代表了基因表达的可重复模式，则 那么知道哪种基因会导致表型，如果什么是 所需的是知道表达模式是否准确表示 表型。现在，cDNA阵列技术的最新进展使之成为可能 这些年来；开发一个真正的“微观检测”测定 理论上检测耐药性肿瘤细胞。但是，应用此 鉴定一小部分抗治疗细胞的方法论 否则，敏感的肿瘤种群仍然有问题。申请人将 在此应用中发展的想法是嫁给基因阵列的方法，药物 动作以及对特定基因的分析将能够提供 这种耐药细胞的亚群。因此，假设是 测试的是，来自治疗患者的肿瘤细胞显示坐标 可以通过其分子检测到的耐药基因的表达 细胞特征。具体目的是：1）定义 复发中MDR1，MRP和其他基因的明显坐标调节 通过研究MRP调节，以及2）使用基因阵列方法 确定与AML中与治疗抗性相关的基因表达模式。