MECHANISMS OF DRUG RESISTANCE IN ACUTE MYELOID LEUKEMIA

急性髓系白血病的耐药机制

• 批准号: 3196970
• 负责人: CHARLES ALAN SCHIFFER
• 金额: $ 29.11万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-05-01 至 1993-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3196970
• 关键词: DNA topoisomerases; P glycoprotein; acute myelogenous leukemia; antileukemic agent; cellular oncology; cyclosporines; daunorubicin; drug resistance; erythroid stem cell; flow cytometry; gene expression; human subject; human therapy evaluation; multidrug resistance; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; nucleic acid hybridization; western blottings

The development of drug resistance in leukemia cells constitutes the major reason for treatment failure in acute myeloid leukemia (AML). Although a number of prognostic factors such as cellular morphology and cytogenetic abnormalities have been identified, the mechanisms by which cellular resistance to chemotherapy occurs are poorly understood. Because even unsuccessful regimens produce substantial cytoreduction, it is likely that characteristics of subpopulations of leukemic cells will be of importance in the development of resistance. The University of Maryland Cancer Center (UMCC) will perform multiple laboratory studies on leukemic blasts to simultaneously evaluate a number of proposed mechanisms in vitro. These results will be correlated with outcome after treatment and clinical parameters in a consecutive cohort of newly diagnosed patients treated on clinical trials. Serial evaluations will be done at the time of treatment failure or relapse. We propose to focus on: cellular and pharmacokinetic mechanisms of resistance of daunorubicin with assessment of the multidrug resistance phenotypes associated with p-glycoprotein and topoisomerase II abnormalities in leukemia cells; evaluation of methods for determination of drug sensitivity; in vitro and subsequent in vivo evaluation of non- cytotoxic modulaters of p-glycoprotein function. Flow cytometry, molecular hybridization and immunologic techniques will be utilized to identify these various parameters in subpopulations of leukemic cells. The UMCC has a large population of leukemia patients, extensive preliminary data on the proposed projects, a history of productive clinical-laboratory interactions and represents an excellent environment in which to study these important questions.

白血病细胞中耐药性的发展是主要的 急性髓样白血病（AML）治疗失败的原因。 虽然 预后因素的数量，例如细胞形态和细胞遗传学 已经鉴定出异常，细胞的机制 对化学疗法的抵抗力的理解很少。 因为均匀 不成功的方案会产生大量的细胞量，很可能 白血病细胞亚群的特征将很重要 在抵抗的发展中。 马里兰大学癌症中心 （UMCC）将对白血病爆炸进行多次实验室研究 同时在体外评估许多提出的机制。 这些 结果将与治疗后的结果相关 连续一组新诊断的患者的参数 临床试验。 串行评估将在治疗时进行 失败或复发。 我们建议专注于：细胞和药代动力学 通过评估多糖的抗性抗毒素的机制 与P-糖蛋白和拓扑异构酶II相关的抗性表型II 白血病细胞异常；评估确定的方法 药物敏感性；体外和随后的非 - P-糖蛋白功能的细胞毒性调节剂。 流式细胞仪，分子 将利用杂交和免疫学技术来识别这些 白血病细胞亚群中的各种参数。 UMCC有一个 大量的白血病患者，广泛的有关 拟议的项目，生产性临床实验室相互作用的历史 并代表了研究这些重要的一个极好的环境 问题。