MECHANISMS OF DRUG RESISTANCE IN ACUTE MYELOID LEUKEMIA

白血病细胞的耐药性的发展构成了主要的 急性髓系白血病(AML)治疗失败原因。尽管一个 细胞形态和细胞遗传学等预后因素的数量 异常已经被识别出来，细胞 对化疗产生的耐药性知之甚少。因为即使是 不成功的方案会产生大量的细胞减少，很可能是 白血病细胞亚群的特征将是重要的 在抗药性的发展过程中。马里兰大学癌症中心 (UMCC)将对白血病母细胞进行多项实验室研究 同时在体外评估一些拟议的机制。这些 结果将与治疗后的结果和临床结果相关 连续队列中接受治疗的新诊断患者的参数 临床试验。将在治疗时进行系列评估 失败或旧病复发。我们建议重点研究：细胞和药代动力学 柔红霉素耐药机制及多药耐药评价 P-糖蛋白和拓扑异构酶II相关的耐药表型 白血病细胞的异常.测定方法的评价 药物敏感性；体外和随后的体内非 P-糖蛋白功能的细胞毒调节剂。流式细胞术，分子 将利用杂交和免疫学技术来鉴定这些 白血病细胞亚群中的各种参数。UMCC有一个 白血病患者人数众多，有广泛的初步数据 提出的项目，富有成效的临床与实验室互动的历史 代表了一个学习这些重要信息的良好环境 问题。

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.