MECHANISMS OF DRUG RESISTANCE IN ACUTE MYELOID LEUKEMIA

白血病细胞耐药性的发展构成了 急性髓细胞白血病（AML）治疗失败的原因。 虽然 许多预后因素，如细胞形态学和细胞遗传学 已经发现了异常，细胞的机制， 对化疗耐药的发生知之甚少。 因为即使 不成功的方案产生大量的细胞减少， 白血病细胞亚群的特征将是重要的 抵抗力的发展。 马里兰州大学癌症中心 （UMCC）将对白血病原始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 接受以下治疗的新诊断患者的连续队列中的参数 临床试验 治疗时将进行系列评价 失败或复发。 我们建议重点关注：细胞和药代动力学 柔红霉素耐药机制及多药耐药机制的评价 与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;体外和随后的体内评价， P-糖蛋白功能的细胞毒性调节剂。 流式细胞术，分子 杂交和免疫学技术将用于鉴定这些 白血病细胞亚群的各种参数。 UMCC有一个 大量的白血病患者，广泛的初步数据， 建议的项目，富有成效的临床实验室互动的历史 并提供了一个很好的环境来研究这些重要的 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.