MECHANISMS OF DRUG RESISTANCE IN ACUTE MYELOID LEUKEMIA

急性髓系白血病的耐药机制

基本信息

批准号：
2007835
负责人：
DOUGLAS DONALD ROSS
金额：
$ 24.79万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
1990
资助国家：
美国
起止时间：
1990-05-01 至 1999-11-30
项目状态：
已结题

项目摘要

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. We propose to build upon observations derived from our physiologic or "functional" assays for a multidrug resistance (MDR) phenotype which reveal that daunorubicin accumulation, retention and cytotoxicity can be enhanced by cyclosporin A (CsA) or verapamil in blast cells from more than half of newly diagnosed AML patients. The major thrust will be the correlation of our "functional" evidence for MDR with expression of P-glycoprotein (Pgp) or mdr1 transcripts. In addition, we will also study multidrug resistance-associated protein (MRP) a newly discovered and cloned membrane protein associated with drug resistance in human neoplastic cell lines. MRP has been found to be overexpressed in the human leukemia cell line HL- 60/Adr, which displays a classical MDR phenotype and impaired accumulation and retention of drug, but does not overexpress Pgp. Flow cytometry and reverse transcriptase-PCR (RT-PCR) will be utilized to identify Pgp expression in leukemic cells, using different approaches than in our previous proposal. MRP expression will be determined by RT-PCR. To validate these assays, these data will be correlated with our "functional" assays for an MDR phenotype, and also with outcome after treatment and clinical parameters, in a consecutive cohort of newly diagnosed patients treated on clinical trials, as well as with data and samples acquired during the previous granting period. Serial evaluations will be done at the time of treatment failure or relapse. Finally, we will also initiate a phase I trial of CsA, a modulator of Pgp-associated MDR, in combination with daunorubicin, etoposide and cytarabine, which is a regimen that could be used as initial induction therapy for AML. 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。我们建议建立在我们的生理学或“功能”的观察基础上多药耐药性（MDR）表型的测定，该表型表明 daunorubicin的积累，保留和细胞毒性可以通过环孢菌素A（CSA）或Verapamil在超过一半以上的爆炸细胞中新诊断的AML患者。主要的推力将是我们用P-糖蛋白表达（PGP）的MDR的“功能性”证据或MDR1成绩单。此外，我们还将研究多饮抗性相关蛋白（MRP）新发现和克隆的膜与人类肿瘤细胞系中耐药性相关的蛋白质。已发现MRP在人白血病细胞系HL-中过表达 60/ADR，显示经典的MDR表型和积累受损和保留药物，但不会过表达PGP。流式细胞仪和逆转录酶-PCR（RT-PCR）将用于识别PGP 在白血病细胞中的表达，使用与我们的不同方法以前的建议。 MRP表达将由RT-PCR确定。到验证这些测定法，这些数据将与我们的“功能”相关 MDR表型的测定，以及治疗后的结果临床参数，连续的新诊断患者队列在临床试验以及获取的数据和样品中进行处理在上一个授予期间。串行评估将在治疗失败或复发时间。最后，我们还将发起 CSA（PGP相关MDR的调节剂）组合的I期试验与daunorubicin，依托泊苷和细胞丁滨有关，这是一种可以用作AML的初始诱导疗法。 UMCC有一个大白血病患者的人口，关于该白血病患者的广泛初步数据拟议的项目，生产临床实验室的历史相互作用，代表了研究的绝佳环境这些重要的问题。