Broad Spectrum MDR Modulation in AML

描述（由申请人提供）：多药耐药（MDR）是急性髓性白血病（AML）治疗失败的主要原因。耐多药通常与能量依赖性药物外排有关，外排可能被非细胞毒性底物（称为耐多药调节剂）的竞争性抑制所阻断。mdri的药理学调节在实验室模型中是有效的，但临床应用一直令人失望。AML中MDR的药理学调节试验针对的是p糖蛋白（Pgp），这是最具特征的MDR相关转运蛋白，但其他转运蛋白，包括多药耐药蛋白（MRP-1）和乳腺癌耐药蛋白（BCRP），也可能导致临床MDR表型。药理学MDR调节也促进细胞凋亡独立于药物外排，但这种作用在很大程度上仍未被探索。本提案的总体目标是开发AML的临床MDR调节方法，该方法考虑到AML细胞中表达的多种外排蛋白和调节剂的药物外排独立效应。这需要确定MRP-1和BCRP以及Pgp在AML中的表达和功能的相关性，以及可用的临床适用调节剂的活性谱。这些研究将利用现有的癌症和白血病B组（CALGB）治疗前样本库，这些样本来自bb60岁的急性髓细胞增生异常综合征（AML）患者，这些患者有很高的临床耐多药发生率，采用单一方案CALGB9720进行治疗。具体目标是：1。探讨Pgp、MRP-1和BCRP在临床耐药高发AML患者群体中的表达及功能变化及其临床意义；2. 比较多种可用的临床适用调节剂，包括PSC-833、环孢素A、Biricodar （VX-710）、VX-853、复美霉素C类似物KO143，以及新型紫杉烷衍生药物IDN5109和tRA96023，对AML细胞中Pgp、MRP-1和BCRP表达和功能的药物保留的影响；3. 比较PSC-833、cyclosporineA、biricodar、VX-853、KO143、IDN5109和tRA96023对aml细胞存活的药物转运不依赖性作用（通过凋亡反应测量）。该研究有望为未来设计广谱MDR调节AML和其他恶性肿瘤的临床试验提供重要信息。

DESCRIPTION (provided by applicant): Multidrug resistance (MDR) is a major cause of treatment failure in acute myeloid leukemia (AML). MDR is frequently associated with energy-dependent drug efflux, and efflux may be blocked by competitive inhibition with non-cytotoxic substrates, termed MDR modulators. Pharmacological modulation of MDRis effective in laboratory models, but clinical application has been disappointing. Trials of pharmacological modulation of MDR in AML have targeted P-glycoprotein (Pgp), the best-characterized MDR-associated transport protein, but additional transport proteins, including muitidrug resistance protein (MRP-1) and breast cancer resistance protein (BCRP), are also likely to contribute to the clinical MDR phenotype. Pharmacological MDR modulation also promotes apoptosis independently of drug efflux, but this effect remains largely unexplored. The overall goal of this proposal is to develop clinical MDR modulation approaches in AML which take into account both the multiple efflux proteins expressed in AML cells and the drug efflux-independent effects of modulators. This requires determining the relevance of expression and function of MRP-1 and BCRP, in addition to Pgp, in AML and the spectrum of activity of available clinically applicable modulators. The studies will utilize the existing Cancer and Leukemia Group B (CALGB) repository of pre-treatment samples from patients > 60 years old with AML occurring de novo and following antecedent myelodysplastic syndromes, a population with a high incidence of clinical MDR, treated on a single protocol, CALGB9720. The specific aims are: 1. To determine the incidence and clinical significance of Pgp, MRP-1 and BCRP expression and function in an AML patient population with a high incidence of clinical drug resistance; 2. To compare the effects of diverse available clinically applicable modulators, including PSC-833, cyclosporine A, Biricodar (VX-710), VX-853, the fumitremorgin C analogue KO143, and the novel taxane-derived agents IDN5109 and tRA96023, on drug retention in AML cells that have been characterized with respect to Pgp, MRP-1 and BCRP expression and function; 3. To compare the drug transport-independent effects of PSC-833, cyclosporineA, biricodar, VX-853, KO143, IDN5109 and tRA96023, onAML cell survival, measured by the apoptotic response. The study is expected to provide essential information for the design of future clinical trials of broad-spectrum MDR modulation in AML and other malignancies.