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。MDR通常与能量依赖性药物外排相关，并且外排可通过与称为MDR调节剂的非细胞毒性底物的竞争性抑制来阻断。药物调节MDR在实验室模型中是有效的，但临床应用一直令人失望。药物调节AML MDR的试验靶向了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，但这种作用仍然在很大程度上未被探索。该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非依赖性作用。这需要确定MRP-1和BCRP（除Pgp外）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组B（CALGB）储存库，储存来自60岁以上初发AML患者和既往骨髓增生异常综合征患者的治疗前样本，这些患者是临床MDR发生率较高的人群，接受单一方案CALGB 9720治疗。具体目标是：1.目的：1.探讨Pgp、MRP-1和BCRP在临床耐药率高的AML患者中的表达和功能变化及其临床意义。比较各种可用的临床上可应用的调节剂，包括PSC-833、环孢菌素A、Biricodar（VX-710）、VX-853、烟曲霉素C类似物K 0143和新型紫杉烷衍生剂IDN 5109和tRA 96023，对AML细胞中药物滞留的作用，其特征在于Pgp、MRP-1和BCRP表达和功能; 3.比较PSC-833、环孢菌素A、biricodar、VX-853、KO 143、IDN 5109和tRA 96023对AML细胞存活的药物转运非依赖性作用（通过凋亡反应测量）。该研究有望为AML和其他恶性肿瘤中广谱MDR调节的未来临床试验设计提供重要信息。

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.