Broad Spectrum MDR Modulation in AML

描述(申请人提供)：多药耐药(MDR)是急性髓系白血病(AML)治疗失败的主要原因。MDR常与能量依赖的药物外排有关，可通过与非细胞毒性底物的竞争性抑制来阻断外排，称为MDR调节剂。MDR的药理调节在实验室模型中是有效的，但临床应用一直令人失望。对急性髓细胞白血病多药耐药的药理调节试验以P-糖蛋白(P-gp)为靶点，P-糖蛋白是多药耐药相关的转运蛋白，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)，也可能与临床多药耐药表型有关。药物多药耐药调节也可促进细胞凋亡，而不依赖于药物外排，但这种作用在很大程度上尚不清楚。这项建议的总体目标是开发AML的临床MDR调控方法，该方法既考虑了AML细胞中表达的多种外排蛋白，又考虑了调节剂的药物外排非依赖性效应。这需要确定除Pgp外，MRP-1和BCRP在AML中的表达和功能的相关性，以及可用于临床的调节因子的活性谱。这些研究将利用现有的癌症和白血病B组(CALGB)治疗前样本储存库，这些样本来自60岁的初发AML患者和既往骨髓增生异常综合征患者，这些患者是临床MDR的高发人群，采用单一方案CALGB9720治疗。其具体目的是：1.确定Pgp、MRP-1和BCRP在临床耐药高发的AML患者中的表达和功能的发生率和临床意义；2.比较各种临床适用的调节剂，包括PSC-833、环孢素A、比利柯达(VX-710)、VX-853、Fumitremorgin C类似物KO143以及新型紫杉烷衍生剂IDN5109和tRA96023对已具有Pgp、MRP-1和BCRP表达和功能特征的AML细胞药物滞留的影响；3.比较PSC-833、环孢素A、比利柯达、VX-853、KO143、IDN5109和tRA96023对AML细胞存活的药物转运非依赖性作用。这项研究有望为AML和其他恶性肿瘤未来的广谱MDR调制临床试验的设计提供必要的信息。

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.