Broad Spectrum MDR Modulation in AML

AML 中的广谱 MDR 调制

• 批准号: 6559990
• 负责人: MARIA R BAER
• 金额: $ 14.16万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-10 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6559990
• 关键词: P glycoprotein; acute myelogenous leukemia; apoptosis; cell line; clinical research; cyclosporines; flow cytometry; human tissue; multidrug resistance; pharmacokinetics; transport proteins; P glycoprotein; acute myelogenous leukemia; apoptosis; cell line; clinical research; cyclosporines; flow cytometry; human tissue; multidrug resistance; pharmacokinetics; transport proteins

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.

描述（由申请人提供）：多药耐药性（MDR）是急性髓样白血病（AML）治疗失败的主要原因。 MDR经常与能量依赖性药物外排相关，而外排可能会因用非胞毒性底物（称为MDR调节剂）的竞争抑制而阻止。在实验室模型中有效的MDRI的药理调节，但临床应用令人失望。 MDR在AML中的药理调节试验具有靶向P-糖蛋白（PGP），是特征最特征的MDR相关的转运蛋白，但还可能对临床MDR MDR型型也可能有助于其他转运蛋白，包括MuitidRug抗性蛋白（MRP-1）和乳腺癌抗性蛋白（BCRP）。药理学MDR调节还独立于药物流出促进凋亡，但这种作用在很大程度上尚未探索。该提案的总体目标是开发AML中的临床MDR调制方法，这些方法都考虑了在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AML中MRP-1和BCRP的表达和功能的相关性以及可用的可用临床适用调节剂的活性范围。这些研究将利用现有的癌症和白血病B组（CALB）仓库的库存库，该库的预处理样品来自60岁的AML发生，并随后从头出现，并在先前的骨髓发育异常综合症中，该综合症患有临床MDR的人群，该临床MDR发生率很高，在单一方案（单一方案），CALGB9720。具体目的是：1。确定PGP，MRP-1和BCRP表达和功能在AML患者群体中的发病率和临床意义； 2。要比较可用可用临床适用的调制剂的影响，包括PSC-833，环孢素A，Biricodar（VX-710），VX-853，Fumitremorgin C类似物KO143，新颖的紫杉烷衍生药物IDN5109和TRA96023，对pg and the and and and and and and and am and the Am and and and the Am a am a and amm and。 BCRP表达和功能； 3。为了比较PSC-833，Cyclosporinea，Biricodar，VX-853，KO143，IDN5109和TRA96023的药物转运无关的作用，ONAML细胞存活，通过凋亡反应测量。预计该研究将为AML和其他恶性肿瘤中广谱MDR调制的未来临床试验设计提供基本信息。