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

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）是急性髓系白血病（AML）治疗失败的主要原因。 MDR 通常与能量依赖性药物流出相关，而流出可能会被非细胞毒性底物（称为 MDR 调节剂）的竞争性抑制所阻断。 MDR 的药理调节在实验室模型中是有效的，但临床应用却令人失望。 AML 中 MDR 的药理学调节试验以 P-糖蛋白 (Pgp) 为目标，这是最典型的 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 调节还可以独立于药物流出促进细胞凋亡，但这种作用在很大程度上仍未被探索。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以及调节剂的药物外排独立效应。这需要确定除 Pgp 之外，MRP-1 和 BCRP 的表达和功能在 AML 中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) 存储库，其中包含来自年龄 > 60 岁的新发 AML 患者以及先前发生骨髓增生异常综合征的患者的治疗前样本库，该人群是临床 MDR 发生率较高的人群，接受过治疗。单一协议，CALGB9720。具体目的是： 1. 确定临床耐药发生率高的 AML 患者群体中 Pgp、MRP-1 和 BCRP 表达和功能的发生率及其临床意义； 2. 比较多种可用的临床适用调节剂，包括 PSC-833、环孢菌素 A、比利考达 (VX-710)、VX-853、夫米曲莫嗪 C 类似物 KO143 以及新型紫杉烷衍生药物 IDN5109 和 tRA96023 对AML 细胞中的药物滞留已通过 Pgp、MRP-1 和BCRP表达及功能； 3. 比较 PSC-833、环孢菌素 A、比立考达、VX-853、KO143、IDN5109 和 tRA96023 对 AML 细胞存活的药物转运依赖性影响（通过凋亡反应测量）。该研究预计将为未来针对 AML 和其他恶性肿瘤的广谱 MDR 调节临床试验的设计提供重要信息。