Studies on a Novel Taxane Pump

新型紫杉烷泵的研究

• 批准号: 7667985
• 负责人: ELIZABETH A HOPPER-BORGE
• 金额: $ 14.91万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7667985
• 关键词: ABCB1 gene; ABCC1 gene; ATP Hydrolysis; ATP phosphohydrolase; ATP-Binding Cassette Transporters; Anions; Anthracyclines; Antineoplastic Agents; Binding; Biochemical; Biological Models; Breast; Cancer Patient; Carrier Proteins; Cells; Drug Binding Site; Drug Transport; Drug resistance; Effectiveness; Elements; Embryo; Epipodophyllotoxin Compound; Estradiol; Family member; Fibroblasts; Genes; Glucuronides; Glutathione; Goals; Health; Human; In Vitro; Knockout Mice; Laboratories; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Membrane; Membrane Transport Proteins; MgATP; Mus; Natural Product Drug; Ovarian; Ovary; P-Glycoprotein; P-Glycoproteins; Paclitaxel; Pharmaceutical Preparations; Phenotype; Play; Protein Family; Proteins; Publishing; Pump; Research; Resistance; Resistance profile; Role; Serum; Structure-Activity Relationship; System; Taxane Compound; Tissues; Vesicle; Vinca Alkaloids; Wild Type Mouse; Work; chemotherapeutic agent; design; efflux pump; human tissue; in vitro Model; in vivo; in vivo Model; information gathering; inhibitor/antagonist; insight; interest; malignant breast neoplasm; member; mouse model; novel; nucleotide analog; protein function; resistance factors; taxane

DESCRIPTION (provided by applicant): Cellular resistance to chemotherapeutic agents is a major obstacle in the treatment of human cancers. Efflux pumps, specifically P-glycoprotein (Pgp) and multidrug resistance protein (MRP) subfamily members contribute to drug resistance by directly effluxing anticancer drugs from cells. MRP subfamily members transport glucuronidated and glutathione conjugated substrates, and confer resistance to a wide range of agents including anthracyclines, epipodophyllotoxins, vinca alkaloids, and nucleotide analogs. Our laboratory has shown that MRP7 is competent in the transport of amphipathic anions, using membrane vesicles, the MgATP dependent transport of 17 p-estradiol-(17-p-D-glucuronide) (E217BG) was established. Further, our previous work has demonstrated that MRP7 has a resistance phenotype which is distinct from other MRP family members: in that MRP7 is the only member of this group to confer resistance to taxanes. MRP7 is only the second pump to demonstrate this resistance, the first identified pump conferring this resistance is Pgp. Taxanes are used primarily in the treatment of ovarian, lung and breast cancer. To date, all of the functional information gathered about MRP7 has been acquired using in vitro model systems. Since MRP7 has a distinct phenotype and has the lowest homology to MRP1 of all the MRP subfamily members, it is of interest to determine the biochemical parameters which are responsible for its activities. Further, biochemical and structural information that would be critical to the rational design of inhibitors or modulators has not yet been elucidated. This proposal will outline plans to elucidate the role MRP7 plays in the in vivo resistance phenotype of this protein using a knockout mouse model that we developed. The second aim will elucidate the specific biochemical activities that are required for MRP7 unction. For example, the specific biochemical activities related to binding, ATP hydrolysis and modulation of the activities which are involved in MRP7's ability to transport drug. The third aim will characterize the structural elements required for MRP7 function. By using a combination of in vivo and in vitro approaches, these aims will lend insight into this recently discovered resistance factor. It is important to have an understanding of the proteins that lower the effectiveness of chemotherapeutic agents used to treat cancer patients. The goal of this proposal is aimed is to obtain information about one of these recently identified proteins.

描述（由申请人提供）：细胞对化疗药物的耐药性是治疗人类癌症的主要障碍。外排泵，特别是 P-糖蛋白 (Pgp) 和多药耐药蛋白 (MRP) 亚家族成员，通过直接从细胞中外排抗癌药物来促进耐药性。 MRP 亚家族成员转运葡萄糖醛酸化和谷胱甘肽结合的底物，并赋予对多种药物的抗性，包括蒽环类药物、表鬼臼毒素、长春花生物碱和核苷酸类似物。我们的实验室已证明MRP7能够运输两亲性阴离子，利用膜囊泡，建立了17对雌二醇-(17-对-D-葡萄糖醛酸)(E217BG)的MgATP依赖性运输。此外，我们之前的工作已经证明MRP7具有与其他MRP家族成员不同的抗性表型：因为MRP7是该家族中唯一赋予紫杉烷抗性的成员。 MRP7 是第二个展示这种阻力的泵，第一个确定的具有这种阻力的泵是 Pgp。紫杉烷类药物主要用于治疗卵巢癌、肺癌和乳腺癌。 迄今为止，收集的有关 MRP7 的所有功能信息都是使用体外模型系统获得的。由于 MRP7 具有独特的表型，并且在所有 MRP 亚家族成员中与 MRP1 的同源性最低，因此有必要确定与其活性相关的生化参数。此外，对于抑制剂或调节剂的合理设计至关重要的生化和结构信息尚未阐明。该提案将概述使用我们开发的基因敲除小鼠模型阐明 MRP7 在该蛋白质体内耐药表型中所起的作用的计划。第二个目标将阐明 MRP7 功能所需的特定生化活性。例如，与结合、ATP水解和MRP7转运药物能力涉及的活性调节相关的特定生化活性。第三个目标将描述 MRP7 功能所需的结构元素的特征。通过结合体内和体外方法，这些目标将有助于深入了解这种最近发现的耐药因子。 了解降低癌症患者化疗药物有效性的蛋白质非常重要。该提案的目的是获取有关这些最近发现的蛋白质之一的信息。