Studies on a Novel Taxane Pump

新型紫杉烷泵的研究

• 批准号: 7910563
• 负责人: ELIZABETH A HOPPER-BORGE
• 金额: $ 15.19万
• 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/7910563
• 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人类癌症治疗的主要障碍。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将抗癌药物从细胞中排出而导致耐药。MRP亚家族成员转运葡萄糖醛酸化和谷胱甘肽结合的底物，并对包括蒽环类、表鬼臼毒素、长春花碱和核苷酸类似物在内的多种药物产生抗药性。我们的实验室已经证明，MRP7具有转运两亲性阴离子的能力，利用膜泡，建立了17-对-雌二醇-(17-对-D-葡萄糖醛酸苷)(E217BG)对镁-三磷酸腺苷的依赖转运。此外，我们以前的工作已经证明，MRP7具有不同于其他MRP家族成员的耐药表型：MRP7是该家族中唯一对紫杉烷具有耐药性的成员。MRP7只是第二个显示这种耐药性的泵，第一个发现这种耐药性的泵是PGP。紫杉烷主要用于治疗卵巢癌、肺癌和乳腺癌。 到目前为止，所有收集到的关于MRP7的功能信息都是通过体外模型系统获得的。由于MRP7具有不同的表型，并且在所有MRP亚家族成员中与MRP1的同源性最低，因此确定影响其活性的生化参数是很有意义的。此外，对合理设计抑制剂或调节剂至关重要的生化和结构信息尚未阐明。这项提案将概述利用我们开发的基因敲除小鼠模型来阐明MRP7在该蛋白的体内耐药表型中所起的作用的计划。第二个目的将阐明MRP7功能所需的特定生化活性。例如，特定的生化活性与结合、三磷酸腺苷的水解和调节的活性有关，这些活性参与了MRP7的S的药物转运能力。第三个目标将描述MRP7功能所需的结构要素。通过使用体内和体外相结合的方法，这些目的将有助于深入了解这种最近发现的耐药因素。 重要的是要了解降低用于治疗癌症患者的化疗药物有效性的蛋白质。这项提议的目标是获得关于这些最近发现的蛋白质之一的信息。