Studies on a Novel Taxane Pump

新型紫杉烷泵的研究

• 批准号: 7475119
• 负责人: ELIZABETH A HOPPER-BORGE
• 金额: $ 12.47万
• 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/7475119
• 关键词: ABCB1 gene; ABCC1 gene; ATP Hydrolysis; ATP phosphohydrolase; ATP-Binding Cassette Transporters; Anions; Anthracycline Antibiotics; Anthracyclines; Antineoplastic Agents; Binding; Biochemical; Biological Models; Breast; Cancer Patient; Carrier Proteins; Cells; Class; Drug Binding Site; Drug Transport; Drug resistance; Effectiveness; Elements; Embryo; Epipodophyllotoxin Compound; Estradiol; Family member; Fibroblasts; Genes; Glucuronides; Glutathione; Goals; Health; Human; In Vitro; Knock-out; 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; Range; 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; glucuronide; 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）：对化学治疗剂的细胞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）和多药耐药性蛋白（MRP）下属成员通过直接从细胞中排出抗癌药物来促进耐药性。 MRP亚家族成员运输葡萄糖醛酸苷和谷胱甘肽共轭底物，并赋予对包括蒽环类药物，附生chomelotoxins，epipododyllotoxin，Vinca生物碱和核苷酸类似物的广泛剂的耐药性。我们的实验室表明，使用膜囊泡，MGATP依赖性运输17 p-雌二醇 - （17-P-D-D-D-D--葡萄糖醛酸）（E217BG）的MGATP依赖性转运（E217BG）。此外，我们以前的工作表明，MRP7具有与其他MRP家族成员不同的抗性表型：因为MRP7是该组中唯一赋予对紫杉烷抗性的成员。 MRP7只是证明这种电阻的第二个泵，第一个鉴定出的泵具有PGP。紫杉虫主要用于治疗卵巢，肺和乳腺癌。 迄今为止，使用体外模型系统收集了有关MRP7的所有功能信息。由于MRP7具有独特的表型，并且与所有MRP亚家族成员的MRP1具有最低的同源性，因此确定负责其活性的生化参数是有意义的。此外，尚未阐明对抑制剂或调节剂的合理设计至关重要的生化和结构信息。该建议将概述使用我们开发的基因敲除小鼠模型，概述MRP7在该蛋白的体内耐药表型中的作用。第二个目的将阐明MRP7 UNICTER所需的特定生化活动。例如，与MRP7运输药物能力有关的结合，ATP水解和调节活动的特定生化活性。第三个目标将表征MRP7功能所需的结构元素。通过结合体内和体外方法，这些目标将深入了解最近发现的抗性因子。 重要的是要了解降低用于治疗癌症患者的化学治疗剂的有效性的蛋白质。该提案的目的是获取有关这些最近确定的蛋白质之一的信息。