Studies on a Novel Taxane Pump

新型紫杉烷泵的研究

• 批准号: 7195429
• 负责人: ELIZABETH A HOPPER-BORGE
• 金额: $ 12.2万
• 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/7195429
• 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）：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从细胞外排抗癌药物来促进耐药。MRP亚家族成员转运葡萄糖醛酸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、表观卟啉毒素、长春花生物碱和核苷酸类似物。我们的实验室已经证明MRP7能够运输两亲性阴离子，利用膜泡，建立了MgATP依赖的17-p-雌二醇-（17-p- d -葡糖苷）（E217BG）的运输。此外，我们之前的工作已经证明MRP7具有不同于其他MRP家族成员的抗性表型：MRP7是该组中唯一具有紫杉烷抗性的成员。MRP7是第二个显示这种抗性的泵，第一个确定的具有这种抗性的泵是Pgp。紫杉烷主要用于治疗卵巢癌、肺癌和乳腺癌。