IMMUNOLOGIC ANALYSIS--MULTIDRUG RESISTANT GENE FAMILY

免疫学分析--多重耐药基因家族

• 批准号: 3192180
• 负责人: James M Croop
• 金额: $ 24.87万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-09-01 至 1993-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3192180
• 关键词: P glycoprotein; acute leukemia; adenosine triphosphate; antibody formation; antibody specificity; cancer risk; chemical binding; combination cancer therapy; combination chemotherapy; cross immunity; drug resistance; gene expression; genetic manipulation; human fetus tissue; human subject; human tissue; immunochemistry; immunoelectron microscopy; laboratory mouse; monoclonal antibody; natural gene amplification; neoplasm /cancer genetics; neoplasm /cancer immunology; neuroblastoma; protein structure; tissue /cell culture

Resistance to multiple chemotherapeutic agents remains a major obstacle in successful management of human malignancies. Recently a specific gene, termed mdr p-glycoprotein, has been demonstrated to be amplified and overexpressed in multidrug resistant cell lines. This gene which is a member of a multigene family has been shown to convey resistance to multiple drugs in vitro. This proposal is focused on the development of antibodies to specific epitopes of the polypeptides which make up the mdr p- glycoprotein family in the mouse and man. The characterization of these antibodies with respect to specificity for each family member and the interaction with specific functional sites on the polypeptide chain will provide essential information for studies on normal and neoplastic tissues. These antibodies will be essential in determining the distribution and expression of the mdr p- glycoprotein in normal tissues and clinically in neoplasms during chemotherapy. As the role of the mdr p-glycoprotein in the development of drug resistance is clarified then the potential application of appropriate monoclonal antibodies for the reversal of multidrug resistance in vivo will be considered. The specific goals of this project are: 1) generation of antibodies to the 3 members of the mdr p-glycoprotein gene family, 2) generate antibodies to specific domains within the different family members, 3) map the structure of the mdr p-glycoproteins 4) determine the tissue distrimdrn of each of the mdr p- glycoproteins, 5) determine the role each member of the gene family in the generation of drug resistance, 6) evaluate functional domains of the mdr p-glycoprotein family members, 7) screen human tumors with these antibodies to determine the role of this gene family in the clinical development of drug resistance.

对多种化学治疗剂的耐药性仍然是主要的 成功管理人类恶性肿瘤的障碍。 最近，一个被称为MDR P-糖蛋白的特定基因一直是 被证明在多药中被放大和过表达 抗性细胞系。 这个基因是多基因的成员 已经证明家庭可以传达对多种药物的抗性 体外。 该提案的重点是抗体的开发 到构成MDR P-的多肽的特定表位 老鼠和人的糖蛋白家族。 表征 这些关于每个家庭的特异性的抗体 成员以及与特定功能位点的相互作用 多肽链将为研究提供基本信息 正常和肿瘤组织。 这些抗体将是必不可少的 在确定MDR P-的分布和表达时 正常组织中的糖蛋白和在肿瘤中的临床期间 化学疗法。 作为MDR P-糖蛋白在 澄清耐药性的发展，然后潜力 应用适当的单克隆抗体进行反转 将考虑在体内的多药耐药性。 该项目的具体目标是：1）产生抗体 对于MDR P-糖蛋白基因家族的三名成员，2） 生成对不同域内特定域的抗体 家庭成员，3）绘制MDR P-糖蛋白的结构 4）确定每个MDR p-的组织分解 糖蛋白，5）确定基因的每个成员的作用 耐药性产生的家族，6）评估功能 MDR P-糖蛋白家族成员的域，7）屏幕 具有这些抗体的人类肿瘤来确定这一点的作用 基因家族在耐药性的临床发展中。