IMMUNOLOGIC ANALYSIS--MULTIDRUG RESISTANT GENE FAMILY

对多种化疗药物的耐药性仍然是一个主要的 成功管理人类恶性肿瘤的障碍。 最近，一种称为MDR P-糖蛋白的特异性基因被发现， 证实在多药耐药细胞中扩增和过表达 抗性细胞系 这个基因是一个多基因的成员， 家族已被证明传递对多种药物的耐药性， 体外 这项提案的重点是开发抗体 与构成MDR β-多肽的特异性表位相关， 糖蛋白家族在小鼠和人。表征 这些抗体对每个家族的特异性 成员和与特定功能位点的相互作用， 多肽链将为研究 正常和肿瘤组织。 这些抗体将是必不可少的 在确定MDR β的分布和表达时， 糖蛋白在正常组织和临床肿瘤中的作用 化疗 由于mdr p-糖蛋白在 发展的耐药性是明确的，然后潜在的 应用适当的单克隆抗体进行逆转 将考虑体内多药耐药性。 该项目的具体目标是：1）产生抗体 MDR P-糖蛋白基因家族的3个成员，2） 产生针对不同细胞内特定结构域的抗体， 家族成员，3）绘制MDR β-糖蛋白的结构 4)确定每个MDR的组织分布， 糖蛋白，5）决定基因的每个成员的作用 耐药家族的产生，6）评价功能 MDR P-糖蛋白家族成员的结构域，7）筛选 人类肿瘤与这些抗体，以确定这一作用， 基因家族在临床耐药发展中的作用。

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.