IMMUNOLOGIC ANALYSIS--MULTIDRUG RESISTANT GENE FAMILY

对多种化疗药物的耐药性仍然是主要的 人类恶性肿瘤成功治疗的障碍。 最近，一种特殊的基因，称为多药耐药P-糖蛋白，已经被 证实在多药中扩增和过度表达 耐药细胞系。这个基因是一个多基因的成员 家族已被证明对多种药物具有耐药性 体外培养。这项提议的重点是开发抗体。 与组成MDR p的多肽的特定表位相结合。 小鼠和人的糖蛋白家族。人物刻画 这些抗体对每个家族的特异性 成员以及与上特定功能站点的交互 多肽链将为研究提供必要的信息 正常组织和肿瘤组织。这些抗体将是必不可少的 在确定多药耐药基因p的分布和表达中 糖蛋白在正常组织和临床肿瘤中的表达 化疗。作为多药耐药P-糖蛋白在乳腺癌中的作用 阐明了耐药性的发展，并对其潜力进行了分析 适当的单抗在逆转中的应用 将考虑体内的多药耐药。 这个项目的具体目标是：1)产生抗体 MDR P-糖蛋白基因家族的3个成员，2) 在不同的 家族成员，3)多药耐药P-糖蛋白的结构 4)确定每种MDR的组织分布。 糖蛋白，5)决定基因每个成员的作用 耐药家族的产生，6)功能评价 MDR P-糖蛋白家族成员的结构域，7)筛选 用这些抗体来确定人类肿瘤的这种作用 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.