IMMUNOLOGIC ANALYSIS--MULTIDRUG RESISTANT GENE FAMILY

对多种化疗药物的耐药性仍然是一个主要问题

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.