Accession Number : ADA302127

Title :   Topology and Function of Human P-glycoprotein in Multidrug Resistant Breast Cancer Cells.

Descriptive Note : Annual rept. 1 Sep 94-31 Aug 95,

Corporate Author : TEXAS UNIV MEDICAL BRANCH AT GALVESTON

Personal Author(s) : Han, Ernest S. ; Reuss, Luis

PDF Url : ADA302127

Report Date : SEP 1995

Pagination or Media Count : 19

Abstract : Multidrug resistance is characterized by the overexpression of P-glycoprotein (Pgp), a 170-kDa glycoprotein coded by the MDRl gene in humans. Pgp actively extrudes chemotherapeutic agents and is related to swelling-activated chloride currents (Ic1). The goal of this research is to understand the relationship between Pgp structure and function. Pgp topology was studied in an in vitro system that generated truncated peptides of human MDRl and hamster pqpl Pgp, inserted into microsomal membranes. We conclude that the C-terminal half topologies of hamster pgpl and human MDRl Pgp are different from the hydropathy-predicted model and from each other. Functional studies examined Pgp's role in Ic1. Using the whole-cell patch-clamp technique, we have shown that the addition of anti-Pgp monoclonal antibody (Mab) C2l9 to the pipette solution blocks Ic1 in cells expressing Pgp (BCl9/3 and KB-Vl cells). Other anti-Pgp Mabs and mouse IgG had no effect on Ic1. C2l9 had no effect on cells without Pgp expression (MCF-7 and BALB/c-3T3 cells). We conclude that Pgp has a regulatory role of Ic1, probably by specific association with swelling-activated Cl channels.

Descriptors :   *GLYCOPROTEINS, *DRUGS, *RESISTANCE(BIOLOGY), *CHEMOTHERAPEUTIC AGENTS, *BREAST CANCER, ACTIVATION, HUMANS, PEPTIDES, IN VITRO ANALYSIS, TOPOLOGY, CHLORIDES, MEMBRANES, MICE, CURRENTS, MICROSOMES, TRUNCATION.

Subject Categories : Medicine and Medical Research
      Anatomy and Physiology
      Pharmacology

Distribution Statement : APPROVED FOR PUBLIC RELEASE