Student Theses and Dissertations

Date of Award

2003

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Simon Laboratory

Abstract

Multi-drug resistance or MDR is a major impediment to the successful administration of chemotherapy. Broadly defined, the term MDR applies to any mechanism the cell uses to counter the effects of chemotherapeutic agents, protecting the cell at once against the toxicity of many, structurally dissimilar compounds. There are several routes to MDR for a cell, and they include everything from decreasing intracellular drug concentrations to increasing rates drug metabolism. The study presented here focuses on the role of drug transporters in conferring drug resistance. MDR transporters are traditionally thought to extrude cytotoxins from the cell at the plasma membrane, and they thereby serve as a permeability barrier for drug entry into the cell. Several MDR transporters have been cloned to date, but this study focuses on the functional characterization of one of these proteins, the human multidrug resistance protein or MRP 1. MRP1, like other members of the MDR transporter family, is thought to be expressed at the plasma membrane and decrease the intracellular accumulation of many different chemotherapeutic compounds. Unlike other MDR transporters, however, MRP 1 is thought to require reduced glutathione to enable the transport of most of its chemotherapeutic substrates. Using a fluourescently tagged MRP1 protein, we make two novel demonstrations: that MRP1 can contribute to a drug resistance phenotype from intracellular membranes, as well as from the plasma membrane; and two, that MRP1 is active in the absence of glutathione.

Comments

A thesis presented to the faculty of The Rockefeller University in partial fulfillment of the requirements for the Degree of Doctor of Philosophy

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