Grant: Operating Grant

A number of nucleoside analogs have anticancer activities and are either in current clinical use or in various stages of preclinical evaluation. Since the pharmacological targets of nucleoside drugs are intracellular, penetration of cells by passage across plasma membranes and, subsequently, across intracellular membrane barriers are critical determinants of drug activities and host toxicities. We have achieved the molecular cloning and structural identification of human and rodent members of two new protein families involved in nucleoside transport across cell membranes: the equilibrative bidirectional (ENT) family and the concentrative sodium/nucleoside cotransporter (CNT) family. The research projects described in this application will study the relationships between molecular structure and the ability of ENT proteins to move molecules across plasma and intracellular membranes. The goal of this research is to increase our understanding of mechanisms by which cells utilize nucleosides and to use knowledge of these mechanisms to enhance the therapeutic selectivity of nucleoside drugs.