INHIBITION OF THYMIDINE TRANSPORT BY 3'-AZIDO-3'-DEOXYTHYMIDINE AND ITS METABOLITES

3'-Azido-3'-deoxythymidine (AZT) competitively inhibited the transport of thymidine (K(m) = 0.23 mM) into human erythrocytes with a K(i) of 1.0 mM at 37-degrees-C. The principal human metabolite of AZT in plasm a, the 5'-glucuronide (GAZT), was a weak inhibitor of the nucleoside t ransporter (<20% inhibition of the influx of 1.0 muM thymidine by 10 m uM GAZT). The minor AZT metabolite, 3'-amino-3'-deoxythymidine (AMT), competitively inhibited thymidine transport with a K(i) of 9.1 mM. The influx of AMT into human erythrocytes was found to be a saturable pro cess (K(m) = 12 mM) that was largely inhibited by dilazep, thus indica ting that AMT influx occurs via the nucleoside transporter. High extra cellular concentrations of AZT may contribute to the synergistic cytot oxicity of AZT plus either 5-fluorouracil or methotrexate by inhibitin g thymidine transport into cancer cells whose de novo biosynthesis of dTMP is impaired pharmacologically or by inhibiting efflux of 2'-deoxy -5-fluorouridine and/or 2'-deoxyuridine from these cells.