Inhibition of thymidine transport by 3'-azido-3'-deoxythymidine and its metabolites.

Abstract:

:3'-Azido-3'-deoxythymidine (AZT) competitively inhibited the transport of thymidine (Km = 0.23 mM) into human erythrocytes with a Ki of 1.0 mM at 37 degrees C. The principal human metabolite of AZT in plasma, the 5'-glucuronide (GAZT), was a weak inhibitor of the nucleoside transporter (< 20% inhibition of the influx of 1.0 microM thymidine by 10 microM GAZT). The minor AZT metabolite, 3'-amino-3'-deoxythymidine (AMT), competitively inhibited thymidine transport with a Ki of 9.1 mM. The influx of AMT into human erythrocytes was found to be a saturable process (Km = 12 mM) that was largely inhibited by dilazep, thus indicating that AMT influx occurs via the nucleoside transporter. High extracellular concentrations of AZT may contribute to the synergistic cytotoxicity of AZT plus either 5-fluorouracil or methotrexate by inhibiting 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.

journal_name

Oncol Res

journal_title

Oncology research

authors

Zimmerman TP,Domin BA,Mahony WB

subject

Has Abstract

pub_date

1993-01-01 00:00:00

pages

483-7

issue

12

eissn

0965-0407

issn

1555-3906

journal_volume

5

pub_type

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