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The mechanism of action of 2′, 3′-dideoxythymidine analogues such as azidothymidine (AZT) and fluorothymidine (FLT) is thought to be chain termination and inhibition of reverse transcriptase by the triphosphate. However, little triphosphate is formed intracellularly relative to monophosphate and diphosphate. Azidothymidine and fluorothymidine are phosphorylated intracellularly by the thymidine salvage pathway and therefore must compete with thymine nucleotides for phosphorylation, which may limit the rate of phosphorylation. We have investigated the degree to which competition with thymidine limits the phosphorylation of azidothymidine and fluorothymidine. In this paper we show that inhibition of thymidylate synthase by 5-fluoro-2′-deoxyuridine monophosphate increases the phosphorylation of azidothymidine and fluorothymidine by reducing the pools of thymine nucleotides and therefore removing the competition. 5-fluoro-2′-deoxyuridine abolished the pools of TTP and dGTP and caused the appearance of dUTP in treated lymphocytes. Three times more triphosphate was formed in cells treated with 5-fluoro-2′-deoxyuridine. Ten times more fluorothymidine triphosphate than azidothymidine triphosphate was formed. The results suggest that while competition with intracellular thymine nucleotides does hinder the phosphorylation of AZT and FLT, the major limiting factor is their ability to act as substrates for the phosphorylating enzymes.

antiviral chemistry and chemotherapy

Comparison of the Intracellular Metabolism of 3′-Azido-3′-Deoxythymidine and 3′-Fluoro-3′-Deoxythymidine in Lymphocytes in the Presence of 5-Fluoro-2′-Deoxyuridine