Comparison of the Mechanism of Toxicity of 3′-Azido-3′-Deoxythymidine and 3′-Fluoro-3′-Deoxythymidine in Human Lymphocytes

Abstract

The thymidine analogue 3′-azido-3′-deoxythymidine (AZT), whilst a useful drug for the treatment of acquired immunodeficiency syndrome, produces toxic side-effects which can be severe and can interfere with therapy. The toxic mechanism of AZT is unknown. We have investigated the relationship between the phosphorylation and effect on natural dNTP pools of 3′-azido-3′-deoxythymidine and the closely related 3′-fluoro-3′-deoxythymidine and their toxicity in human lymphocytes. We attempted to reduce the toxicity by co-administration of natural nucleosides. The toxicity of 3′-fluoro-3′-deoxythymidine could be reduced with thymidine or deoxyuridine five- and 10-fold, respectively. The toxicity of 3′-azido-3′-deoxythymidine could be reduced twofold with cytidine or uridine but was increased by all other nucleosides, including thymidine. Neither analogue caused significant changes in the dNTP pools at cytotoxic concentrations; the effect of the nucleosides in reducing toxicity was not owing to replacement of a depleted dNTP. Thymidine reduced the phosphorylation of 3′-azido-3′-deoxythymidine and 3′-fluoro-3′-deoxythymidine 6 and 17 times, respectively. 3′-azido-3′-deoxythymidine and 3′-fluoro-3′-deoxythymidine appear to have different mechanisms of toxicity. The toxic mechanism of 3′-fluoro-3′-deoxythymidine is probably inhibition of cellular DNA synthesis by the triphosphate. The toxicity of 3′-azido-3′-deoxythymidine in lymphocytes does not appear to be directly related to the amounts of the phosphorylated forms. The mechanism may be interference with RNA metabolism or precursors, perhaps by the nucleoside.