Abstract
3′-azido-3′-deoxythymidine (AZT) affected deoxynucleotide metabolism in the human cell lines, HL-60, H-9, K-562, and RPMI-8402. The respective ED 50 values of AZT for growth were 670, 110, 100, and 20 μM. When cells were exposed to 200 μM AZT, dTTP and dGTP decreased and dCTP increased. The increase in dCTP is in contrast to previous reports [Furman, et al., Proc. Nat. Acad. Sci. USA (1986) 83, 8333–8337]. Recovery of the dNTP pools was generally seen at 8 to 24 hrs. Pools of dCTP were the last to recover. Changes in the dNTP pools induced by AZT are consistant with a decline in dTTP affecting the allosteric regulation of ribonucleotide reductase.
After 24 hrs in 200 μM AZT, AZT-5′-monophosphate reached 2800, 4700, 15700, and 12800 μM in the HL-60, H-9, K-562 and RPMI-8402 cells, respectively. The corresponding AZT-5′-triphosphate levels were 25, 15, 60, and 45 μM. Thymidine and deoxyuridine in the media increased after treatment of the cells with AZT. All cell lines treated with AZT secreted AZT-5′-monophosphate.
Radiolabeled thymidine was used to study thymidine anabolism in cells treated with 20 μM AZT for 4 hrs. Pools of dTMP increased 3, 2, 4, and 7 fold in the respective cell lines. These data support the idea that thymidylate kinase is inhibited by AZT-5′-monophosphate (Furman et al., ibid) and suggest that cells in culture are able to overcome the effects of AZT on deoxynucleotide metabolism by expansion of their dTMP pool.
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Frlck, L., Nelson, D., St. Clair, M. et al. 36 DEOXYNUCLEOTIDE METABOLISM IN CULTURED CELLS EXPOSED TO 3′-DEOXY-3′-AZIDOTHYMIDINE. Pediatr Res 24, 117 (1988). https://doi.org/10.1203/00006450-198807000-00060
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DOI: https://doi.org/10.1203/00006450-198807000-00060