Abstract
It was shown earlier that combined exposure of 5-fluorouracil and azidothymidine (AZT) causes synergistic cytotoxicity in various human tumour cell lines. The influence of AZT, a competitive inhibitor of thymidine kinase, on the metabolism of 5-fluorouracil was investigated in this study. Sequential combination treatment with 100 μM AZT and 5-fluorouracil decreased the 50% growth inhibitory concentration of 5-fluorouracil (IC50) from 5.98 μM in untreated control cells to 3.96 μM in cells pretreated with AZT. AZT did not alter the intracellular levels of 5-fluorouracil but significantly increased intracellular fluorodeoxyuridine levels as determined by high performance-liquid chromatography (1.97 ± 0.64 vs 3.69 ± 0.67 pmol/50 times 106 cells). Intracellular levels of fluorouridine increased slightly but not significantly from 6.43 ± 1.99 to 7.49 ± 1.54. However, fluorodeoxyuridine monophosphate dropped in cells preincubated with AZT from 8.34 ± 1.04 to 5.91 ± 5.91 pmol/50 times 106 cells as well as in the culture supernatant (4.37 ± 0.87 vs. 2 44 ± 0.43 pmol/50 times 106 cells). These results indicate that the inhibition of thymidine kinase by AZT might increase intracellular levels of fluorodeoxyuridine and fluorouridine, thus causing more pronounced cytotoxic effects.
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