Mechanism of action of 2',5-difluoro-1-arabinosyluracil

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Abstract
Results are described which demonstrate that the cytotoxic action of 2'',5-difluoro-1-arabinosyluracil (FFara-Ura) involves conversion to the corresponding 5''-phosphate, FFara-UMP, and subsequent inhibition of thymidylate synthetase. The evidence for this is as follows: S-49 mouse lymphoma cells lacking thymidine kinase are 120-fold more resistant to FFara-Ura; FFara-Ura markedly inhibits the incorporation of 2''-deoxyuridine into DNA wiht little or no effect on 2''-deoxythymidine incorporation: and FFara-Ura causes changes in deoxynucleoside triphosphate pool sizes, which are characteristic of specific inhibition of dTMP synthetase. Binding and spectroscopic studies demonstrate that FFara-UMP inactivates dTMP synthetase from Lactobacillus casei in a manner analogous to that described for 5-fluoro-2''-deoxyuridylate. FFara-Ura is not a substrate for the pyrimidine phosphorylases; the significance of this finding with regard to the possible chemotherapeutic utility of FFara-Ura is discussed.