Mechanism of action of 2',5-difluoro-1-arabinosyluracil.
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: (a) cells lacking thymidine kinase are 120-fold more resistant to FFara-Ura; (b) FFara-Ura markedly inhibits the incorporation of 2'-deoxyuridine (dUrd) into DNA with little or no effect on 2'-deoxythymidine (dThd) incorporation; (c) 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 FdUMP. Furthermore, 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.
D000818:Animals; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives* / Q000494:pharmacology; D001088:Arabinonucleotides / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002850:Chromatography, Gel; D003856:Deoxyuracil Nucleotides / Q000494:pharmacology*; D005468:Fluorodeoxyuridylate / Q000031:analogs & derivatives / Q000494:pharmacology*; D008223:Lymphoma / Q000473:pathology; D051379:Mice; D013056:Spectrophotometry, Ultraviolet; D013940:Thymidylate Synthase / Q000378:metabolism; D014529:Uridine / Q000031:analogs & derivatives*
D001088:Arabinonucleotides; D003856:Deoxyuracil Nucleotides; D005468:Fluorodeoxyuridylate; D001086:Arabinofuranosyluracil; C038723:2',5-difluoro-2'-deoxy-1-arabinosyluracil; C038724:2',5-difluoro-1-arabinosyluridine monophosphate; D013940:Thymidylate Synthase; D014529:Uridine