Inhibitory Effect of 2′,2′-Difluorodeoxycytidine on Cytidine 5′-Triphosphate Synthetase
2′,2′-Difluorodeoxycytidine (dFdC) is a deoxycytidine analog which induces inhibition of DNA synthesis and cell death . dFdC is intracellularly phosphorylated by deoxycytidine kinase and the 5′-triphosphate (dFdCTP) accumulates as the main metabolite. Elimination of intracellular dFdCTP is biphasic, an observation also reported for circulating leukemia cells . dFdC was shown to act as an inhibitor of several cellular enzyme systems: ribonucleotide reductase , deoxycytidylate deaminase , and DNA polymerases . Investigations in a number of cell lines demonstrated a depletion of cellular CTP pools after exposure of cells to dFdC. The present study investigates this CTP depletion in CHO cells and provides evidence for the hypothesis that high concentrations of dFdCTP are inhibitory to CTP synthetase. It is further hypothesized that a relation may exist between dFdC-mediated depletion of cellular CTP pools and inhibition of RNA synthesis.
KeywordsRibonucleotide Reductase Ehrlich Ascites Tumor Cell Deoxycytidine Kinase High Cellular Concen Deoxycytidylate Deaminase
Unable to display preview. Download preview PDF.
- 2.Grunewald R, Kantarjian H, Du M, Foucher K, Tarassoff P, Plunkett W (1992) Gemcitabine in leukemia: a phase I clinical, plasma, and cellular pharmacology study. J Clin Oncol (in press)Google Scholar