Metabolism of 4'-thio-beta-D-arabinofuranosylcytosine in CEM cells.

Academic Article


  • Because of the excellent in vivo activity of 4'-thio-beta-D-arabinofuranosylcytosine (T-araC) against a variety of human solid tumors, we have studied its metabolism in CEM cells to determine how the biochemical pharmacology of this compound differs from that of beta-D-arabinofuranosylcytosine (araC). Although there were many quantitative differences in the metabolism of T-araC and araC, the basic mechanism of action of T-araC was similar to that of araC: it was phosphorylated to T-araC-5'-triphosphate (T-araCTP) and inhibited DNA synthesis. The major differences between these two compounds were: (i) T-araC was phosphorylated to active metabolites at 1% the rate of araC; (ii) T-araCTP was 10- to 20-fold more potent as an inhibitor of DNA synthesis than was the 5'-triphosphate of araC (araCTP); (iii) the half-life of T-araCTP was twice that of araCTP; (iv) the catalytic efficiency of T-araC with cytidine deaminase was 10% that of araC; and (v) the 5'-monophosphate of araC was a better substrate for deoxycytidine 5'-monophosphate deaminase than was the 5'-monophosphate of T-araC. Of these differences in the metabolism of these two compounds, we propose that the prolonged retention of T-araCTP is a major factor contributing to the activity of T-araC against solid tumors. The data in this study represent another example of how relatively small structural changes in nucleoside analogs can profoundly affect the biochemical activity.
  • Published In


  • Animals, Antineoplastic Agents, Arabinonucleosides, Biological Transport, Cell Division, Cytarabine, Cytidine Deaminase, DNA, Deamination, Deoxycytidine, Deoxycytidine Kinase, Deoxycytosine Nucleotides, Humans, Male, Mice, Mice, Nude, Thionucleosides, Tumor Cells, Cultured
  • Author List

  • Parker WB; Shaddix SC; Rose LM; Waud WR; Shewach DS; Tiwari KN; Secrist JA
  • Start Page

  • 1925
  • End Page

  • 1932
  • Volume

  • 60
  • Issue

  • 12