86 Reduction of Ara-c Cytotoxicity in Hl 60 Cells by Addition of Deoxycytidine, Cytidine or Increased Levels of Cytidine Deaminase

Abstract

Ara-C closely resembles the natural nucleosides cytidine and deoxycytidine. The deamination of the three compounds are catalyzed by the enzyme cytidine deaminase (CDD). Tetrahydrouridine (THU), an inhibitor of the enzyme, was found to increase the cytoxicity of Ara-C in 3 days suspension cultures of HL 60 cells. THU alone was found without any effect. The activity of CDD in extracts of HL 60 cells could be induced to increase, when the cells were exposed to the differentiation inducer 1,25 dihydroxy D3. This was not seen with retinoic acid another inducer of differentiation. Corresponding to these findings, the cytotoxicity of Ara-C was found to be antagonized by 1,25 dihydroxy D3, while retinoic acid increased the cytotoxicity of Ara-C, supporting the assumption, that CDD activity is relevant for the Ara-C effect.Cytidine added together with Ara-C reduced the Ara-C erfect. However, the combination of cytidine and uridine was able to neutralize the effect of cytidine on the Ara-C effect, probably by competetive inhibition of uridine cytidine kinase.Similarly, deoxycytidine could neutralize the Ara-C effect, which then could be restored by the addition of THU. An explanation for this could be a higher degree of Ara-C phosphorylation compared to deoxycytidine phosphorylation, both catalyzed by deoxycytidine kinase, which has been observed in acute myeloid leukemia cells.

DOI: 10.1203/00006450-198807000-00110

Cite this paper

@article{Mejer198886RO, title={86 Reduction of Ara-c Cytotoxicity in Hl 60 Cells by Addition of Deoxycytidine, Cytidine or Increased Levels of Cytidine Deaminase}, author={Johannes Mejer and B\orge t Mortensen}, journal={Pediatric Research}, year={1988}, volume={24}, pages={125-125} }