Enhancement of the antileukemic activity of 5-aza-2′-deoxycytidine by cyclopentenyl cytosine in HL-60 leukemic cells

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Abstract
We have Investigated the capacity of cyclopentenyl cytosine (CPE-C), a potent Inhibitor of CTP synthetase, to modulate the antineoplastic activity of 5-aza-2′-deoxycytidine (DAC) on HL-60 myeloid leukemic cells. The combination of CPE-C and DAC produced an additive effect on the growth inhibition of the cells following a treatment of 48–96 h. Cytotoxicity experiments measured by the cloning of cells in soft agar following 24 and 48 h exposures produced a more than additive effect when the drugs were used in combination. Evaluation of the effect of CPE-C and DAC on the Induction of differentiation of HL-60 cells following a 48 h treatment revealed that the combination of the drugs produced a more than additive effect than when the drugs were used alone. Measurement of the intracellular pool of deoxycytidine triphosphate (dCTP) showed that a 6 h exposure to 0.05 and 0.1 μM of CPE-C reduced the pool by 60 and 88%, respectively. The decrease in the dCTP pool was correlated with a higher incorporation of radioactive DAC into DNA. The deamination of CPE-C to cyclopentenyl uridine by cytidine deaminase was investigated with the purified enzyme from human placenta. We report here that CPE-C is a very poor substrate for cytidine deaminase as compared with cytidine. These studies suggest that CPE-C could be used as a biochemical modulator to increase the antileukemic action of DAC.

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