Enhancement of the antileukemic activity of 5-aza-2'-deoxycytidine by cyclopentenyl cytosine in HL-60 leukemic cells.
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 microM 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.
Bouffard
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Département de Pharmacologie, Université de Montréal, Hópital Ste-Justine, Québec, Canada.
Momparler
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Momparler
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D000970:Antineoplastic Agents / Q000494:pharmacology*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D003562:Cytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003564:Cytidine Deaminase / Q000378:metabolism; D004273:DNA, Neoplasm / Q000096:biosynthesis; D000077209:Decitabine; D003845:Deoxycytosine Nucleotides / Q000378:metabolism; D004357:Drug Synergism; D006801:Humans; D007942:Leukemia, Experimental / Q000188:drug therapy* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D003845:Deoxycytosine Nucleotides; C024107:2'-deoxycytidine 5'-triphosphate; D003562:Cytidine; C045911:cyclopentenyl cytosine; D000077209:Decitabine; D003564:Cytidine Deaminase; D001374:Azacitidine