Reversal of deamination-related cytotoxicity of 5-methyl-2'-deoxycytidine by tetrahydrouridine in human leukemia cells.
The present experiments were conducted to test the effects of the potent cytidine deaminase inhibitor tetrahydrouridine (THU) on the metabolism and cytotoxicity of 5-methyl-2'-deoxycytidine (5-Med-Cyd) in several human leukemia cell lines in vitro. It was observed that 5-Med-Cyd exerts its effects via deamination to thymidine, which is particularly toxic to human promyelocytic (HL-60) and T-cell (JM) leukemia cell lines in vitro. The deamination and the cytotoxicity of 5-Med-Cyd were effectively hindered by 10(-3) M THU in 3-day cultures of HL-60 cells. Although the catabolism of [14C]5-Med-Cyd in the HL-60 cell cultures was blocked by THU, no radioactive 5-Med-Cyd was incorporated into DNA. The cytotoxicity and DNA incorporation of fluorodeoxycytidine are enhanced by THU. Unlike that compound 5-Med-Cyd resembled more bromodeoxycytidine and iododeoxycytidine; THU decreases the toxicity of both of these deoxycytidine analogues.
D001711:Biotransformation; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D006801:Humans; D007700:Kinetics; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D013767:Tetrahydrouridine / Q000494:pharmacology*; D014529:Uridine / Q000031:analogs & derivatives*
D003841:Deoxycytidine; D013767:Tetrahydrouridine; C016569:5-methyldeoxycytidine; D014529:Uridine