Altered 5-azacytidine metabolism following 3-deazauridine treatment of L5178Y and human myeloblasts.
The effect of 3-deazauridine pretreatment on 5-azacytidine metabolism was studied in suspension cultures of L5178Y murine leukemia. A 3-hr exposure to 2 microM 3-deazauridine followed by a 1-hr exposure to 5 microM [14C]-5-azacytidine resulted in a 2-fold increase in total intracellular 5-azacytidine accumulation compared to untreated controls. Under the same conditions, incorporation of 5-azacytidine into the acid precipitable fraction of L5178Y cells was increased 3-fold. Incorporation of 5-azacytidine into RNA increased 85% following 3-deazauridine pretreatment, but 5-azacytidine incorporation into DNA did not change significantly. In cells pretreated with 3-deazauridine, there was an 80% reduction of intracellular cytidine triphosphate, the natural feedback inhibitor of uridine-cytidine kinase, the rate-limiting enzyme in the phosphorylation of 5-azacytidine. Intracellular levels of 5-azacytidine triphosphate, the presumed lethal metabolite of 5-azacytidine, increased from 28.8 pmol/10(6) cells in control cells to 56.4 pmol/10(6) cells following 3-deazauridine treatment. The sequence of 3-deazauridine followed by 5-azacytidine demonstrated synergistic cell killing when measured by an in vitro soft-agar cloning assay. Similar biochemical alterations were also seen in human leukemic myeloblasts. It appears that 3-deazauridine-induced alterations in 5-azacytidine metabolism may account for the enhanced cytotoxicity of this drug sequence.
D015092:3-Deazauridine / Q000627:therapeutic use*; D000818:Animals; D001374:Azacitidine / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D002999:Clone Cells / Q000473:pathology; D004273:DNA, Neoplasm / Q000378:metabolism; D006801:Humans; D007940:Leukemia L5178 / Q000188:drug therapy / Q000378:metabolism*; D007942:Leukemia, Experimental / Q000378:metabolism* / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D012265:Ribonucleotides / Q000378:metabolism; D014529:Uridine / Q000031:analogs & derivatives*
D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D012265:Ribonucleotides; D015092:3-Deazauridine; D001374:Azacitidine; D014529:Uridine