Effect of uridine on response of 5-azacytidine-resistant human leukemic cells to inhibitors of de novo pyrimidine synthesis.
A uridine-cytidine kinase-deficient human promyelocytic leukemic subline (HL-60-5-aza-Cyd) has been isolated which is highly resistant to the antileukemic agent 5-azacytidine. Resistant cells exposed to 10(-5) M 5-azacytidine for 2 hr exhibit a marked reduction in both the total intracellular accumulation of 5-azacytidine (11.9 versus 156.0 pmol/10(6) cells) as well as its incorporation into RNA (3.1 versus 43.4 pmol/micrograms D-ribose) compared to the parent line. These biochemical changes are associated with nearly a 100-fold decrease in sensitivity to the growth inhibitory effects of 5-azacytidine (concentration of drug associated with a 50% reduction in cell growth, 3.5 X 10(-5) versus 5.0 X 10(-7) M). 5-Azacytidine-resistant cells exhibit cross-resistance to 3-deazauridine, 6-azauridine, and 5-fluorouridine, but not to 1-beta-D-arabinofuranosylcytosine, 2'-deoxyazacytidine, or 5-aza-1-beta-D-arabinofuranosylcytosine. Coadministration of 50 microM uridine prevented depletion of pyrimidine nucleoside triphosphates and inhibition of colony formation of HL-60 cells exposed to 3 mM N-(phosphonacetyl)-L-aspartate) or 5 X 10(-6) M pyrazofurin but was not capable of protecting HL-60-5-azacytidine under the same conditions. This uridine concentration was also able to restore control colony formation to normal human bone marrow progenitor cells (granulocyte-macrophage colony-forming units) exposed to de novo pyrimidine biosynthetic blockade. These in vitro studies suggest that 5-azacytidine resistant cells lacking the pyrimidine salvage pathway enzyme uridine-cytidine kinase may be selectively vulnerable to a regimen using pyrimidine antagonists administered in conjunction with the naturally occurring nucleoside uridine.
D001374:Azacitidine / Q000378:metabolism / Q000633:toxicity*; D002460:Cell Line; D004351:Drug Resistance; D006801:Humans; D007700:Kinetics; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D011742:Pyrimidine Nucleotides / Q000378:metabolism; D011743:Pyrimidines / Q000096:biosynthesis / Q000633:toxicity*; D013329:Structure-Activity Relationship; D014529:Uridine / Q000378:metabolism / Q000494:pharmacology*
D011742:Pyrimidine Nucleotides; D011743:Pyrimidines; D001374:Azacitidine; D014529:Uridine