Effect of uracil arabinoside on metabolism and cytotoxicity of cytosine arabinoside in L5178Y murine leukemia.
Pretreatment of L5178Y murine leukemia cells with uracil arabinoside (ara-U) enhances the cytotoxicity of cytosine arabinoside (ara-C). This effect is mediated by the cytostatic effect of ara-U, which causes a delay of cell progression through S-phase. Consequently, the specific activity of enzymes that peak during S-phase increases, and deoxycytidine kinase increases 3.6-fold over untreated controls. This allows enhanced anabolism of ara-C to nucleotides, as well as increased incorporation into DNA with ultimate synergistic cytotoxicity. It is postulated that the systemic metabolism of high-dose ara-C to sustained high levels of ara-U in patients with acute leukemia may enhance the activity of subsequent doses of ara-C, and thus contribute to a means for pharmacologic self-potentiation, contributing to the unique therapeutic activity of high-dose ara-C.
D000818:Animals; D001086:Arabinofuranosyluracil / Q000097:blood / Q000494:pharmacology*; D003561:Cytarabine / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004347:Drug Interactions; D006801:Humans; D007700:Kinetics; D007940:Leukemia L5178 / Q000097:blood / Q000188:drug therapy*; D007942:Leukemia, Experimental / Q000188:drug therapy*; D014410:Tumor Stem Cell Assay; D014529:Uridine / Q000031:analogs & derivatives*
D003561:Cytarabine; D001086:Arabinofuranosyluracil; D014529:Uridine