Metabolism and chemotherapeutic activity of 9-beta-D-arabinofuranosyl-2-fluoroadenine against murine leukemia L1210 and evidence for its phosphorylation by deoxycytidine kinase.
The 2-fluoro derivative of 9-beta-D-arabinofuranosyladenine (2-F-ara-A) and its soluble 5'-formate and 5'-phosphate derivatives were therapeutically effective against the parent leukemia L1210 (L1210/0). 2-F-ara-A and 9-beta-D-arabinofuranosyladenine 5'-formate were inactive aginst a 1-beta-D-arabinofuranosylcytosine-resistant subline (L1210/ara-C) that was deficient in deoxycytidine kinase. Deoxycytidine prevented 2-F-ara-A-induced inhibition of proliferation of L1210/0 cells in culture and alleviated 2-F-ara-a inhibition of DNA synthesis. After treatment of mice with 9-beta-D-arabinofuranosyladenine 5'-formate, intracellular levels of the 5'-triphosphate of 9-beta-D-arabinofuranosylfluoroadenine in leukemia cells were more than 10 times higher in L1210/0 cells than in L1210/ara-C cells. Similar results were obtained in this line of leukemia cells from mice treated with the 5'-monophosphate of 9-beta-D-arabinofuranosyl-2-fluoroadenine. Thus, L1210/ara-C cells deficient in deoxycytidine kinase activity were also deficient in capacity to phosphorylate 2-F-ara-A. Kinase activity from L1210/0 cells for deoxycytidine and for 2-F-ara-A coeluted from calcium phosphate cellulose and from diethylaminoethyl cellulose columns and had similar mobility on gel electrophoresis. Deoxyadenosine kinase was clearly separated from deoxycytidine kinase. Deoxycytidine competed with 2-F-ara-A for phosphorylation by the partially purified enzyme from L1210 cells. These results indicate that 2-F-ara-A is phosphorylated to the 5'-monophosphate by deoxycytidine kinase of leukemia L1210 cells.
D000818:Animals; D002460:Cell Line; D002848:Chromatography, DEAE-Cellulose; D004247:DNA / Q000096:biosynthesis; D003842:Deoxycytidine Kinase / Q000302:isolation & purification / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D009154:Mutation; D010085:Oxidative Phosphorylation; D010770:Phosphotransferases / Q000378:metabolism*; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use
D004247:DNA; D010770:Phosphotransferases; D003842:Deoxycytidine Kinase; D014740:Vidarabine; C024352:fludarabine