title: Comparative studies of the cytostatic action and metabolism of 5-azacytidine and 5,6-dihydro-5-azacytidine.
abstract: 5,6-Dihydro-5-azacytidine hydrochloride, a chemically stable, soluble analog of 5-azacytidine, has cytostatic activity against mouse leukemic L1210 cells grown in culture, but concentrations on the order of 10 micronM, 10-fold higher, than the parent drug, are necessary to inhibit cell growth. The addition of either cytidine or uridine protected against growth inhibition by 5-azacytidine and 5,6-dihydro-5-azacytidine, whereas thymidine potentiated the cytostatic action of both drugs. Deoxycytidine also enhanced the action of 5-azacytidine but had no effect with the reduced analog. Cell suspensions of L1210 cells were able to phosphorylate 5-azacytidine and, to a lesser extent, 5,6-dihydro-5-azacytidine. In cell-free extracts in the presence of ATP and Mg2+, both drugs were converted to nucleotides but at less than 5% the rate of cytidine. As a substrate for mouse kidney cytidine deaminase, the apparent Km value for 5,6-dihydro-5-azacytidine (33 micronM) is of the same order of magnitude as that for cytidine (37 micronM) but less than that for 5-azacytidine (2.1 X 10(3) micronM). The Vm for deamination of the reduced analog is one-tenth that for 5-azacytidine. 3,4,5,6-Tetrahydrouridine, a potent inhibitor of cytidine deaminase, is more effective in blocking deamination of 5-azacytidine than 5,6-dihydro-5-azacytidine.
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003562:Cytidine / Q000494:pharmacology; D003564:Cytidine Deaminase / Q000378:metabolism; D003841:Deoxycytidine / Q000494:pharmacology; D004357:Drug Synergism; D007700:Kinetics; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000378:metabolism; D010085:Oxidative Phosphorylation; D013767:Tetrahydrouridine / Q000494:pharmacology; D013936:Thymidine / Q000494:pharmacology; D014529:Uridine / Q000494:pharmacology
chemical_list: C013938:5,6-dihydro-5-azacytidine; D003841:Deoxycytidine; D013767:Tetrahydrouridine; D003562:Cytidine; D003564:Cytidine Deaminase; D001374:Azacitidine; D013936:Thymidine; D014529:Uridine