Incorporation of a potent antileukemic agent, 5-aza-2'-deoxycytidine, into DNA of cells from leukemic mice.
5-Aza-2'-deoxycytidine administered at a daily dose of 1.5 mg/kg increased the life-span of P388 leukemia-bearing BALB/c X DBA/2 F1 mice by 5 times and that of second generation lymphoma-bearing AKR mice by 2.5 times. Higher doses (total dose, 20 mg/kg) led to favorable results when administered in two portions on Days 4 and 5 after the s.c. inoculation of leukemic cells. The same total dose given on 5 consecutive days was toxic. The lethal dose that killed 50% of the animals was 190 mg/kg. The drug was also effective in L1210 leukemia. 5-Aza-2'-deoxycytidine inhibited the phosphorylation of 2'-deoxycytidine in the acid-soluble pool of cells from leukemic AKR mice as well as its incorporation into DNA. In vitro the inhibition of the uptake of 2'-deoxycytidine into cells from leukemic mice by 5-aza-2-deoxycytidine had a competitive character (Ki, 8 X 10(-5) M). Although 5-aza-2'-deoxy[4-14C]cytidine of low-specific activity was not detected in DNA isolated from the lives of leukemic mice, the same tritium-labeled drug of high-specific radioactivity was selectively localized in the nuclei of leukemic cells as revealed by autoradiography. The incorporation of [3H]-5-aza-2'-deoxycytidine into DNA of cells from leukemic mice was confirmed by the chromatographic separation of DNA on a column of kieselguhr coated with methylated albumin.
D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D003841:Deoxycytidine / Q000378:metabolism; D004848:Epithelium / Q000648:ultrastructure; D005260:Female; D007939:Leukemia L1210 / Q000188:drug therapy / Q000378:metabolism; D007942:Leukemia, Experimental / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008198:Lymph Nodes / Q000378:metabolism; D051379:Mice; D008806:Mice, Inbred AKR; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D011230:Precancerous Conditions / Q000648:ultrastructure*; D013936:Thymidine / Q000378:metabolism
D003841:Deoxycytidine; D001374:Azacitidine; D013936:Thymidine