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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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.[1]


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