ROLE OF DEOXYCYTIDINE KINASE IN THE INHIBITORY ACTIVITY OF 5-SUBSTITUTED 2'-DEOXYCYTIDINES AND CYTOSINE ARABINOSIDES ON TUMOR-CELL GROWTH

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  • 1 January 1983
    • journal article
    • research article
    • Vol. 23  (1) , 175-181
Abstract
A number of 5-substituted derivatives of dCyd [deoxycytidine] and 1-.beta.-D-arabinofuranosylcytosine (araC) were evaluated for their inhibitory effects on the growth of 3 murine leukemia cell lines (L1210/0, L1210/BdUrd and L1210/araC). The L1210/BdUrd and L1210/araC cell lines were selected from the parental L1210/0 cell line by their ability to grow at high concentrations of 5-bromo-2''-deoxyuridine and araC, respectively. The L1210/BdUrd cell line was deficient in dThd [deoxythymidine] kinase activity; the L1210/araC cell was deficient in dCyd kinase activity. The most effective inhibitors of L1210/0 cell proliferation were 5-fluro-2''-dCyd, araC and 5-fluoro-araC. Their 50% inhibitory dose fell within the 0.001-0.015 .mu.g/ml range. The 5-substituted araC analogs were much less inhibitory for L1210/araC cells, but equally inhibitory for L1210/BdUrd as for the parental L1210/0 cell line. The role of dCyd kinase in the antitumor activity of the dCyd and araC analogs was further assessed by kinetic studies with dCyd kinase extracted from L1210/0 cells. All dCyd and araC analogs caused a competitive inhibition of dCyd kinase, the most potent inhibitor being 5-fluro-2''-dCyd (Ki/Km value 0.24). The Km of dCyd kinase from L1210/0 cells for dCyd was 23.1 .mu.M as compared with 50 .mu.M for araC. These values were increased to 53 and 182 .mu.M, respectively, for the dCyd kinase isolated from L1210/araC cells.