METABOLISM AND EFFECTS OF "5-(BETA-D-RIBOFURANOSYL)ISOCYTOSINE IN P815 CELLS

  • 1 January 1979
    • journal article
    • research article
    • Vol. 39  (3) , 720-728
Abstract
5-(.beta.-D-Ribofuranosyl)isocytosine (Cyd), a C-nucleoside, was active against P815 leukemia in mice. In P815 cells treated with [2-14C]Cyd, radioactivity was detected in nucleotide fractions and in RNA and DNA. Degradation to nucleosides of the labeled triphosphate nucleotide fraction and of RNA showed that the radioactivity present was chromatographically identical to Cyd. Half-saturation concentrations for the incorporation of [2-14C]Cyd into the triphosphate nucleotide fraction and into RNA and DNA were 370, 280 and 94 .mu.g/ml, respectively, which were > 100-fold higher than those for 3H-cytidine. The incorporation of Cyd was competitively inhibited by cytidine. Phosphorylation and incorporation of Cyd into nucleic acids of P815 cells and of a P815 subline resistant to 1-.beta.-D-arabinofuranosylcytosine were about 2- to 20-fold higher than in P815 sublines resistant to Cyd or to both 5-azacytidine and 1-.beta.-D-arabinofuranosylcytosine. The phosphorylation of Cyd and possibly its incorporation into nucleic acids are essential for therapeutic activity in P815 leukemias. In vitro metabolic studies also suggest that Cyd and 5-azacytidine are cross-resistant and that P815 cells resistant to Cyd are collaterally sensitive to 1-.beta.-D-arabinofuranosylcytosine. These predictions were confirmed by therapeutic experiments carried out in mice bearing P815 leukemias.