Biosynthesis of pyrimidine nucleotides in human leukemic cells.

Abstract

The biosynthetic pathways of pyrimidine nucleotides were studied in cells obtained from 10 patients with acute leukemia (AL), 3 with chronic myelocytic leukemia in blastic crisis (CML-crisis) and 4 with chronic myelocytic leukemia (CML) and from 8 controls. In the de novo pathway, synthesis of intermediates was analyzed with NaH[14C]O3 as a tracer. In the salvage pathway, the formation of nucleotides and free bases was studied with [3H]nucleosides (uridine, cytidine, thymidine, deoxyuridine, and deoxycytidine) tracers. Radioactivities of nucleotides were significantly lower in AL and CML-crisis cells than in CML and control cells in both pathways. These results suggest that the proliferative rate of cells was lower in the former cases than in the latter. Biosynthetic activities of nucleotides in the salvage pathway were about 100-300 times higher than those in the de novo pathway. It was calculated however, that as much as 70% of the amount of nucleic acids necessary for AL cells can be supplied by de novo biosynthesis, while in normal bone marrow cells the figure was about 30%. The greater part of pyrimidine biosynthesis can be carried out through the de novo pathway. In particular, AL cells with a longer generation time seemed to depend more on de novo biosynthesis than do normal bone marrow cells. This finding could be important in connection with the design of antileukemic agents.