Effects of 2'-deoxycoformycin on the metabolism of purines and the survival of malignant cells in a patient with T-cell leukemia

Abstract

The in vitro effects of deoxyadenosine and an adenosine deaminase inhibitor, deoxycoformycin, on the synthesis of DNA and the metabolism of purines were investigated in human leukemic T-cells. In the presence of 10 microM deoxycoformycin, the synthesis of DNA was completely inhibited by concentrations of deoxyadenosine of 10 microM or greater. In contrast, the synthesis of DNA in normal bone marrow cells was not inhibited in the presence of up to 20 microM deoxycoformycin and up to 10 microM deoxyadenosine. Following incubation of leukemia T-cells with deoxycoformycin and deoxyadenosine, there was a significant rise in the concentration of deoxyadenosine 5'-triphosphate which was accompanied by reductions in the concentrations of adenosine 5'-triphosphate and guanosine 5'-triphosphate, as revealed by high-pressure liquid chromatographic analysis. The effects of deoxycoformycin on T-cell leukemia were examined in vivo. A patient with acute T-cell leukemia in the terminal stage received five daily injections of 250 micrograms of deoxycoformycin per kg. Among the noted changes, most prominent was the drop in the leukocyte count. Initially, the cell count rose from 7,200 cells/microliters on Day 1 to 120,000 cells/microliters on Day 3. On Day 5, the cell count began to decline and reached a nadir of 600 cells/microliter on Day 10. The leukocyte count remained below 1,000 cells/microliter through Day 12. The reduction in cell count was preceded by a decline in the incorporation of [3H]thymidine in the cells, which dropped to negligible amount by Day 7. The other prominent change was a decrease in adenosine deaminase activity in both red cells and leukemic cells. Adenosine deaminase activity of red cells dropped to 5% on Day 4, and that of leukemic cells dropped to 59% on Day 5. In addition, there were considerable alterations in the concentrations of purine metabolites which were characterized by a progressive reduction in the concentrations of total purine metabolites, especially adenosine 5'-triphosphate, and a transient rise in the concentrations of deoxyadenosine 5'-triphosphate, adenosine 5'-monophosphate, and adenosine 5-diphosphate. These findings suggest that treatment with deoxycoformycin may be of therapeutic value for T-cell leukemia. It may provide opportunities for studying the purine metabolism in T-leukemic cells which could lead to better approaches to treatment.