Deoxycoformycin-induced response in chronic lymphocytic leukaemia: deoxyadenosine toxicity in non-replicating lymphocytes

Abstract

The occurrence of severe immunodeficiency disease in children with inherited adenosine deaminase deficiency, and reports of remission induction in T cell acute lymphoblastic leukemia with the adenosine deaminase inhibitor deoxycoformycin, prompted a study of the effects of deoxyadenosine (dAdo) on resting peripheral blood lymphocytes (PBL) and chronic lymphocytic leukemic (CLL) lymphocytes in short-term culture. In the presence of an inhibitor of adenosine deaminase, micromolar concentrations of dAdo caused elevation of dATP pools and in vitro lysis of non-dividing PBL and CLL lymphocytes. This death of nonreplicating cells indicates a mechanism of deoxyadenosine toxicity independent of DNA replication and ribonucleotide reductase inhibition. Similar changes occurred in vivo in a patient with advanced CLL who responded to treatment with deoxycoformycin, 0.1 mg/kg, days 1-5, with a fall in the WCC [white blood cell count] from 102.0 .times. 109/l to 6.8 .times. 109/l over 21 days. Therapeutic blockade of deoxyadenosine catabolism deserves further investigation in the treatment of lymphoproliferative disease and as a method of lympholytic immunosuppression.