Deoxycoformycin-induced response in chronic lymphocytic leukaemia: deoxyadenosine toxicity in non-replicating lymphocytes.
The occurrence of severe immunodeficiency disease in children with inherited adenosine deaminase deficiency, and reports of remission induction in T-cell acute lymphoblastic leukaemia with the adenosine deaminase inhibitor deoxycoformycin, prompted a study of the effects of deoxyadenosine on resting peripheral blood lymphocytes (PBL) and chronic lymphocytic leukaemic (CLL) lymphocytes in short-term culture. In the presence of an inhibitor of adenosine deaminase, micromolar concentrations of dAdo caused elevation of deoxyadenosine-5'-triphosphate (dATP) pools and in vitro lysis of non-dividing PBL and CLL lymphocytes. This death of non-replicating 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 from 102.0 x 10(9)/1 to 6.8 x 10(9)/l over 21 d. Therapeutic blockade of deoxyadenosine catabolism deserves further investigation both in the treatment of lymphoproliferative disease and as a method lympholytic immunosuppression.
D058892:Adenosine Deaminase Inhibitors; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003070:Coformycin / Q000031:analogs & derivatives / Q000627:therapeutic use*; D004261:DNA Replication; D003838:Deoxyadenine Nucleotides / Q000097:blood; D003839:Deoxyadenosines / Q000494:pharmacology*; D006801:Humans; D007945:Leukemia, Lymphoid / Q000097:blood / Q000188:drug therapy*; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015649:Pentostatin; D012263:Ribonucleosides / Q000627:therapeutic use*
D058892:Adenosine Deaminase Inhibitors; D003838:Deoxyadenine Nucleotides; D003839:Deoxyadenosines; D012263:Ribonucleosides; D003070:Coformycin; D015649:Pentostatin; C026600:2'-deoxyadenosine triphosphate