Studies on the biochemical sequelae of therapy in Thy-acute lymphoblastic leukaemia with the adenosine deaminase inhibitor 2' deoxycoformycin.
In four patients with Thy-acute lymphoblastic leukaemia changes in blast cell deoxynucleoside triphosphate concentrations and, in three, changes in blast cell S-adenosyl homocysteine hydrolase activity were measured during treatment with 2' deoxycoformycin, a potent inhibitor of adenosine deaminase. These studies were aimed at identifying the molecular basis of cell killing by this drug. In three patients an increase in blast deoxyadenosine triphosphate (dATP) concentration occurred which was found to be temporally related to cell killing and was accompanied by decreased concentrations of the other three deoxyribonucleoside triphosphates. In the one patient with Thy-ALL who responded poorly to treatment, the increase in dATP concentration was delayed and was not accompanied by a fall in the concentrations of the other deoxyribonucleoside triphosphates. Progressive inactivation of blast cell S-adenosyl homocysteine hydrolase was found to occur in the three patients tested but was maximal only after a substantial reduction of peripheral blast cell count. These results show that 2' deoxycoformycin has a potent cytoreductive effect in Thy-ALL and suggest that the molecular basis of this toxicity is related both to the intracellular accumulation of dATP with inhibition of ribonucleotide reductase. Inactivation of S-adenosyl homocysteine hydrolase may be of importance as an additional mechanism.
D000243:Adenosine Deaminase / Q000378:metabolism; D043383:Adenosylhomocysteinase; D000293:Adolescent; D000328:Adult; D001853:Bone Marrow / Q000378:metabolism; D003070:Coformycin / Q000031:analogs & derivatives / Q000627:therapeutic use*; D003838:Deoxyadenine Nucleotides / Q000097:blood; D003845:Deoxycytosine Nucleotides / Q000378:metabolism; D003848:Deoxyguanine Nucleotides / Q000378:metabolism; D006801:Humans; D006867:Hydrolases / Q000378:metabolism; D007945:Leukemia, Lymphoid / Q000188:drug therapy* / Q000378:metabolism; D007958:Leukocyte Count; D008297:Male; D015649:Pentostatin; D012263:Ribonucleosides / Q000627:therapeutic use*; D013942:Thymine Nucleotides / Q000378:metabolism
D003838:Deoxyadenine Nucleotides; D003845:Deoxycytosine Nucleotides; D003848:Deoxyguanine Nucleotides; D012263:Ribonucleosides; D013942:Thymine Nucleotides; D003070:Coformycin; C024107:2'-deoxycytidine 5'-triphosphate; D015649:Pentostatin; C029603:deoxyguanosine triphosphate; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000243:Adenosine Deaminase; C026600:2'-deoxyadenosine triphosphate; C024157:thymidine 5'-triphosphate