Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism of the depletion of ATP, recorded in the erythrocytes of adenosine deaminase-deficient children and of leukemia patients treated with deoxycoformycin, was investigated in normal human erythrocytes treated with this inhibitor of adenosine deaminase. Deoxyadenosine, which accumulates in both clinical conditions, provoked a dose-dependent accumulation of dATP, depletion of ATP, and increases in the production of inosine plus hypoxanthine. Concomitantly, there was an increase of AMP and IMP, but not of adenosine, indicating that catabolism proceeded by way of AMP deaminase. A series of nucleoside analogues (9-beta-D-arabinofuranosyladenine, N6-methyladenosine, 6-methylmercaptopurine ribonucleoside, tubercidin, ribavirin, and N-1-ribosyl-5-aminoimidazole-4-carboxamide riboside) also stimulated adenine nucleotide catabolism and increased AMP and IMP to various extents. The effects of deoxyadenosine and of the nucleoside analogues were prevented by 5'-iodotubercidin, an inhibitor of adenosine kinase. Strikingly, they were reversed if the inhibitor was added after the accumulation of nucleotide analogues and initiation of adenine nucleotide catabolism. Further analyses revealed linear relationships between the rate of phosphorylation of deoxyadenosine and nucleoside analogues and the increase in AMP and between the elevation of the latter above a threshold concentration of 10 microM and the rate of adenine nucleotide catabolism. Kinetic studies with purified erythrocytic AMP deaminase, at physiological concentrations of its effectors, showed that the enzyme is nearly inactive up to 10 microM AMP and increases in activity above this threshold. We conclude that the main mechanism whereby deoxyadenosine and nucleoside analogues stimulate catabolism of adenine nucleotides by way of AMP deaminase in erythrocytes is elevation of AMP, secondary to the phosphorylation of the nucleosides.
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PMID:Mechanism of adenosine triphosphate catabolism induced by deoxyadenosine and by nucleoside analogues in adenosine deaminase-inhibited human erythrocytes. 278 93

The 2-fluoro derivative of 9-beta-D-arabinofuranosyladenine (2-F-ara-A) and its soluble 5'-formate and 5'-phosphate derivatives were therapeutically effective against the parent leukemia L1210 (L1210/0). 2-F-ara-A and 9-beta-D-arabinofuranosyladenine 5'-formate were inactive aginst a 1-beta-D-arabinofuranosylcytosine-resistant subline (L1210/ara-C) that was deficient in deoxycytidine kinase. Deoxycytidine prevented 2-F-ara-A-induced inhibition of proliferation of L1210/0 cells in culture and alleviated 2-F-ara-a inhibition of DNA synthesis. After treatment of mice with 9-beta-D-arabinofuranosyladenine 5'-formate, intracellular levels of the 5'-triphosphate of 9-beta-D-arabinofuranosylfluoroadenine in leukemia cells were more than 10 times higher in L1210/0 cells than in L1210/ara-C cells. Similar results were obtained in this line of leukemia cells from mice treated with the 5'-monophosphate of 9-beta-D-arabinofuranosyl-2-fluoroadenine. Thus, L1210/ara-C cells deficient in deoxycytidine kinase activity were also deficient in capacity to phosphorylate 2-F-ara-A. Kinase activity from L1210/0 cells for deoxycytidine and for 2-F-ara-A coeluted from calcium phosphate cellulose and from diethylaminoethyl cellulose columns and had similar mobility on gel electrophoresis. Deoxyadenosine kinase was clearly separated from deoxycytidine kinase. Deoxycytidine competed with 2-F-ara-A for phosphorylation by the partially purified enzyme from L1210 cells. These results indicate that 2-F-ara-A is phosphorylated to the 5'-monophosphate by deoxycytidine kinase of leukemia L1210 cells.
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PMID:Metabolism and chemotherapeutic activity of 9-beta-D-arabinofuranosyl-2-fluoroadenine against murine leukemia L1210 and evidence for its phosphorylation by deoxycytidine kinase. 625 36

In humans Adenosine Deaminase activity (ADA) differs in serum and tissues in pH optimum, Km, and relative substrate specificity. Thus, on the basis of a major or a minor activity on 2'Deoxyadenosine, a "serum type"enzyme can be distinguished from a "tissue type" enzyme. The examination of ADA or relative substrate specificity (ratio 2'Deoxyadenosine/adenosine deaminase) in the serum of 174 patients with variant pathology, revealed the occurrence of a "tissue type" enzyme in sera of acute Lymphoblastic Leukaemia patients.
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PMID:[Serum 2'deoxyadenosine/adenosine deaminase ratio in clinical diagnosis]. 697 76