Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.5.4.4 (adenosine deaminase)
5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Deoxyadenosine (AdR) appears to be central to the molecular events mediating immunodeficiency in children born with adenosine deaminase (ADA) deficiency but it is still uncertain whether lymphotoxicity is due to AdR directly inhibiting transmethylation reactions in which S-adenosylmethionine is the methyl group donor, or is due to phosphorylation of AdR to deoxyadenosine triphosphate (dATP) which then inhibits ribonucleotide reductase or is due to other mechanisms. Using AdR and the ADA inhibitor deoxycoformycin (dCF) and assessing cell viability, nucleoside incorporation into RNA and DNA, as well as measuring deoxyribonucleoside triphosphate (dNTP) concentrations and S-adenosylhomocysteine (SAH) hydrolase activity, we have studied various types of human lymphoid cells and demonstrated in them the relative importance of the above two mechanisms of AdR toxicity. Treatment of normal resting peripheral blood lymphocytes in culture with AdR and dCF resulted in impaired viability. Although elevated dATP levels as well as decreased SAH hydrolase activities were both observed, the failure of a known inhibitor of ribonucleotide reductase (hydroxyurea) to produce toxicity, and the inability of deoxycytidine (CdR) to achieve a rescue effect, point to another mechanism, possibly inhibition of trans-methylation or ATP depletion being the more likely causes of toxicity in resting lymphocytes. The same mechanism may well account for the rapid and severe lymphopenia in patients treated with dCF. On the other hand, in cultured lymphoblasts in the exponential phase of growth. AdR and dCF produced marked inhibition of growth and cell death both in a Thy-ALL line and in a c-ALL line, in the absence of significant inhibition of SAH hydrolase, but with a substantial elevation in dATP concentrations and depressed levels of the other dNTP. Minor toxicity occurred in a proliferating B lymphoblast line despite almost complete inactivation of SAH hydrolase. These observations indicate inhibition of ribonucleotide reductase as the more likely mechanism of toxicity in rapidly proliferating lymphocytes. Other T-cells actively synthesizing DNA, such as PHA-stimulated or MLC activated lymphocytes and T-lymphoid colony forming cells, are also likely to be affected by the same mechanism. Indeed in PHA-stimulated lymphocytes, deoxycytidine caused significant although incomplete rescue from toxicity due to dCF and AdR. In patients with ADA deficiency or treated with ADA inhibitors, both mechanisms could be operative. These observations are also relevant to the possible use of dCF and AdR as immunosuppressive agents and for the removal of T-cells or residual Thy-ALL blasts from bone marr
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PMID:Mechanisms of deoxyadenosine toxicity in human lymphoid cells in vitro: relevance to the therapeutic use of inhibitors of adenosine deaminase. 623 Oct 47

Deoxycoformycin (DCF) is an inhibitor of adenosine deaminase (ADA). Twenty-one courses of DCF were administered to 13 patients ranging in age from 15 to 78 yr. Eight patients had T-cell disorders, and five patients had non-T-cell malignancies. The i.v. bolus dose was escalated from 5 to 30 mg/sq m/day, and the duration of the courses ranged from 1 to 5 days. The DCF plasma half-life ranged from 4.9 to 6.2 hr and was independent of dose. The dose-limiting toxicities involved the central nervous system (CNS) and the kidneys. Other toxicities included bronchitis, decreases in hematocrit, arthralgias, and myalgias. Mortality was encountered in three patients. These toxic effects may have been secondary to the accumulation of the metabolites adenosine and deoxyadenosine. Deoxyadenosine and adenosine were both detectable in plasma (10(-6) M) and in urine (10(-3) M). Two partial remissions were observed: one in a patient with T-cell ALL and another in a patient with mycosis fungoides. Minimal responses characterized by either declines in peripheral blast counts or partial resolution of adenopathy were observed in five other patients. No responses were observed in six patients. These observations suggest that DCF is effective in the treatment of T-cell lymphoid malignancies.
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PMID:Clinical pharmacology of deoxycoformycin. 626 81

Three enzymes concerned in purine degradation, 5'nucleotidase (5'NT), adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) have been measured biochemically in the bone marrow or peripheral blood blasts from 75 patients with acute leukaemia, from 18 patients with blast crisis of chronic granulocytic leukaemia and in the bone marrow and peripheral blood lymphocytes from 14 normal donors. Characteristic patterns among the different sub-types of acute leukaemia have been detected, with high ADA, low 5'NT and PNP in Thy-ALL, high 5'NT and ADA in c-ALL, high PNP and low ADA in AML. The cells in CGL blast transformation resembled the enzymatic pattern of either AML or c-ALL respectively. However, no significant correlation was found between any pair of enzymes in any group of leukaemia, normal bone marrow or peripheral blood lymphocytes studied here.
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PMID:5'nucleotidase, adenosine deaminase and purine nucleoside phosphorylase activities in acute leukaemia. 629 84

Lymphocytes from patients with acute and chronic T-cell malignancy or chronic T gamma lymphocytosis were characterized by studying the activity of three enzymes involved in purine metabolism and by determining the isoenzyme pattern of lactate dehydrogenase (LDH) in addition to analysis of surface marker expression with monoclonal antibodies. Four clinically different types of disease were distinguished on the basis of the enzyme parameters. Lymphocytes from patients with acute lymphocytic leukemia (T-ALL) showed an enzyme profile similar to that of normal thymocytes, i.e., an elevated level of adenosine deaminase (ADA) activity as compared with normal T lymphocytes, reduced activities of purine 5'nucleotidase (5'NT) and purine nucleoside phosphorylase (PNP), and a binomial distribution of the LDH isoenzyme pattern. Cells from "null"-ALL patients had an ADA/PNP ratio that was intermediate between that of normal T cells and that of T-ALL cells or thymocytes, but their 5'NT activity and LDH isoenzyme pattern were thymocyte-like. Patients with chronic T-cell proliferation were subdivided into those with chronic T gamma lymphocytosis and those with proven chronic T malignancy. The lymphocytes from these patients had ADA and PNP activities within the ranges of those of normal T lymphocytes. However, the ADA activity and/or the ADA/PNP ratio were consistently higher in the cells from the patients with chronic T gamma lymphocytosis than in those with chronic T malignancy. The enzyme profile of the cells from the T gamma patients was similar to that of T gamma cells of normal individuals. The cells from patients with chronic T malignancies showed a heterogeneous enzyme pattern as compared with that of normal T lymphocytes. Analysis with monoclonal antibodies enabled us to distinguish null-ALL patients from the other leukemias studied, but a distinction between chronic and acute T-cell proliferation disease, for instance, was not possible with monoclonal antibodies alone. Our data demonstrate that the enzyme profiles studied provide supplementary information for classification and diagnosis of lymphoproliferative diseases to that obtained with cell surface markers alone.
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PMID:Enzyme analysis of lymphoproliferative diseases: a useful addition to cell surface phenotyping. 630 82

A human thymus-leukemia-like antigen has been identified that is antigenically distinct from T6/HTA-1. This was accomplished with a rabbit antiserum (513) which was prepared against lymphoblasts that were E rosette negative (E-), human thymus antigen positive (HuTA+), cALLA-, DR-, SmIg- from a patient who presented with a mediastinal mass and a WBC count of 130 X 10(9) cells/1. Following absorption with B cell and "null" cell lines, 513 exhibited prominent reactivity with a membrane antigen that was present on normal thymocytes and lymphoblasts from 11 of 13 patients with T cell ALL and 1 of 16 patients with common ALL, but was not detected on normal peripheral blood lymphocytes, normal bone marrow cells and leukemic lymphoblasts with an undifferentiated phenotype. SDS-PAGE analysis of this antigen indicated that it was composed of two subunits, 43-kDa and 12-kDa. Sequential absorption experiments revealed that: (1) the 12-kDa subunit was antigenically similar to beta 2 microglobulin; (2) the intact molecule did not exhibit HLA-A, B or C "framework" determinants; (3) the molecule was antigenically distinct from a human thymus-leukemia antigen HTA-1 (recognized by monoclonal antibodies NA1/34 and OKT6); and (4) the molecule was antigenically distinct from adenosine deaminase. It is concluded that 513 reacts with a membrane protein (designated 513TL) which exhibits properties characteristic of a histocompatibility-like antigen whose expression is restricted to thymocytes and some leukemias (TL antigen). Its antigenic distinction from another recently characterized human TL antigen, HTA-1, suggests polymorphism among this family of alloantigens.
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PMID:Identification and characterization of a human thymus-leukemia antigen (43-kDa/513TL) bearing a structural relationship to HLA. 633 39

Acute lymphoblastic leukemia with hand-mirror cells (HMC) was diagnosed in nine adult patients. Blast HMC were seen only in the bone marrow (12-57% range). Cytochemical studies revealed a positive reaction to tartrate-sensitive acid phosphatase in the tail portion of the cells in seven cases, with a strong, localized cytoplasmic reaction in four. Leukemic cells lacked surface immunoglobulins and were E rosette negative in all cases. Normal levels of adenosine deaminase activity (ADA) were found in five of the seven patients. Electron microscope studies confirmed the hand-mirror shape of the cell. These HMC contained large numbers of mitochondria and microspikes in the handle portion of the cell. The patients failed to respond to initial conventional ALL chemotherapy, but the prolonged survival with passable health of the majority of these, despite their lack of complete remission, is emphasized.
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PMID:Acute lymphoblastic leukemia hand-mirror cells. Study of nine cases. 657 58

Changes in levels of purine degradative enzymes have been shown to occur during T-cell maturation in both rats and humans with a fall in adenosine deaminase (ADA) and a rise in purine nucleoside phosphorylase (PNP) and 5'-nucleotidase (5'NT) activities. We have investigated the effects of four thymic factors: thymosin fraction 5 (TMS-F5); thymosin alpha 1 (TMS-alpha 1); thymopoietin pentapeptide (TP-5); and thymic conditioned medium (CM) on TdT activity, purine enzyme levels and the phenotypic markers OKT3 (a marker for mature T cells) and NA1/34 (which reacts with immature cortical thymocytes) in human thymocytes and in the lymphoid leukaemic cell lines RPMI-8402 and JM1 (derived from Thy-ALL). All four thymic factors caused one or more maturation change in human thymocytes, e.g. TMS-F5 caused a significant increase in OKT3 expression, TMS-alpha 1 a fall in TdT and ADA activities and a rise in OKT3-positive cells, TP-5 an increase in PNP and CM a rise in 5'NT activity. TMS-F5 also caused a marked elevation of 5'NT in both the T lymphoblastic lines (P less than 0.001). On the other hand the non-physiological phorbol ester, 12-O-tetradecanoyl phorbol acetate (TPA), a tumour promotor with potency of inducing differentiation in some leukaemic cell lines, induced changes in both normal thymocytes and in the leukaemic line JM1 were inconsistent with maturation, e.g. a fall in the percentage of OKT3 cells. These observations suggest that maturation of normal thymocytes might proceed stepwise, each step requiring at least one of the thymic hormones. Although thymosin also induces differentiation changes in a malignant lymphoid line, the pattern of these differs from that induced in their normal counterparts.
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PMID:Biochemical and immunological differentiation of human thymocytes induced by thymic hormones. 660 5

The cellular levels of the purine catabolic enzymes adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) and those for the pyrimidine activities thymidine phosphorylase and thymidine kinase isozymes have been measured concurrently in peripheral blood nucleated cells of patients with acute lymphoblastic leukaemia, chronic lymphocytic or prolymphocytic leukaemia and correlated with the spontaneous tritiated thymidine uptake of the isolated cells. Highest ADA levels occurred in T-ALL cells but considerable overlap of individual activities occurred for non-T, non-BALL, B-CLL and T-CLL cells. The levels of PNP showed no distinct discriminatory trend in cells of the lymphoid proliferative disorders examined. Thymidine phosphorylase activity was markedly reduced in T-ALL and T-CLL cells with a stepwise increase in the level of mean activities for non-T, non-B ALL, B-CLL and B-PLL cells to that of isolated normal peripheral blood lymphocytes. Spontaneous tritiated thymidine uptake of the abnormal lymphoid cells exhibited a correlation between cellular thymidine kinase isozyme 1 and elevated ADA levels. The use of ADA inhibitors together with thymidine infusion for the treatment of lymphoproliferative disorders is discussed.
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PMID:Purine and pyrimidine activities in acute and chronic lymphocytic leukaemia: relation to cellular proliferative status. 681 8

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.
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PMID:Studies on the biochemical sequelae of therapy in Thy-acute lymphoblastic leukaemia with the adenosine deaminase inhibitor 2' deoxycoformycin. 697 3

We have analyzed the distribution and prognostic significance of terminal deoxynucleotidyl transferase (TdT) and adenosine deaminase (ADA) in connection with conventional cytology, cytogenetics, response to therapy, and survival. The study population consisted of 78 patients with AML, 44 patients with Ph1 + CML in chronic phase, and 35 adult patients with Ph1 + CML in blastic phase, among which 5 cases presented as Ph1 + acute leukemia. Nine percent of the AML cases were positive for TdT and were characterized by a high percentage of blast cells in bone marrow, myeloid features by cytochemistry and absence of the Philadelphia chromosome. The median ADA values of the TdT+ AML cases were several times higher than those obtained for the TdT- cases. The survival calculated for the two groups of AML cases subdivided according to ADA levels was significantly longer (p less than 0.025) for the patients with low levels of ADA (less than 250 U/10(8) cells). In chronic phase of CML, TdT was absent and ADA values were increased over normal controls only in cases with early signs of transformation. In blastic phase, 31% of the 35 cases were positive for TdT, and ADA values were significantly higher (p less than 0.001) in TdT+ than TdT- cases. The survival calculated from the onset of transformation was significantly longer for the TdT+ acute phase (10.4 mo) compared to the TdT- patients (4.8 mo; p less than 0.025). Four cases presenting as Ph1 + acute leukemia were TdT+ and had elevated levels of ADA; 3 of them responded to ALL therapy, reverting to a stable phase of CML.
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PMID:Prognostic significance of terminal transferase and adenosine deaminase in acute and chronic myeloid leukemia. 704 66


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