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)

Two patients with relapsed acute lymphoblastic leukaemia of thymic phenotype (Thy-ALL) resistant to all conventional chemotherapy achieved complete remission when treated with 2'-deoxycoformycin, a selectively lymphocytotoxic compound that acts by inhibition of the enzyme adenosine deaminase. These observations show that malignant thymocytes are dependent on adenosine-deaminase activity and suggest that it may be possible to use deoxycoformycin in other patients with Thy-ALL to induce remission or to kill Thy-ALL blasts in bone marrow harvested before autologous bone-marrow transplantation, leaving normal haemopoietic stem cells intact.
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PMID:Remission induction with adenosine-deaminase inhibitor 2'-deoxycoformycin in Thy-lymphoblastic leukaemia. 610 39

Seventeen patients with acute leukaemia refractory to conventional chemotherapeutic agents were treated with the adenosine deaminase inhibitor, 2'-deoxycoformycin (dCF). Of the twelve patients with acute lymphoblastic leukaemia of the thymic phenotype (Thy-ALL), seven went into complete remission after one or two courses of therapy. Two other (Thy-ALL) patients showed good partial response, and three were resistant to dCF. The five patients with acute leukaemia of other phenotypes had progression of disease despite treatment with dCF. Response to dCF can be predicted from the pattern of change in cellular nucleotide levels in blood and/or bone marrow blasts which have been treated in vitro with dCF and deoxyadenosine. The main adverse effects of dCF therapy were renal and liver dysfunction, conjunctivitis, and haemolysis.
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PMID:Therapeutic selectivity of and predication of response to 2'-deoxycoformycin in acute leukaemia. 611 69

The activities of adenosine deaminase (ADA) were measured in the blood plasma, erythrocytes, and lymphocytes of healthy reference persons and in patients affected with leukaemia. ADA is increased in patients with acute immature cell leukaemia, in patients with chronic lymphatic leukaemia it is comparatively low in lymphocytes. In chronic myeloic leukaemia ADA activities are different depending on the activity of the disease. ADA-activities in the blood plasma, erythrocytes, and lymphocytes do not correlate with each other. ADA-activities in leukaemias may be regarded as an indicator of increased purin metabolism rather a as parameter of disturbed cellular immunofunction.
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PMID:[Adenosine deaminase activity in leukemia patients]. 617 99

Activity of terminal deoxynucleotidyl transferase (TdT), adenosine deaminase, and 5'nucleotidase and the cellular concentration of glucocorticoid (dexamethasone) receptor were determined in 25 patients with acute non-lymphocytic leukaemia. All patients were treated according to a common protocol. Increased activity of TdT (greater than 0.1 unit/microgram DNA) was found in 11 patients. This group of patients was shown to have higher remission and survival rates (p = 0.06) compared with patients with low activity of TdT. The glucocorticoid receptor concentration of the leukaemic blast cells ranged from 0 to 0.94 fmol/microgram DNA. Thirteen patients had blast cells with a glucocorticoid receptor concentration over 0.22 fmol/microgram DNA. These patients had significantly increased remission and survival rates (p = 0.006) compared with those with a low receptor concentration. This finding cannot be explained by a difference in sensitivity to glucocorticoids since these were not used as therapeutic agents. Adenosine deaminase and 5'nucleotidase activities both varied within two orders of magnitude. No correlation could be found between activities of these enzymes and remission or survival rate. These results show that measurements of TdT activity and the glucocorticoid receptor concentration yield valuable prognostic information in acute non-lymphocytic leukaemia.
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PMID:Glucocorticoid receptor concentrations and terminal transferase activity as indicators of prognosis in acute non-lymphocytic leukaemia. 626 1

Activities of enzymes of the purine metabolic pathway, adenosine deaminase (ADA), purine nucleoside phosphorylase (PNP), and 5'-nucleotidase (5'-N), were investigated in the lymphoblasts of a patient with B-cell acute lymphoblastic leukemia. These lymphoblasts exhibited increased ADA activity and diminished activities of both PNP and 5'N' as compared to normal lymphocytes as well as non-T, non-B leukemia cells. This enzymatic pattern is identical to that which has been described in T-cell leukemic lymphoblasts and differs from that which has been observed in the malignant cells of undifferentiated B-cell lymphomas. These data suggest that there is biochemical heterogeneity within the spectrum of B-cell malignancies. Furthermore, inhibitors of ADA may be of use in those B-cell lymphoid neoplasms that exhibit increased ADA activity.
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PMID:Lymphoblast purine pathway enzymes in B-cell acute lymphoblastic leukemia. 626 97

Cultured human T-cell leukemia lymphocytes have enhanced sensitivity to growth inhibition by deoxyadenosine. We have used flow cytometry to investigate the mechanism of deoxyadenosine toxicity in cultured T-leukemic cells. Comparative studies on deoxyadenosine-resistant Epstein-Barr virus-transformed B-lymphocyte cell lines were also performed. After exposure of T-cells to low concentrations of deoxyadenosine (3 microM), in the presence of an adenosine deaminase inhibitor (erythro-9-[3-(2-hydroxynonyl)]adenosine), accumulation of cells of cells with a G1 DNA content was demonstrated. In contrast, B-cell lines showed a similar degree of growth inhibition after exposure to 200 to 400 microM deoxyadenosine but were blocked in S phase. The T-cell G1 block was associated with a rise in the deoxyadenosine triphosphate pool, and both these phenomena were prevented by the addition of deoxycytidine. The biochemical mechanism of this G1 block induced by deoxyadenosine in T-cells is not understood.
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PMID:G1-phase arrest of cultured human leukemic T-cells induced by deoxyadenosine. 627 90

The analysis of seven differentiation markers following incubation with the tumor promotor 12-O-tetradecanoylphorbol-13-acetate (TPA) was examined in the human leukemic T-cell line MOLT-3. Significant changes were observed in the activity of the markers terminal deoxynucleotidyl transferase (TdT). spontaneous proliferation and the ability of these cells to bind sheep erythrocytes. Levels of human thymus-leukemia-associated antigen (HThy-L) recently identified as a low molecular weight form of adenosine deaminase (ADA), were reduced by about 50%. No significant changes were observed in ecto-5'-nucleotidase [5'-NT) activities, in the proliferative response to PHA, or in the expression of IA-like antigens. These data and the time kinetics of the changes suggest that following incubation of these T-lymphoblasts with TPA there is a sequential loss of TdT, loss of the capacity for spontaneous proliferation, and the appearance of receptors for sheep erythrocytes. Subsequently there is a decrease in the level of HThy-L/ADA. This sequence appears to follow that proposed for prethymic precursor T-cell differentiation following activation with thymic epithelium.
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PMID:Modulation of human T-cell differentiation markers by 12-O-tetradecanoylphorbol-13-acetate. 627 66

Leukemic cells incubated in vitro with 2'-deoxyadenosine (dAdo) plus an inhibitor of adenosine deaminase, 2'-deoxy-coformycin (DCF), show different metabolic responses depending on the histologic and immunologic type of the leukemia. Leukemic cells were obtained from 54 patients with acute lymphoblastic leukemia (ALL), 9 with myeloid or nonlymphoblastic leukemia, 3 with chronic lymphocytic leukemia (CLL), and 3 with lymphoma. There was a wide variation in the LD50, the concentration of dAdo that caused 50% inhibition of the incorporation of 3H-thymidine into cells in the presence of 20 microM DCF. T-cell leukemia specimens were much more sensitive to dAdo than were specimens of pre-B-ALL and null-ALL. In leukemic cells that had been incubated with 14C-dAdo plus DCF, a good correlation was observed between the LD50 and the ratio of 14C-deoxyATP to ATP (correlation coefficient for the fit to a hyperbola = 0.853). The accumulation of deoxyATP by the leukemic cell specimens was correlated best with the activity of ecto-ATPase, less well with cytoplasmic 5'-nucleotidase and deoxyadenosine kinase, and poorly with adenosine deaminase and ecto-5'-nucleotidase. The clinical response to DCF therapy of a patient with T-ALL and another with pre-B-ALL was consistent with the in vitro metabolic response of their cells to DCF and dAdo.
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PMID:Biochemical correlates of the differential sensitivity of subtypes of human leukemia to deoxyadenosine and deoxycoformycin. 628 41

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

The adenosine deaminase (ADA) inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), at low concentrations (less than 10 microM), enhances the inhibitory activity of adenosine against lymphocyte-mediated cytolysis (LMC) without itself being inhibitory. At higher concentrations, EHNA alone is inhibitory to LMC with an IC50 of 160 microM. This inhibition is reversible upon washout, appears to affect an early stage of the lytic process, and does not appear to involve changes in basal levels of cyclic AMP (cAMP), ribonucleoside 5'-triphosphate pool sizes, S-adenosylhomocysteine levels, or protein carboxymethylation. EHNA does enhance the cAMP response of cytolytic lymphocytes (CL) to activators of adenylate cyclase such as prostaglandin E1. EHNA inhibits lymphocyte high-affinity cAMP phosphodiesterase at immunosuppressive levels, exhibiting hyperbolic mixed-type inhibition (Ki = 83 microM, alpha = 0.47, beta = 0.18). Whereas inhibition of intralymphocytic ADA is complete at low concentrations (less than 25 microM) of EHNA, inhibition of LMC and intralymphocytic cAMP phosphodiesterase increases linearly with EHNA concentration to at least 200 microM. The presence of 200 microM EHNA during the centrifugation of mixtures of CL and EL4 leukemia target cells leads to increased CL cAMP levels. 2'-Deoxycoformycin, a more potent ADA inhibitor than EHNA, is not inhibitory to LMC and shows none of these cAMP-related effects. These results suggest that CL-target cell contact stimulates adenylate cyclase in the CL and that EHNA inhibits LMC due to its enhancement of this target cell-stimulated elevation of cAMP.
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PMID:Inhibition of lymphocyte-mediated cytolysis and cyclic AMP phosphodiesterase by erythro-9-(2-hydroxy-3-nonyl)adenine. 629 34


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