Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.5.4.4 (adenosine deaminase)
 5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is evidence that 2'-deoxycoformycin (DCF) functions as a differentiating agent. We examined the effects of DCF on the differentiation of HL-60 cells, a standard model of leukemic cell differentiation. DCF did not induce morphologic or histochemical evidence of differentiation, nor did it interact with retinoic acid, 1,25-dihydroxyvitamin D3, or interferon-gamma in inducing differentiation. Furthermore, DCF and agents that differentiated HL-60 cells had opposing effects on adenosine deaminase and 2',5'-oligoadenylate synthetase activity.
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PMID:Effects of 2'-deoxycoformycin on HL-60 cell differentiation, adenosine deaminase, and oligoadenylate synthetase. 231 12

The in vitro effect of short-term culture as well as the effect of retinol (ROH), retinoic acid (RA), muramyl dipeptide [( Abu']MDP), lipopolysaccharide (LPS), and gamma interferon (IFN-gamma) on the induction of the purine metabolic enzymes, adenosine deaminase (ADA), purine nucleoside phosphorylase (PNP), and 5'nucleotidase (5NT) in human peripheral blood monocytes (HPBM) was examined. HPBM isolated by centrifugal elutriation were cultured for up to 96 h. Following an initial time lag of 24 h, mean ADA activity from seven separate experiments as measured in nmoles/10(6) cells/h increased from a baseline of 31.3 +/- 9.3 to 57.8 +/- 16.4 (P less than 0.005) at 72 h and to 72 +/- 21.5 (P less than .025) by 96 h. 5NT activity increased from a baseline of 2.2 +/- 0.9 to a maximum of 44 +/- 10.1 by 72 h and then declined to 29 +/- 18 (P less than 0.005) by 96 h, while no significant change in PNP activity was observed. HPBM incubated for 3 d with optimal concentrations of LPS, RA, and IFN-gamma had increases in ADA and 5NT activity ranging from three- to 10-fold compared to HPBM cultured in media alone, whereas no effect was observed with ROH and [Abu']MDP. RA, but not ROH, significantly enhanced ADA activity in a monocytic leukemia cell (THP-1) line. Addition of RA or the tumor promoter, phorbol 12-myristic 13-acetate (PMA), to HPBM or THP-1 cells resulted in significant increases in 5NT activity with opposite effects on ADA activity. These findings suggest that the biological mechanisms associated with differentiation in normal and malignant monocytes seem to be related and that the sequence and degree to which the various differentiation agents induce the enzyme elevations are also related to the mechanisms of activation/differentiation.
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PMID:Induction of adenosine deaminase and 5' nucleotidase activity in cultured human blood monocytes and monocytic leukemia (THP-1) cells by differentiating agents. 284 22

The activities of the enzymes cytidine deaminase (CDD), deoxycytidine kinase (dCK), adenosine deaminase (ADA), and purine nucleoside phosphorylase (PNP), have been investigated in the promyelocytic leukemia cell line HL60. The activities of the enzymes corresponded well with that seen in acute myeloid leukemia cells except, that the CDD activity was very low in the HL60 cells. Induction of differentiation in HL60 cells by 1,25 dihydroxy D3 resulted in an increase in CDD from 12 to 247 nmol/h/mg and a decrease in ADA from 1326 to 896 nmol/h/mg, while the activities of dCK, and PNP were unchanged. Retinoic acid, another used inducer of differentiation, gave no changes of the enzyme activities. The increase in CDD activity induced by 1,25 dihydroxy D3 was prevented by inhibition of protein synthesis, whereas inhibition of proliferation of the cells did not abolish the increase of CDD. The changes correspond well with the differences seen between immature and mature myeloid cells. The results may have consequences for the interpretation of results obtained with cytostatics, which are metabolized by the enzymes.
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PMID:Changes in the activities of cytidine deaminase during differentiation of HL60 cells induced by 1,25 dihydroxy D3. 316 86

Human gene therapy for diseases involving leukocytes would be facilitated by the identification of specific promoter/enhancer sequences capable of directing high levels of tissue and stage-specific expression of the requisite cDNA when used in a retroviral vector. We tested the promoter sequences from the leukocyte integrin CD11a (LFA-1), CD11b (Mac-1), and CD18 subunits in retroviral vectors to express a reporter gene, adenosine deaminase, in the human leukocyte cell lines K562 and HL-60. The leukocyte integrins are expressed in leukocytes, and they are inducible in HL-60 cells, a model system for myeloid differentiation. Although the leukocyte integrin promoter/enhancer sequences direct the expression of reporter genes in myeloid lineage cell lines in transient transfection assays, in these studies, the leukocyte integrin promoters direct low levels of reporter gene expression following retroviral-mediated transduction in K562 and HL-60 cells and selection of stable integrants. Treatment of HL-60 cells transduced with retroviral vectors containing the leukocyte integrin promoters with retinoic acid or phorbol myristate acetate results in less than a two-fold increase in reporter gene expression. These studies indicate that: (i) expression from the leukocyte integrin promoters from stable integrants in retroviral vectors does not parallel the results observed in transient transfection assays, and (ii) additional promoter/enhancer sequences will likely be required for these promoters to direct high levels of tissue and stage-specific expression in retroviral vectors.
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PMID:Expression from leukocyte integrin promoters in retroviral vectors. 794 33

On the basis of early study on effects of retinoic acid (RA) on the differentiation of mouse lymphocytic leukemia-lymphoma cell strain (SACIIB 2), further research has been performed by studying the effects of retinoic acid on the human T lymphocytic leukemia cell line CCRF-CEM(CEM). The results showed that the growth of CEM cells was inhibited by RA at a concentration of 10 mumol/L. The activity of alpha-naphthyl acetate esterase (ANAE) and the percentage of CD3 positive cells rose after 10 days' RA treatment but the E rosette forming cells didn't increase. The activity of purine nucleoside phosphorylase (PNP) of the treated CEM cells increased significantly without change in activity of adenosine deaminase (ADA). The expression of terminal deoxynucleotidyl transferase (TdT) was also reduced to some degree. The analysis of lactic acid dehydrogenase (LDH) isoenzyme showed that the activity of LDH3 increased after RA treatment but without LDH1 and LDH2 expression. The results indicate that RA can induce CEM cells to differentiate.
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PMID:[Retinoic acid induces differentiation of human T lymphocytic leukemia CCRF-CEM cells]. 817 76

To identify vectors that provide optimal gene expression in human hematopoietic cells, we investigated retroviruses containing the adenosine deaminase (ADA) gene under the transcriptional control of the promoters/enhancers of Moloney murine leukemia virus and the human cytomegalovirus (CMV) immediate-early gene. ADA expression was monitored in transduced human multipotential promyelocytic leukemic HL-60 cells and human monocytic leukemic THP-1 cells. HL-60 cells can be induced by phorbol ester to differentiate into macrophage lineage cells and by retinoic acid into granulocytic cells. THP-1 cells undergo phorbol ester-induced differentiation to macrophage cells. In LNCA-transduced HL-60 derived macrophage cells, ADA controlled by the CMV promoter was expressed at 100.0 mumol/hr.mg, in contrast to 1.2 mumol/hr.mg from LN-transduced control cells. LNCA-transduced THP-1 macrophage cells showed a similar increase in ADA activity over control cells. These elevated enzyme activities were confirmed by Northern blots, which showed substantial increases in ADA mRNA derived from the CMV promoter. This suggests use of the CMV promoter for gene therapy targeted at macrophages, as, for example, in the treatment of lysosomal storage disorders such as Gaucher disease. These inducible cell lines have allowed the evaluation of transduced gene expression in proliferating and differentiating hematopoietic cells that may serve as an in vitro model of bone marrow-targeted gene therapy.
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PMID:High-level expression from a cytomegalovirus promoter in macrophage cells. 859 Jul 37

2'-Deoxycoformycin (dCF), a specific and potent inhibitor of adenosine deaminase, has demonstrated significant antitumor effect on lymphoid malignancies. The drug induced functional and morphologic differentiation of myeloid leukemia cells in combination with 2'-deoxyadenosine (dAd), but not dCF alone. NB4, a cell line derived from a patient with t(15; 17) acute promyelocytic leukemia (APL) underwent granulocytic differentiation when treated with all-trans retinoic acid (ATRA) or dCF plus dAd, but not with cytosine arabinoside. Pre-exposure of NB4 cells to ATRA greatly potentiated differentiation induced by dCF plus dAd, but pretreatment with dCF plus dAd before exposure to ATRA was less effective. Differentiation of NB4 cells was effectively induced by clinically applicable concentrations of dCF in combination with dAd. These findings may provide useful information about induction of differentiation in vivo.
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PMID:Induction of differentiation of human myeloid leukemia cells by 2'-deoxycoformycin in combination with 2'-deoxyadenosine. 929 60

Several adenosine analogs induce the functional and morphological differentiation of myelomonocytic leukemia cells. They can be classified into two types; i.e., those that do/do not require phosphorylation to induce the differentiation of leukemia cells. Neplanocin A, a potent S-adenosylhomocysteine hydrolase inhibitor, induces the differentiation of some leukemia cells without phosphorylation. On the other hand, deoxycoformycin (dCF), a potent adenosine deaminase inhibitor, also induces the myelomonocytic differentiation of leukemia cells when it is treated with deoxyadenosine (dAdo). This differentiation is inhibited by 5'-amino-deoxyadenosine, an inhibitor of (deoxy)adenosine kinase, suggesting that kinase-dependent phosphorylation is involved in the differentiation-inducing effect of dCF plus dAdo. Retinoids induce the differentiation of NB4 cells, a cell line derived from human promyelocytic leukemia. When used in combination with all-trans retinoic acid (ATRA), both NPA and dCF plus dAdo greatly enhance the granulocytic differentiation of NB4 cells. This enhancing effect is greatest when the cells are pretreated with NPA and then with ATRA. On the other hand, pre-exposure of NB4 cells to ATRA greatly potentiates the differentiation induced by dCF plus dAdo, while pretreatment with dCF plus dAdo before exposure to ATRA is less effective. The ATRA-induced differentiation of NB4 cells is effectively augmented by clinically applicable concentrations of these analogs. A clinical strategy that combines intermittent treatment with these analogs and a low dose of ATRA may increase the clinical response and decrease the adverse effects of ATRA.
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PMID:Adenosine analogs as possible differentiation-inducing agents against acute myeloid leukemia. 1043 63