Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.5.4.17 (adenosine deaminase)
 5,206 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

2-Bromo-2'-deoxyadenosine (BdA) is one of a group of recently synthesised halogenated deoxyadenosine analogues that are relatively resistant to inactivation by adenosine deaminase (ADA). Its activity has been studied in human acute myeloid leukemia (AML) in vitro. In these studies BdA behaved as a cycle-active, phase-active agent that blocked cells at the G1-S transition. It did not exhibit significant cross-resistance with cytosine arabinoside (Ara-C) in either clinical AML samples (from patients who exhibited Ara-C resistance in vivo) or in HL60 in which Ara-C resistance had been induced in vitro. Deoxycytidine kinase levels were not reduced in resistant lines. Erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), an adenosine deaminase (ADA) inhibitor, with BdA produced a simple additive response without the dramatic synergism reported when it is used with deoxyadenosine. This is consistent with the idea that BdA is a poor substrate for ADA. This group of compounds warrants further investigation to determine their suitability for clinical use, especially in situations where Ara-C resistance is likely to be a problem.
Cancer Chemother Pharmacol 1987
PMID:Lack of cross-resistance between cytosine arabinoside and a new halogenated nucleoside analogue, 2-bromo-2'-deoxyadenosine in human acute myeloid leukaemia cells. 349 52

Serum adenosine deaminase (ADA) levels were estimated in a group of 40 patients with head and neck cancer. The mean value was significantly higher in patients compared to controls. The increase was higher in cases of ulcerative growths than of proliferative growths, and activity was increased with advancement in the stage of the cancer. After radiotherapy, a gradual and significant decrease in serum ADA activity was observed.
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PMID:Serum enzymes in head and neck cancer III. 368 Nov 30

The dynamics of lymphocyte response in peripheral blood, the tumor draining lymph node, spleen and thymus, was followed in a model system of syngeneically transplanted rat MC-1 tumor. Electrophoretic mobility (EPM) of lymphoid cells was determined by the automatic mode of measurement. The results revealed a two-phase pattern of EPM changes during the course of cancer growth. The first phase (day 3 to 6 following intramuscular injection of tumor cells) was characterized by a prevalence of high-mobility cells, while in the second phase (day 14 to 20), depletion of high-mobility cells was compensated for by an increased number of low-mobility cells. The mean EPM value was found to be increased only in the thymus at that time. Changes in the adenosine deaminase activity proved to be most expressive in the tumor draining lymph node and in the second phase also in splenic and thymic lymphocytes. An increased percentage of active lymphocytes with compact nucleoli with nucleolonemas became evident already on the 3rd day in all the lymphoid organs followed. The response was two-phasic only in the lymphocyte population of the peripheral blood, while their percentage in the other organs remained higher even on day 20. Changes in the proportion of high- and low-mobility cells in the lymphoid organs followed here, in correlation with the adenosine deaminase activity and the percentage of active lymphocytes, were interpreted as a response of immunocompetent cells in animals with a growing tumor.
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PMID:Kinetics of some immunological and biochemical changes of immunocompetent cells during tumor growth in rats. 378 65

Previous work has shown that 6-thioguanine (TGua) is an effective inducer of differentiation of Friend and HL-60 leukemia cells which lack hypoxanthine-guanine phosphoribosyltransferase but is at best only weakly active in inducing maturation in parental wild-type cells. Studies in wild-type and mutant HL-60 cells have provided evidence that the free-base TGua is the form of this drug that induces differentiation, while the formation of TGua nucleotides leads to cytotoxicity and inhibits differentiation. To attempt to increase the potential of TGua to serve as an inducer of parental HL-60 leukemia cells, physiological purine and pyrimidine nucleosides were tested for their ability to protect HL-60 cells against TGua-induced cytotoxicity. Adenosine, deoxyadenosine, inosine, and deoxyinosine completely prevented the toxic action of the purinethiol, while guanosine and deoxyguanosine were only partially effective. The capacity of adenosine and deoxyadenosine to prevent the cytotoxicity of TGua was abolished by the inhibitor of adenosine deaminase, deoxycoformycin, implying that inosine and deoxyinosine were the active forms of the protecting agents. The protective activities of inosine and deoxyinosine appeared to depend on phosphorolysis catalyzed by purine nucleoside phosphorylase, since exogenously added hypoxanthine was as effective as inosine in reducing the cytotoxicity of the purine antimetabolite. Accumulation of TGua nucleotides in the acid-soluble fraction of HL-60 cells treated with TGua was significantly decreased by the presence of inosine. Inosine also served under these circumstances as a D-ribose 1-phosphate donor to TGua, as evidenced by its increased conversion to 6-thioguanosine. The prevention of the cytotoxicity of TGua by the simultaneous administration of hypoxanthine or its nucleosides resulted in an expression of the differentiation-inducing properties of TGua in HL-60 cells, as measured by the accumulation of nitroblue tetrazolium-positive cells. These findings support the concept that the processes of cytotoxicity and differentiation are separable events produced by different metabolic forms of the purine antimetabolite.
Cancer Res 1985 Jan
PMID:Enhancement of the differentiation-inducing properties of 6-thioguanine by hypoxanthine and its nucleosides in HL-60 promyelocytic leukemia cells. 385 87

A comparison of adenosine deaminase activity in intact human plasma cells and lymphocytes in vitro showed that plasma cells had at least as much activity of this enzyme as did T or non-T lymphocytes. This observation led us to examine the effectiveness of deoxycoformycin in the treatment of multiple myeloma. Thirteen patients with advanced refractory myeloma were treated with deoxycoformycin at 5 mg/m2 daily for 3 days every 2 weeks until response or progression. Of the seven evaluable patients who received more than one cycle of therapy, two had a greater than 50% reduction in the level of myeloma protein and two had a demonstrable reduction in soft tissue disease. Toxicity consisted of marked nausea, anorexia lasting several days, and mild transient confusion in some patients. Plasma levels of deoxyadenosine and adenosine peaked on day 4 or 5 with average values of 1.9 and 0.6 microM, respectively. Red cell levels of dATP reached approximately 40% of ATP levels. The viability of plasma cells was shown to be greatly reduced in in vitro incubations with deoxycoformycin and low levels of deoxyadenosine (ID50 of 6 microM).
Cancer Chemother Pharmacol 1985
PMID:Treatment of multiple myeloma with deoxycoformycin. 387 Nov 75

Cultured human T-lymphoblastoid cell lines are more sensitive than B-cell lines to 2'-deoxyadenosine in the presence of 2'-deoxycoformycin, a potent inhibitor of adenosine deaminase. This difference is related to the greater efficiency with which T-lymphoblasts accumulate cytotoxic levels of dATP derived from the adenosine deaminase substrate 2'-deoxyadenosine (dAdo). Previous work has shown that differences in dATP accumulation by cultured T- and B-lymphoblastoid cell lines cannot be explained by large differences in the levels of dAdo-phosphorylating or dAdo nucleotide (dAXP)-degrading activities in cytoplasmic extracts of these cells, although it has been proposed that intact B-cell lines may catabolize intracellular dAXP more rapidly than do T-cell lines. To further examine the determinants of dAdo sensitivity in T- and B-lymphoblasts, we have studied dAdo and dAXP metabolism in the human T- and B-cell lines CEM and WI-L2 and in hybrids generated by fusion of these cell lines. The hybrid nature of the fusion products was established by nutritional studies and by analyses of cellular surface antigens, DNA content, and enzymatic activities. We found that WI-L2 X CEM hybrids and another T X B hybrid derived from fusion of the SB human B-cell line with CEM were 30- to 40-fold less sensitive to dAdo and about 10-fold less sensitive to the dAdo analogue 9-beta-D-arabinofuranosyladenine than was CEM, or about as resistant as were their B-cell parental lines. Our studies confirm that CEM avidly accumulates dAXP from dAdo but does not catabolize intracellular dAXP. In contrast, WI-L2, SB, and WI-L2 X CEM and SB X CEM hybrids rapidly degraded intracellular dAXP, which limited their ability to undergo dAXP pool expansion. Expression of dAXP catabolic activity in T X B hybrids behaved as a dominant mechanism, conferring resistance to dAdo- and dAdo-related nucleosides to T X B hybrids. It has been postulated that cell fusion may play a role in the progression of tumors and contribute to diversity among the cells that compose clonal tumors. We have speculated that fusion of a malignant T-lymphoblast with an activated B-cell might be a mechanism for the evolution of drug resistance in acute T-cell leukemia.
Cancer Res 1985 Apr
PMID:Determinants of deoxyadenosine toxicity in hybrids between human T- and B- lymphoblasts as a model for the development of drug resistance in T-cell acute lymphoblastic leukemia. 387 67

It remains unclear how lympholysis occurs in children with an inherited deficiency of adenosine deaminase (ADA) and in leukemic patients undergoing treatment with an inhibitor of ADA, deoxycoformycin. Adenosine deaminase deficiency with subsequent lympholysis can be simulated in vitro by treatment of lymphoid cells with deoxyadenosine plus deoxycoformycin. We found that such in vitro treatment caused fragmentation of the nucleus, disintegration of nuclear chromatin, and the formation of cytoplasmic blebs in T-lymphoblast lines, but not in B-lymphoblast lines. For all but one of the cell lines tested, the extent of morphological changes paralleled the sensitivity to growth inhibition by deoxyadenosine plus deoxycoformycin. Similar morphological changes were observed in normal peripheral blood lymphocytes treated with deoxyadenosine plus deoxycoformycin. These morphological changes were energy-dependent processes. They were preceded by inhibition of DNA synthesis and deoxyadenosine triphosphate (dATP) accumulation, but followed by depletion of adenosine triphosphate (ATP) and cell lysis. These changes may represent an intermediate step between metabolic alterations and lympholysis.
Cancer Invest 1985
PMID:Morphological changes in leukemic lymphoblasts and normal lymphocytes treated with deoxyadenosine plus deoxycoformycin. 387 81

The antiproliferative effect of 2',5' A3 core and 2',5'-3'dA3 (cordycepin trimer) core was measured in 8 human tumor cell lines. Cells were treated in a dose-response manner for 72 hr and the concentration of drug necessary to inhibit cell growth 50% (GI50) was determined. A wide range of sensitivities to these drugs was found, even among tumors of the same histological type. The cell lines showed different sensitivities and dose-response curves to the 2',5'A3 and 2',5'-3'dA3 cores. Uptake studies of the 2',5'A3 and 2',5'-3'dA3 cores, using high-pressure liquid chromatography, demonstrated that both cores were rapidly degraded in the tissue culture medium and taken up as adenosine or cordycepin, respectively. There was a direct correlation between the uptake of cordycepin and the antiproliferative effect. In contrast, there was no correlation between cell sensitivity and the uptake of the 2',5'A3 core degradation products. Analysis of intracellular nucleosides and nucleotides indicated that differences in intracellular metabolism of adenosine might explain the different sensitivities of the various cell lines to 2',5'A3 core. Molar equivalent concentrations of adenosine and cordycepin inhibited cell growth; however, equimolar concentrations of these nucleosides were not effective. In addition, the antiproliferative effect of both core compounds and their corresponding nucleosides could be potentiated by the addition of the adenosine deaminase inhibitor, deoxycoformycin. The results indicate that these cores act as prodrugs and that the active metabolites are their corresponding nucleosides.
Int J Cancer 1985 Sep 15
PMID:Differential antiproliferative actions of 2',5' oligo A trimer core and its cordycepin analogue on human tumor cells. 387 70

Immunoreactive adenosine deaminase complexing protein (ADCP) was studied in 91 human colorectal adenocarcinomas. The expression of ADCP was correlated with that of secretory component (SC) and carcinoembryonic antigen (CEA), with the histological grade and the Dukes' stage of the carcinomas. The histological grade was scored semi-quantitatively according to 5 structural and 4 cytological variables. ADCP expression was observed in 3 different staining patterns, namely: (1) diffuse cytoplasmic (77% of the carcinomas); (2) granular cytoplasmic (13%); and (3) membrane-associated (66%). These patterns were observed alone or in combination. Eleven percent of the carcinomas exhibited no ADCP immunoreactivity. Linear regression analysis showed that the expression of ADCP correlates with that of SC and CEA. However, no significant correlation emerged between the histological parameters or the Dukes' stage and any of the immunohistological parameters. Comparison of the histological characteristics of carcinomas exhibiting little or no ADCP immunoreactivity with those showing extensive immunoreactivity, showed that membranous ADCP immunoreactivity occurs more frequently in well-differentiated carcinomas. Structural parameters showed a better correlation with membranous ADCP expression than the cytological variables. It is concluded that membranous expression of ADCP and CEA are indicators of a high level of differentiation as reflected primarily in the structural characteristics of the tumor.
Int J Cancer 1986 Apr 15
PMID:Adenosine deaminase complexing protein (ADCP) immunoreactivity in colorectal adenocarcinoma. 395 58

As an aid in the differential diagnosis of exudative pleural effusions, tumor markers were investigated. We measured immunosuppressive acidic protein (IAP), carbohydrate antigen 19-9 (CA 19-9), tissue polypeptide antigen (TPA), carcinoembryonic antigen (CEA), adenosine deaminase (ADA), and alpha 1-acid glycoprotein (AGP) in the pleural fluid of 36 patients with carcinomatous pleural effusions and of 35 patients with tuberculous pleurisy because we have frequently found these diseases to be associated with exudative pleuritis. Tuberculous pleural effusions had significantly higher levels of IAP, ADA, and AGP than carcinomatous effusions (p less than 0.005). On the other hand, CEA, CA 19-9, and TPA were significantly higher in carcinomatous pleural fluids than in tuberculous fluids (p less than 0.05). There was a correlation between IAP and AGP levels, and their specificity was low. Therefore, combined assays of CEA, CA 19-9, and ADA may be useful in distinguishing pleural effusions due to malignancies from those of tuberculous origin.
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PMID:Carcinomatous and tuberculous pleural effusions. Comparison of tumor markers. 397 60


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