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)

The effect of 3'-deoxyadenosine N(1)-oxide (3'-dANO) on Ehrlich ascites tumor and a human squamous lung cell carcinoma was investigated. The 3'-dANO concentration that inhibited the cell growth 50% (IC(50)) in Ehrlich ascites tumor cells in vitro was 0.15 mM, and the killing efficiency concentration (concentration of the drug that kills all cells) was 1 mM. By simultaneous administration of 3'-dANO and the adenosine deaminase inhibitor erythro-9-(2-hydroxyl-3-nonyl) adenine (EHNA), the IC(50) of 3'-dANO was unchanged, but the killing efficiency concentration of 3'dANO was reduced to 0.3 mM. When mice bearing Ehrlich ascites tumor were treated i.p. with 3'-dANO doses of 200 mg/kg daily for 4 days, the mean increased life span (ILS) was 200%. 3'-dANO in combination with EHNA did not further increase the life span of the tumor-bearing mice. The specific growth delay (SGD) of the Ehrlich tumor and of a human squamous lung cell carcinoma growing subcutaneously in 3'-dANO-treated mice were calculated from Gomperts tumor growth curves. The Ehrlich tumor-bearing mice received 3'-dANO i.p. at doses of 250 mg/kg daily for 4 days, and the nude mice bearing human carcinoma received 3'-dANO i.p. at doses of 225 mg/kg daily for 5 days. The SGD for the investigated tumors were calculated to be 1.0 and 1.1, respectively.
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PMID:The effect of 3'-deoxyadenosine N(1)-oxide on growth in vitro and in vivo on Ehrlich ascites tumor and on a human squamous lung cell carcinoma xenograft in nude mice. 859 87

Because of the difficulty in isolating the causative organism, pericardial tuberculosis is rarely diagnosed. Adenosine deaminase activity measured in the pericardial fluid of 108 patients was initially of undetermined origin. Subsequently, we classified five sources: (1) tuberculosis (20 cases); (2) idiopathy (82 cases); (3) neoplasia (three cases); (4) purulent bacterial infection (two cases); and (5) radiotherapy (one case). The highest mean adenosine deaminase value (126 +/- 16.68 U.l(-1) was found in group 1; other values were 29.4 +/- 8.9, 27 +/- 7.21, 29.5 +/- 13.4, 26 U.l(-1) in the idiopathy, neoplasia, purulent bacterial infection and radiotherapy groups, respectively. there was a statistically significant difference between group 1 and the other groups (P less than 0.001), indicating that the adenosine deaminase value has 100% sensitivity and 91% specificity. In addition, there was a positive correlation between high adenosine deaminase values and the development of constrictive pericarditis. In this study, two patients required pericardectomy. Therefore, the adenosine deaminase value is a significant prognostic indicator for the development of constrictive pericarditis in tuberculous pericarditis.
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PMID:The diagnostic and prognostic value of adenosine deaminase in tuberculous pericarditis. 866 76

Newcastle disease virus (NDV) has received much attention recently because of its non-specific immune stimulating potential and its various anti-tumor activities. Here we describe that NDV induces synthesis of NO and causes an activation of nuclear factor-kappa B (NF-kappa B) in murine macrophages. These reactions were part of an activation process which included also stimulation of adenosine deaminase and inhibition of 5'-nucleotidase. NDV-mediated NO synthesis and NF-kappa B activation were blocked by an antioxidant (butylated hydroxyanisole), by an inhibitor of protein tyrosine kinase (genistein) and of protein kinase A (H-89), but not by an inhibitor of protein kinase C (staurosporin). These data suggest that signalling requirements of NF-kappa B activation and NO production in NDV-treated macrophages are similar.
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PMID:Induction of NO synthesis in macrophages by Newcastle disease virus is associated with activation of nuclear factor-kappa B. 867 35

Adenosine deaminase activity was studied in tissue slices taken endoscopically from gastric mucosa of patients with the intestinal type of gastric carcinoma. The enzyme activity was measured in mucosal homogenates by determination of ammonia liberated from substrate during 10-min incubation. It was found that: (1) the enzyme activity of de novo gastric cancer was significantly lower than that of recurrent cancer of the gastric remnant; and (2) the enzyme activity of uninvaded gastric mucosa surrounding the neoplastic lesion of non-operated stomach was significantly lower than of the gastric mucosa of partially resected stomach due to malignancy. Since the enzyme activity in gastric cancer and surrounding uninvaded gastric mucosa correlated well with the advance of neoplastic disease estimated by ultrasonography examination, we speculate that some systemic factors associated with tumor progression might be implicated in the regulation of adenosine deaminase activity.
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PMID:Adenosine deaminase activity in patients with the intestinal type of gastric carcinoma. 902 Sep 21

The purine nucleoside adenosine (9-beta-D-ribofuranosyladenine) inhibits a number of lymphocyte functions in vitro, including the ability of activated T lymphocytes and natural killer cells to adhere to and kill tumor targets. Solid tumors, such as adenocarcinomas of the lung and colon, are frequently hypoxic and are, therefore, likely to exhibit increased adenine nucleotide breakdown through the 5'-nucleotidase pathway, yielding adenosine. We examined whether the concentration of adenosine in the extracellular fluid of such tumors is adequate to cause immunosuppression. Murine tumors grown in syngeneic hosts or human tumors grown in immunodeficient nu/nu mice were subjected to microdialysis, and adenosine levels in the microdialysate were measured by high-performance liquid chromatography. Treatment of the tumor microdialysates with adenosine deaminase eliminated the adenosine peak. Recovery of adenosine ranged from 15 to 29%, depending on the microdialysis probe, and concentrations of adenosine in tumors ranged from 0.2 to 2.4 microM with a mean of 0.5 microM. In contrast, the adenosine concentration measured s.c. at the same location was 30 +/- 5 nM (mean +/- SE). Inclusion of the adenosine deaminase inhibitor coformycin (10 microM) and the adenosine kinase inhibitor 5'-iodotubercidin (0.1 microM) in the microdialysis perfusion buffer increased extracellular adenosine concentration in tumors to as high as 13 microM. These data show that extracellular adenosine levels in solid tumors are sufficient to suppress the local antitumor immune response and that interference with pathways of adenosine metabolism causes marked increases in tumor extracellular adenosine concentration.
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PMID:The extracellular fluid of solid carcinomas contains immunosuppressive concentrations of adenosine. 920 63

Identification of A1 adenosine receptors (A1Rs) in a tumor cell line derived from rat pituitary (GH4 cells) was performed by ligand binding and immunological experiments. Subsequently, the involvement of A1Rs in the regulation of calcium conductance was studied in these cells. The agonist N6-(R)-(2-phenylisopropyl)adenosine (R-PIA) did not modify the intracellular calcium basal levels, whereas it inhibited the increase produced by 15 mM KCl depolarization. The antagonist 1,3-dipropyl-8-cyclopentylxanthine led to the opening of voltage-dependent cell surface calcium channels in the absence of exogenous KCl. The channels were of the L type because the effect was abolished by calciseptine and by verapamil. These results suggest that endogenous adenosine exerts a tonic inhibitory effect on calcium transport. This was confirmed by the high adenosine concentration found in cell supernatants (up to 1 microM) and by the calcium mobilization produced by exogenously added adenosine deaminase. In depolarizing conditions, the calcium peak in the presence of adenosine deaminase was reduced when cells were preincubated with R-PIA, thus suggesting that A1R activation regulates the intensity of depolarization. These results demonstrate that adenosine is an important regulator of the physiological state of pituitary tumor cells by modulating, in an autocrine manner, the activity of L-type voltage-dependent calcium channels.
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PMID:Regulation of L-type calcium channels in GH4 cells via A1 adenosine receptors. 937 88

Host-cell reactivation (HCR) of UV-C-irradiated herpes simplex virus type 1 (HSV-1) has been determined in skin fibroblasts from the following hereditary cancer-prone syndromes: aniridia (AN), dysplastic nevus syndrome (DNS), Von Hippel-Lindau syndrome (VHL), Li-Fraumeni syndrome (LFS) and a family with high incidence of breast and ovarian cancer. Cells from AN, DNS or VHL patients were found to exhibit heterogeneity in HCR. Cells from individuals belonging to an LFS family show reduced HCR in all cases where the cells were derived from persons carrying one mutated p53 allele, whereas cells derived from members with two wild-type alleles show normal HCR. LFS cells with reduced HCR also reveal reduced genome overall repair, and a slower gene-specific repair of the active adenosine deaminase (ADA) gene, but little if any repair of the inactive 754 gene. In the breast/ovarian cancer family, reduced HCR is observed in skin fibroblasts derived from both afflicted and unaffected individuals. In addition, these cells display lower survival after exposure to UV-C and exhibit higher levels of SCEs than those in normal cells. These observations indicate that various hereditary cancer-prone syndromes, carrying mutations in different tumor-suppressor genes, exhibit an unexplained impairment of the capacity to repair UV-damaged DNA.
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PMID:Impaired DNA repair capacity in skin fibroblasts from various hereditary cancer-prone syndromes. 963 47

T cells are important effector cells in natural antiviral and anticancer immunity. It is important to reveal the cellular and molecular requirements for T cell differentiation and effector functions. We explored the idea that the final outcome of antigen receptor-driven immune processes is at least partially determined by physiologically abundant small signaling molecules in extracellular environment of lymphocytes in different tissues. Extracellular purines (ATP and adenosine) and their (purinergic) receptors were studied as an example of such molecules. Studies of functional effects of extracellular ATP and adenosine in immunoregulation have evolved in studies of individual molecules of purinergic receptors and of phosphorylation of extracellular domains of functionally important proteins. ATP-gated membrane pore, p2x 7(formerly p2z receptor) and A2a adenosine receptors are found to be predominantly expressed in T cells. The Gs-protein coupled A2a receptors activate cAMP-dependent protein kinase which was shown to have dual role in regulation of T cells functions. The results of our recent studies of adenosine receptors indicate that A2a receptors on T cell surface may play immunosuppressive role in conditions which lead to accumulation of extracellular adenosine. These conditions include pharmacological intervention with widely used anti-inflammatory drugs (methotrexate and sulfasalazine) and extracellular environment near large solid tumors. Hypoxic conditions in such tumors are known to cause accumulation of extracellular adenosine, which, in turn, as we have shown, could inhibit incoming antitumor cytotoxic T-lymphocytes from destroying the tumor. Normal development and functions of immune cells require adenosine deaminase (ADA) activity. Absence or low levels of ADA in humans result in severe combined immunodeficiency (SCID), which is characterized by hypoplastic thymus, T lymphocyte depletion, and autoimmunity. ADA SCID is currently explained only by intracellular lymphotoxicity of accumulated adenosine. We propose that T cell depletion, immunodeficiency, and autoimmunity could also be due to extracellular adenosine-induced signaling, which inhibits the antigen receptor (TCR) signaling and therefore affects the TCR-driven positive and negative selection of thymocytes. This, in turn, may lead to changes in antigen receptor repertoires and to immunodeficiency, Such properties of adenosine receptors suggest an expanded understanding of pathogenesis of ADA SCID as being due to two independent (intracellular and extracellular) mechanisms of adenosine action. It was conclusively demonstrated that functionally important T cell surface proteins including T cell receptor- are constitutively Ser/Thr phosphorylated on their ectodomains. We identified the major ecto-protein kinase activity in T-lymphocytes as casein kinase II-like (CKII-like) protein kinase. Consensus phosphorylation sites for serine and threonine protein kinases were found to be strongly evolutionary conserved in both alfa and beta TCR chains constant region. We have shown that ecto- or releasable by T-cells protein phosphatase has properties of PP1 and PP2a class protein phosphatase. Such covalent modifications of ectodomains may change T cells cognate interactions by e.g. affecting TCR-multimolecular complex formation and antigen binding affinity. It is suggested that TCR ectodomain phosphorylation could serve as a potential mechanism for regulation of TCR-mediated T-lymphocytes response.
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PMID:Extracellular purines and their receptors in immunoregulation. Review of recent advances. 980 87

N6-Cyclopropyl-PMEDAP (cPr-PMEDAP) is a novel derivative of the acyclic nucleoside phosphonate 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP). Its cytostatic activity was found to be 8- to 20-fold more pronounced than that of PMEDAP and equivalent to that of the guanine derivative 9-(2-phosphonylmethoxyethyl)guanine (PMEG) against a variety of tumor cell lines. Unlike PMEDAP, but like PMEG, cPr-PMEDAP was equally cytostatic to wild-type and 9-(2-phosphonylmethoxyethyl)adenine/PMEDAP-resistant variants of the human erythroleukemia K562 and the murine leukemia L1210 cell lines. Also, cPr-PMEDAP and PMEG proved to be equipotent inducers of K562 and rat choriocarcinoma RCHO cell differentiation, whereas the differentiation-inducing activity of PMEDAP was 5- to 25-fold less pronounced. Furthermore, compared to PMEDAP, cPr-PMEDAP and PMEG were 10- to 25-fold more potent in inhibiting the progression of K562 cells through the S phase of the cell cycle, resulting in a marked accumulation of the four 2'-deoxyribonucleoside 5'-triphosphate pools. The biological effects of cPr-PMEDAP, but not PMEDAP, were reversed by the adenylate deaminase inhibitor 2'-deoxycoformycin (dCF). Formation of the deaminated derivative of cPr-PMEDAP (i.e. PMEG) was demonstrated in crude extracts from K562 and L1210 cells and in metabolism studies with radiolabeled cPr-PMEDAP and PMEG. This is the very first example of an acyclic nucleoside phosphonate analogue that is susceptible to deamination. However, cPr-PMEDAP was not recognized as a substrate by purified adenosine deaminase or by adenylate deaminase. These findings might point to an as yet unidentified cellular enzyme, sensitive to dCF but different from the common adenosine and AMP deaminases. Our data demonstrate the superior antiproliferative and differentiation-inducing effects of cPr-PMEDAP on tumor cells, as compared to the parent compound PMEDAP, based on the unique metabolic properties of this novel compound.
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PMID:N6-cyclopropyl-PMEDAP: a novel derivative of 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP) with distinct metabolic, antiproliferative, and differentiation-inducing properties. 1042 73

Polymer conjugation is of increasing interest in pharmaceutical chemistry for delivering drugs of simple structure or complex compounds such peptides, enzymes and oligonucleotides. For long time drugs, mainly with antitumoral activity, have been coupled to natural or synthetic polymers with the purpose of increasing their blood permanence time, taking advantage of the increased mass that reduces kidney ultrafiltration. However only recently complex constructs were devised that exploit the 'enhanced permeability and retention' (EPR) effect for an efficient tumor targeting, the high molecular weight for adsorption or receptor mediated endocytosis and finally a lysosomotropic targeting, taking advantage of acid labile bonds or cathepsin susceptible polypeptide spacers between polymer and drug. New original, very active conjugates of this type, as those based on poly(hydroxyacrylate) polymers, are already in advanced state of development. Labile oligonucleotides, including antisense drugs, were also successfully coupled to polymers in view of an increased cell penetration and stabilization towards nucleases. However, the most active research activity resides in the field of polypeptides and proteins delivery, mainly for the two following reasons: first of all because a great number of therapeutically interesting compounds are now being produced by genetic engineering in large quantity and, secondly, because these products are difficult to administer to patients for several inherent drawbacks. Proteins are in fact easily digested by many endo- and exo-peptidases present in blood or in other body districts; most of them are immunogenic to some extent and, finally, they are rapidly excreted by kidney ultrafiltration. Covalent polymer conjugation at protein surface was demonstrated to reduce or eliminate these problems, since the bound polymer behaves like a shield hindering the approach of proteolytic enzymes, antibodies, or antigen processing cell. Furthermore, the increase of the molecular weight of the conjugate allows to overcome the kidney elimination threshold. Many successful results were already obtained in peptides and proteins, conjugated mainly to water soluble or amphiphilic polymers like poly(ethylene glycol) (PEG), dextrans, or styrenemaleic acid anhydride. Among the most successful are the conjugates of asparaginase, interleukin-2 or -6 and neocarcinostatin, to remind some antitumor agents, adenosine deaminase employed in a genetic desease treatment, superoxide dismutase as scavenger of toxic radicals, hemoglobin as oxygen carrier and urokinase and streptokinase as proteins with antithrombotic activity. In pharmaceutical chemistry the conjugation with polymers is also of great importance for synthetic applications since many enzymes without loss of catalytic activity become soluble in organic solvents where many drug precursors are. The various and often difficult chemical problems encountered in conjugation of so many different products prompted the development of many synthetic procedures, all characterized by high specificity and mild condition of reaction, now known as 'bioconjugation chemistry'. Bioconjugation developed also the design of new tailor-made polymers with the wanted molecular weight, shape, structure and with the functional groups needed for coupling at the wanted positions in the chain.
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PMID:Bioconjugation in pharmaceutical chemistry. 1051 Aug 47


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