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 previously reported resistance of 9-substituted adenines to ring alkylation in alkaline medium was profited from to prepare all seven possible O' methyl derivatives of the therapeutically important 9-beta-D-arabinofuranosyladenine (araA) by mild methylation of the latter with dimethylsulfate in aqueous alkaline medium. All the products were fractionated and isolated in a single step on a Dowex OH- column. The sequence of elution of the various derivatives was strikingly similar to that for the O' methyl derivatives of 1-beta-D-arabinofuranosylcytosine, previously reported, suggestive of a similar sequence of acidities of the sugar hydroxyls. The products were identified by various criteria, including PMR spectroscopy, extensive data for which are supplied. The 2'-O-methyl and 3'-O-methyl derivatives of araA exhibited appreciably lower susceptibility to calf intestinal adenosine deaminase than the parent araA. The 5'-O-methyl analogue was fully resistant to enzymatic deamination.
Cancer Biochem Biophys 1976 May
PMID:Preparation and properties of the O-methyl derivatives of 9-beta-D-arabinofuranosyladenine. 97 22

Adenosine deaminase (EC 3.5.4.4., ADA) has been measured in the blast cells of 36 patients with acute lymphoblastic, acute myeloid, chronic myeloid and chronic myeloid blast crisis leukaemia. Particularly high levels were found in acute lymphoblastic and chronic myeloid blast crisis patients. The measurement of ADA may be useful diagnostically in the undifferentiated acute leukaemias and in detecting the early onset of blast crisis in chronic myeloid leukaemia. Possible reasons for the elevation of ADA in malignant cells are discussed.
Br J Cancer 1975 May
PMID:Adenosine deaminase activity in leukaemia. 105 44

Adenosine deaminase (EC 3.5.4.4, ADA) has been assayed in lymphocytes, granulocytes and erythrocytes from 45 patients with haematological malignancies. Activities were uniformly low in lymphocytes from patients with chronic lymphocytic leukaemia. Variable, but abnormal activities were frequently found in multiple myeloma, untreated lymphoma and leukaemic reticuloendotheliosis. High values were observed in lymphocytes from patients with lymphoma during intensive combination chemotherapy. ADA levels in lymphocytes were not correlated with levels in granulocytes or erythrocytes. ADA was elevated in blasts of patients with acute lymphocytic and myelogenous leukaemias but the ranges of activities per cell were so similar that ADA assay is unlikely to be of major help in distinguishing the two diseases.
Br J Cancer 1976 Mar
PMID:Adenosine deaminase activity in peripheral blood cells of patients with haematological malignancies. 106 90

Deamination of many analogs of adenine nucleosides results in the loss of their chemotherapeutic efficacy. Two approaches have been used in this study to overcome this problem. First, some adenine nucleotides, which are resistant to mammalian adenosine deaminase, are more toxic to animal cells than are the respective nucleosides. For toxic to animal cells than are the respective nucleosides. For example, 9-beta-D-arabinofuranosyladenine 5'-phosphate, a molecule that penetrates the cell without degradation, has a more sustained toxicity against mouse fibroblasts (L-cells) than does 9-beta-D-arabinofuranosyladenine (ara-A). Furthermore, L-cells treated with 2',3'-dideoxyadenosine 5'-phosphate are extensively killed after 48 hr, whereas 2',3'-dideoxyadenosine is almost nontoxic to L-cells. Specific inhibition of adenosine deaminase by nontoxic concentrations of erythro-9-(2-hydroxy-3-nonyl)adenine greatly potentiates the biological activity of both ara-A and 3'-deoxyadenosine (cordycepin). Simultaneous administration of cytostatic concentrations of ara-A and the inhibitor of adenosine deaminase to L-cells killed greater than 99.9 percent of cells in 36 hr. A similar concentration of ara-A plus the deaminase inhibitor also markedly extended the mean survival of mice bearing Ehrlich ascites carcinoma as compared to ara-A alone. A cytostatic concentration of cordycepin 1 x 10-4 M), administered in the presence of deaminase inhibitor, killed greater than 99.9 percent of cultured L-cells in only 8 hr. During the latter incubation, accumulation of uridine in acid-insoluble material reached a maximum after 30 min, and incorporation of thymidine into acid-insoluble material was almost totally arrested after 2 hr.
Cancer Res 1975 Jun
PMID:Two approaches that increase the activity of analogs of adenine nucleosides in animal cells. 107 75

Previous studies have demonstrated that human malignancies can synthesize large amounts of thromboxane. It has also been reported that thromboxane can significantly alter multiple components of physiologic and immunologic function. We investigated the effect of elevated levels of thromboxane on host response to tumor using multiple rat models, and the long acting thromboxane analogue U-46619. Administration of the thromboxane analogue was not found to significantly alter the growth of primary tumors or peritoneal metastases. The analogue was found to significantly decrease mean survival time with a pulmonary metastases model. The thromboxane analogue failed to alter macrophage cytotoxicity, lymphocyte cytotoxicity, T lymphocyte subset numbers, or lymphocyte blastogenic response. Administration of the thromboxane analogue decreased the rate of lymphocyte metabolism of glucose and decreased lymphocyte intracellular adenosine deaminase activity. In conclusion, elevated thromboxane levels do not appear to alter primary tumor growth or host immune function, but do decrease resistance to pulmonary metastases.
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PMID:The effect of elevated levels of thromboxane on host response to tumor. 154 78

8-Chloroadenosine 3':5'-monophosphate (8ClcAMP) inhibits the growth of human glioma cell lines at much lower concentrations than more commonly used cyclic AMP analogues, without inducing morphological differentiation. The mechanism by which 8ClcAMP exerts this effect is not fully understood. We examined whether the growth-inhibitory effect of this compound is due to an active metabolite, using a sulforhodamine protein stain assay to determine the proliferation rate of the WF human glioma cell line. 8-Chloroadenosine, one of the metabolites, inhibited the proliferation of WF human glioma cells more potently than 8ClcAMP. In the presence of adenosine deaminase, which converts 8-chloroadenosine into 8-chloroinosine, 8-chloroadenosine no longer inhibited human glioma cell growth. Addition of adenosine deaminase also largely reduced the growth-inhibitory effect of 8ClcAMP, but not of 8-(4-chlorophenylthio)cAMP. High performance liquid chromatography analysis revealed that at least part of the 8ClcAMP in the culture medium is converted into 8-chloroadenosine. We concluded that 8ClcAMP exerts its growth-inhibitory effect through its active metabolite 8-chloroadenosine. Adenylate cyclase assays showed that 8-chloroadenosine does not affect the intracellular cAMP production through adenosine A1 or A2 receptor activation, which makes it unlikely that 8-chloroadenosine inhibits glioma cell growth by increasing the intracellular cyclic AMP concentration.
Cancer Res 1992 Jul 15
PMID:Growth inhibition of human glioma cells induced by 8-chloroadenosine, an active metabolite of 8-chloro cyclic adenosine 3':5'-monophosphate. 161 76

Fludara I.V. (fludarabine phosphate) (9-beta-D-arabinosyl-2-fluoroadenine, F-ara-A) is an adenine nucleoside analogue resistant to adenosine deaminase that shows promising therapeutic activity in the clinical treatment of lymphocytic hematologic malignancies. F-ara-A is transported into cells, where it is converted to its 5'-triphosphate (F-ara-ATP), the principal active metabolite. Deoxycytidine kinase is the enzyme responsible for the initial step of this activation metabolism. The differential transport and phosphorylation of F-ara-A and accumulation of F-ara-ATP by normal and cancer cells may constitute the metabolic basis of its positive therapeutic index. The major action of F-ara-A is the inhibition of DNA synthesis. F-ara-ATP competes with deoxyadenosine triphosphate for incorporation into the A sites of the elongating DNA strand by DNA polymerases and terminates DNA synthesis at the incorporation sites. That action is potentiated by the decrease of cellular dATP that results from inhibition of ribonucleotide reductase by F-ara-ATP. In vitro experiments demonstrated that DNA polymerase delta is able to excise the incorporated F-ara-AMP residues from DNA with its 3' to 5' exonuclease activity. The terminal incorporation of F-ara-AMP into DNA results in deletion of genetic material. That mechanism may be responsible for the observed mutagenicity of Fludara I.V., and ultimately its cytotoxic action.
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PMID:Metabolism and action of fludarabine phosphate. 169 80

Fludarabine phosphate is the 2-fluoro, 5'-monophosphate derivative of vidarabine (ara-A) with the advantages of resistance to deamination by adenosine deaminase (ADA) and improved solubility. The mechanism of cytotoxic action of the compound appears to involve metabolic conversion to the active triphosphate. Fludarabine phosphate has substantial activity against lymphoid malignancies, particularly chronic lymphocytic leukemia (CLL) and low-grade non-Hodgkin's lymphoma (NHL). Its single-agent activity in CLL appears at least comparable to those of other conventional combination regimens. Its activity in Hodgkin's disease, mycosis fungoides, and macroglobulinemia, although suggestive, needs to be further defined and clinical trials are warranted in hairy cell leukemia, prolymphocytic leukemia, and previously untreated myeloma. The compound does not appear active against most common solid tumors. Early clinical trials indicated significant myelosuppression and the potential for severe neurotoxicity. Toxicity on the currently used low-dose schedules includes transient and reversible myelosuppression, nausea and vomiting, diarrhea, somnolence/fatigue, and elevations of liver enzymes and/or serum creatinine. Possible pulmonary toxicity has been suggested in several patients. The currently used low-doses of fludarabine phosphate, even with repeated administration, are well tolerated and appear safe with a negligible risk for severe neurotoxicity. Based on its single-agent activity and tolerability, the Food and Drug Administration recently granted group C designation of the drug for the treatment of patients with refractory CLL outside the clinical trials setting. The use of fludarabine phosphate in combination regimens and its impact on the natural history of the lymphoid malignancies is yet to be determined. Fludarabine phosphate may well occupy a pivotal role in the management of CLL and low-grade NHL.
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PMID:Fludarabine phosphate: a synthetic purine antimetabolite with significant activity against lymphoid malignancies. 170 43

8-Chloroadenosine 3',5'-monophosphate has been reported to inhibit growth of various mammalian cell lines at micromolar concentrations. We have used Chinese hamster ovary cell lines with mutated cyclic AMP-dependent protein kinase or altered cyclic nucleotide metabolism to show that a metabolite, 8-chloroadenosine, is formed in the medium and is the active inhibitor of cell growth in Chinese hamster ovary cells. Adding adenosine deaminase to the Chinese hamster ovary cell growth media removes the inhibition of cell growth attributed to 8-chloroadenosine 3',5'-monophosphate. Adenosine deaminase or dipyridamole also protects Molt-4 lymphoblasts from the growth-inhibitory effects of 8-chloroadenosine 3',5'-monophosphate.
Cancer Res 1991 Mar 15
PMID:8-Chloroadenosine 3',5'-monophosphate inhibits the growth of Chinese hamster ovary and Molt-4 cells through its adenosine metabolite. 193 80

The application of bone marrow gene therapy has been stalled by the inability to achieve stable high-level gene transfer and expression in the totipotent stem cells. We show that retroviral vectors can stably introduce genes into antigen-specific murine and human T lymphocytes in culture. Murine helper T cells were transduced with the retroviral vector SAX to express both neomycin-resistance and human adenosine deaminase genes. These cells were expanded in culture and selected for expression of neomycin resistance with G418. The gene insertion, selection, and culture expansion did not alter antigen specificity or growth characteristics of the T cells in vitro. To determine if cultured T cells might be used for gene therapy, their persistence and continued expression of the introduced genes was evaluated in nude mice transplanted with the SAX-transduced T cells. G418-resistant cells could be readily recovered from the spleens of recipients of transduced T cells for several months. In addition, recovered cells continued to produce human adenosine deaminase. Based on these observations, we studied cultured human tumor-infiltrating lymphocytes as a candidate cell for a trial of gene transfer in man. Exponential cultures of interleukin-2-stimulated tumor-infiltrating lymphocytes were efficiently transduced with the neomycin-resistance gene using the retroviral vector N2. Gene insertion and subsequent G418 selection did not substantially alter the growth characteristics, interleukin 2 dependence, membrane phenotype, or cytotoxicity profile of the transduced T cells. These studies provided a portion of the experimental evidence supporting the feasibility of the presently ongoing clinical trials of lymphocyte gene therapy in cancer as well as in patients with adenosine deaminase deficiency.
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PMID:Lymphocytes as cellular vehicles for gene therapy in mouse and man. 201 35


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