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)

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.
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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

Ara-C at very low dosage has been reported to decrease the host toxicity of ara-AMP or ara-A in combination with 2'-deoxycoformycin, a potent adenosine deaminase inhibitor, while increasing the toxicity to intracerebral L1210 leukemia. The possibility of increasing the selectivity of ara-A by prior administration of ara-C is explored. The importance of deoxynucleoside kinases, some of which may be cancer-induced, in obtaining selective anticancer effects is discussed. The possibility of a conformational basis for the differing degrees of selectivity and activity of various novel arabinosyl nucleosides is evaluated. The levels of cyclic nucleotides, which have opposing effects on leukemia, may possibly be manipulated to interfere with the growth of cancer cells. Approaches to minimizing major metabolic distortions, such as the progressive accumulation of dATP associated with the use of potent adenosine deaminase inhibitors and which limit the therapeutic effects of ara-A, are proposed.
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PMID:Biochemical and biophysical approaches to improving the anticancer effectiveness of Ara-adenine. 629 45

Whole-blood cultures of human lymphocytes were exposed in the G2-phase (3.5 h before harvesting) to various doses of X-rays and post-treated for 3 h with inhibitors of DNA synthesis. The inhibitors used were 2'-deoxyadenosine (dAdo), hydroxyurea (HU) and 1-beta-D-arabinofuranosylcytosine (ara-C). To prevent deamination of dAdo by adenosine deaminase (ADA), the dAdo treatments were carried out in the presence of the ADA inhibitor coformycin. HU and Ara-C were used either alone or in combination. After the 3-h inhibitor treatments, the cultures were harvested and slides prepared and analyzed for chromatid aberrations in metaphase. When the inhibitors were used at concentrations high enough to cause marked chromosome damage by themselves, very low doses of X-rays (0.025-0.2 Gy) were sufficient to produce a dramatic increase in the frequency of chromatid aberrations. High frequencies of chromatid aberrations were also obtained when cultures that had received moderate doses of X-rays (0.4-0.8 Gy) were post-treated with low inhibitor concentrations that produce no or only a few aberrations by themselves.
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PMID:High frequencies of chromatid aberrations produced during G2 in human lymphocytes by very low doses (0.025-0.4 Gy) of X-rays in combination with inhibitors of DNA synthesis. 633 81

We have investigated the mechanism of resistance of leukemia cells to Ara-C using an in-house cDNA microarray designed for the analysis of leukemia cells. We produced Ara-C-resistant cells from the CCRF-CEM (acute lymphoblastic leukemia) cell line and compared their gene-expression profile with that of wild-type cells. The adenosine deaminase (ADA) gene was highly up-regulated in Ara-C-resistant cells, while equilibrative nucleoside transporter 1 (ENT1) and several cell-cycle-related genes were down-regulated. Of all these genes, ENT1 seemed the most likely to be relevant to Ara-C resistance. To investigate the role of ENT1 in Ara-C-resistant cells, we transfected the cells with the gene. ENT1-transfected Ara-C-resistant cells resembled wild-type CCRF-CEM cells more closely than untransfected Ara-C-resistant cells in terms of growth rate, Ara-C-uptake characteristics, and ADA expression levels. The down-regulation of the ENT1 gene is expected to result in nucleotide deficiency in addition to blockage of Ara-C influx. Accordingly, Ara-C-resistant cells showed low growth rates, which were restored by transfection with ENT1. These low growth rates were also correlated with the phosphorylation level of cell-cycle checkpoint kinase 2. In this study we identified down-regulation of ENT1 as the factor responsible for Ara-C resistance, and this knowledge may be used to devise a clinical regimen that will overcome the resistance.
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PMID:Gene-expression profiling reveals down-regulation of equilibrative nucleoside transporter 1 (ENT1) in Ara-C-resistant CCRF-CEM-derived cells. 1563 14