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)

Antimetabolic anticancer agents possess their own target enzymes: that of methotrexate is dihydrofolate reductase; 5-fluorouracil and ZD1604, thymidylate synthase; hydroxyurea, ribonucleotide reductase; 2'-deoxycoformycin, adenosine deaminase; N-(phosphonacetyl)-L-aspartate, aspartate transcarbamylase. Overproduction of each target enzyme has been observed with various animal and human cell lines which acquired resistance to all these agents. These facts suggest that this is a common mechanism for resistance to these agents. Most of these resistant cells showed amplification of the corresponding genes in double minute chromosome or homogeneously stained region of the chromosome. The relation between the degree of resistance and those of enzyme overproduction, the expression and amplification of the gene coding for each enzyme protein in various resistant cell lines are demonstrated and discussed.
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PMID:[Acquisition of resistance to anticancer agents by overproduction of target enzymes]. 915 48

The studies on the metabolism and toxic mechanism of 2-chloro-2'-deoxyadenosine (2CdA, Cladribine), a new antileukemic drug, were reviewed. 2CdA, being a 2-halogenated, adenosine deaminase-resistant analogue of deoxyadenosine, is phosphorylated to the mono-, di, and triphosphate chlorodeoxy adenosine and the first step of phosphorylation is taken in the presence of enzymes, mainly kinase deoxycytidine (although in mitochondria it is phosphorylated by kinase deoxyguanosine). Triphosphate derivative of 2CdA is commonly considered to be the agent inducing cell apoptosis resulting from inhibition of ribonucleotide reductase, DNA polymerases and DNA repair. Recent studies on toxicity of 2CdA showed that the nucleoside possesses inhibitory activity against enzymes which are responsible for metabolism of deoxyadenosine, which suggests that the mechanism of toxicity by 2CdA includes a block in dAdo metabolic pathways which is very important for normal function of immune system cells. The agent under discussion and two other adenosine analogues (i.e. fludarabine and 2'-deoxycoformycin) which exhibit cytotoxicity against dividing and resting lymphocytes revolutionized the treatment of indolent lymphoid malignancies (i.e. chronic lymphocytic leukemia, non-Hodgkin's lymphoma, cutaneous T cell lymphoma and hairy cell leukemia). Particularly, in the treatment of hairy cell leukemia, 2-chloro-2'-deoxyadenosine demonstrated excellent efficacy, achieved after a single 7-day course, with an acceptable tolerability profile, suggesting that cladribine is likely to be more effective than other agents recommended in this disease. Preliminary clinical data, extremely encouraging in the case of 2CdA indicate that biomolecular mechanisms of the drug cytotoxicity is worth wide presentation.
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PMID:2-Chloro-2'-deoxyadenosine (2CdA) biochemical aspects of antileukemic efficacy. 941 93

The effects of 2-chloro-2'-deoxyadenosine (CdA, cladribine), an adenosine deaminase-resistant analogue toxic for both proliferating and resting lymphoid cells, were investigated in the human leukemia cell line EHEB, which was derived from a patient with B-cell chronic lymphocytic leukemia. These cells were found to be less sensitive to CdA than B-cell chronic lymphocytic leukemia lymphocytes (approximately 25-fold) and other human lymphoblastic cell lines (10-1000-fold). Phosphorylation of CdA by deoxycytidine kinase and intracellular accumulation of 2-chloro-2'-deoxyadenosine triphosphate (CdATP) were similar in EHEB cells and in other CdA-sensitive cell lines. In contrast, the inhibitory effect of CdA on ribonucleotide reductase activity, which was investigated in situ by the conversion of cytidine into deoxyribonucleotides and its incorporation into DNA, was much less pronounced in EHEB cells than in other human lymphoblastic cells. Accordingly, concentrations of deoxynucleoside triphosphates did not decrease and even tended to rise. Unexpectedly, incorporation of thymidine and deoxycytidine into DNA was increased severalfold after a 24-h incubation with CdA. CdA also increased the activities of deoxycytidine kinase and thymidine kinase approximately 4-fold. Analysis of the cell cycle by flow cytometry showed that after 24 h, CdA provoked an increase in the proportion of cells in S phase, synthesizing DNA. We conclude that the EHEB cell line is resistant to the cytotoxic action of CdA not only because of a lack of inhibition of ribonucleotide reduction but also because CdA, in contrast with its known effects, provokes in this cell line an increase in the proportion of cells replicating their DNA. Unraveling of the mechanism of this effect may shed light on clinical resistance to CdA.
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PMID:Resistance to 2-chloro-2'-deoxyadenosine of the human B-cell leukemia cell line EHEB. 1170 77

Pentostatin (Nipent), formerly known as deoxycoformycin, is a profound inhibitor of the enzyme adenosine deaminase, resulting in the accumulation of metabolites that inhibit ribonucleotide reductase, which in turn inhibits DNA synthesis. Pentostatin was the first of the purine analogs to undergo extensive testing as an anticancer agent and the first to receive US Food and Drug Administration approval for a treatment indication. It is highly effective as first-line monotherapy in hairy cell leukemia, with a complete response rate of 80% and a 10-year survival rate of around 80%. Pentostatin is also active in chronic lymphocyte leukemia as a single agent, but appears even more promising in combination approaches with the alkylating agents chlorambucil or cyclophosphamide. Due to the increasing recognition of delayed severe stem cell and immune suppression following therapy with other purine analogs, there has been renewed interest in pentostatin, especially in combination with chemotherapy and/or the monoclonal antibody rituximab (Rituxan) in chronic lymphocyte leukemia.
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PMID:Pentostatin (Nipent) in the treatment of chronic lymphocyte leukemia and hairy cell leukemia. 1474 54


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