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)

The rational design of antitumor and antiviral agents must ultimately take advantage of biochemical differences between normal host cells and transformed cells. The initial experiments must be performed with subcellular or cellular model systems. For the studies with arabinosyl nucleosides we have chosen those enzyme systems, synthesizing DNA and RNA; being precursor analogues, the different arabinosyl nucleosides have been added in the triphosphate state to the different DNA- and RNA polymerase assays. 1-beta-D-Arabinofuranosylcytosine-5'-triphosphate has been found to inhibit the RNA-dependent DNA polymerases (isolated from oncogenic RNA viruses) 200-fold more sensitively than viral and cellular DNA-dependent DNA polymerases. Recent results, showing that RNA-leukemia-virus-related sequences are present in DNA of some human leukemia patients might support the assumption that the efficacy of this antimetabolite in the treatment of acute leukemia is due to its, at least relative selective inhibitory activity on reverse transcriptase. 9-beta-D-Arabinofuranosyladenine-5'-triphosphate is a strong inhibitor of cellular DNA polymerases with the cytological consequence of an inhibition of cell proliferation. The clinical benefit of the compound in treatment of tumors is dependent on their levels of adenosine deaminase. The triphosphate of this compound is a 100-fold more sensitive inhibitor of the herpesvirus DNA polymerase compared to the cellular replicative DNA polymerase. In addition the analogue, incorporated into herpesvirus DNA, acts as chain terminator. These effects are the biochemical basis for the highly selective antiherpesvirus activity of this antimetabolite. The anomer 9-alpha-D-arabinofuranosyladenine-5'-triphosphate only inhibits cellular replicative DNA polymerase and has no effect on herpesvirus DNA polymerase. Consequently this agent acts only cytostatically and not antivirally. Concerning 1-beta-D-arabinofuranosyluracil and 1-beta-D-arabinofuranosylthymine no pronounced antitumor or antiviral effect is known.
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PMID:Rational design of arabinosyl nucleosides as antitumor and antiviral agents. 61 2

The new fluorinated adenine analog, fludarabine, has been tested for efficacy in many tumor types over the past ten years. Two other similar nucleoside analogs are currently available for commercial use. Cytarabine is used principally as an antileukemic agent, and vidarabine as an antiviral. Unlike vidarabine, fludarabine is resistant to deactivation by adenosine deaminase. Data from Phase I and II trials suggest that fludarabine is potentially effective in a number of leukemias, including acute lymphocytic leukemia, acute nonlymphocytic leukemia, and chronic lymphocytic leukemia (CLL). Unfortunately, the doses required to achieve adequate response in the acute leukemias (greater than 75 mg/m2) were above the maximum tolerated dose, resulting in intolerable granulocytopenia, thrombocytopenia, and a life-threatening neurotoxic syndrome. In CLL: however, the dose required to achieve a satisfactory response is well within tolerated limits. Long-term survival statistics are not yet available, but historical perspective strongly correlates response to other agents with increased survival times. Toxicities seen at dose regimens of 15-40 mg/m2/d for five consecutive days include somnolence, metabolic acidosis, confusion, fatigue, nausea, vomiting, increase in serum creatinine and aminotransferase concentrations, and pulmonary and hepatic abnormalities. Mild to severe hematologic toxicity has been observed at all dose levels.
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PMID:Fludarabine: a review. 206 37

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

This review establishes the pharmacokinetic characteristics of the major nucleoside analogues with cytotoxic activity. Cytarabine, pentostatin, fludarabine, cladribine and gemcitabine are all prodrugs whose plasma pharmacokinetics do not fully reflect their therapeutic activity; after cellular uptake, these compounds undergo phosphorylation by deoxycytidine kinase before their incorporation into DNA results in cell death. Cytarabine is principally active in the S phase of the cell cycle and is most toxic to replicating cells, whereas pentostatin, fludarabine and cladribine are incorporated into DNA during the process in which strand breaks are repaired and are therefore cytotoxic to slowly replicating cells (although the action of pentostatin results from its inhibition of adenosine deaminase). Gemcitabine is unusual in being highly metabolised in solid tumour cells. The cytotoxic activity of pentostatin, fludarabine and cladribine against the clonal cells of lymphoproliferative disorders is accompanied by damage to normal lymphoid cells, which results in significant and long-lasting immunosuppression. Useful interactions between nucleoside analogues have been defined. Cells that are primed by exposure to fludarabine or cladribine exhibit enhanced accumulation of cytarabine triphosphate (the cytotoxic nucleotide of cytarabine) and an improved therapeutic effect against acute myeloid leukaemia and chronic lymphocytic leukaemia can be achieved by clinical schedules that exploit this effect. Combinations of alkylating agents and fludarabine or cladribine are also synergistic in producing significantly enhanced activity against refractory lymphoid malignancies, but at the cost of increased haematological toxicity. Developments in the clinical administration of gemcitabine are concentrating on efforts to extend the duration of exposure to the drug as a means of counteracting its rapid catabolism in the circulation. Future developments with this group of agents will further explore the use of fludarabine-based combination therapies to produce a transient period of myelosuppression and immunosuppression that is sufficient to permit the engraftment of allogeneic haemopoietic stem cells and also exploit the immunological benefits of graft-versus-tumour reactions. In addition, the clinical spectrum of activity of gemcitabine is also being extended by combining the drug with other active chemotherapeutic agents, such as cisplatin, and by early studies of its role as a radiosensitiser.
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PMID:Clinical pharmacokinetics of nucleoside analogues: focus on haematological malignancies. 1092 48

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