Elsevier

Biochemical Pharmacology

Volume 26, Issue 21, 1 November 1977, Pages 1967-1972
Biochemical Pharmacology

Specificity of adenosine deaminase inhibitors

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Abstract

The specificity of the potent adenosine deaminase inhibitors deoxycoformycin (covidarabine), coformycin and erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), has been assessed in Ehrlich ascites tumor cells in vitro and in cultured mouse lymphoma L5178Y cells. EHNA is both less potent an inhibitor of adenosine deaminase than deoxycoformycin, and is less specific. High concentrations of deoxycoformycin and EHNA inhibit all pathways of purine ribonucleotide synthesis, and inhibit the conversion of inosinate to adenine and guanine nucleotides. These drugs also inhibit purified adenylate deaminase, but inhibition of this enzyme in intact cells can only be detected at high rates of deamination of adenylate. Deoxycoformycin potentiates the toxicity of adenine against cultured cells.

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      The development of a quantitative and selective method to determine the concentration of adenosine in tumors is needed to assess the impact that adenosine concentrations have on adenosine receptor targeted therapies, to understand differences in adenosine concentrations across different tumor models, and their relationship to response to adenosine antagonists. The method needs to overcome challenges in the quantitative bioanalysis of adenosine in biological matrices which includes: analyte hydrophilicity, low molecular weight, separation from other nucleosides, and a very short half-life from enzymatic degradation [3,5–9]. Additionally, the complexity of a tissue matrix poses problems regarding isolation of the compound of interest from matrix components that lead to perturbations in ionization efficiency in the mass spectrometer (MS).

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    This work was supported by the National Cancer Institute and Medical Research Council of Canada.

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