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Molecular Pharmacology, Vol 18, 287-295, Copyright © 1980 by the American Society for Pharmacology and Experimental Therapeutics

An in Vivo and in Vitro Evaluation of 1-beta-D-Ribofuranosyl-1,2,4-triazole-3-carboxamidine: An Inhibitor of Human Lymphoblast Purine Nucleoside Phosphorylase

RANDALL C. WILLIS 1, ROLAND K. ROBINS 2, and J. EDWIN SEEGMILLER 1

1 Department of Medicine, University of California, San Diego, La Jolla, California 92093
2 Department of Chemistry, Brigham Young University, Provo, Utah 84601

The synthetic nucleoside analog, 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamidine (TCNR), is a competitive, reversible inhibitor of inosine phosphorolysis by human lymphoblast punne nucleoside phosphorylase. TCNR is not a substrate for the enzyme. The apparent Ki of TCNR is 5 x 10-6 M under conditions providing an apparent Km of 2.5 x 10-5 M for inosine phosphorolysis. In both in vivo and in vitro assays TCNR is 7-10 times more potent than a previously described inhibitor of purine nucleoside phosphorylase, Formycin B. TCNR and Formycin B have growth inhibitory properties unrelated to inhibition of purine nucleoside phosphorylase. This additional effect of TCNR, inhibition of IMP dehydrogenase, is eliminated in studies using lymphoblast lines deficient in adenosine kinase, but this mutation has no effect on the growth inhibition produced by Formycin B. The primary effect of TCNR on purine nucleoside phosphorylase in intact cells is best demonstrated with a human lymphoblast line deficient in both adenosine kinase and hypoxanthine-guanine phosphoribosyltransferase which allows accumulation of inosine, guanosine, deoxyinosine, and deoxyguanosine in the medium. The accumulation of these nucleosides does not inhibit the growth of the human B lymphoblast.

Submitted on November 5, 1979
Accepted on April 28, 1980




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