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Molecular Pharmacology, Vol 20, 200-205, Copyright © 1981 by the American Society for Pharmacology and Experimental Therapeutics

Metabolism of 9-beta-D-Xylofuranosyladenine by the Chinese Hamster Ovary Cell

BRUCE A. HARRIS 1, PRISCILLA P. SAUNDERS 1, and WILLIAM PLUNKETT 1

1 The Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, and the Department of Developmental Therapeutics, The University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute, Houston, Texas 77030

The uptake, phosphorylation, and biological half-life of the purine nucleoside analogue 9-beta-D-xylofuranosyladenine (xyl-A) was studied in wild-type Chinese hamster ovary cells and in nucleoside kinase-deficient mutants. It was found that [3H]xyl-A and [3H]adenosine were readily phosphorylated to the triphosphate level in both the wild-type and deoxycytidine kinase (EC 2.7.1.74)-deficient mutant, but neither of these adenine nucleosides was phosphorylated by the adenosine kinase (EC 2.7.1.20)-deficient cells. The reproductive capacity of wild-type and deoxycytidine kinase deficient cells was inhibited 50% by 3 and 4 µM xyl-A, respectively, whereas cells deficient in adenosine kinase were resistant to 100 µM xyl-A. Cellular uptake of xyl-A into the wild-type cells was followed through 6 hr of incubation. Values for the apparent Km and Vmax of this uptake process were 43.9 µM and 118.7 nmoles/min/109 cells, respectively. The major intracellular metabolite of xyl-A, the 5'-triphosphate xyl-ATP, accumulated to a 3.6-fold higher concentration than xyl-ADP, with very little xyl-AMP detected. The biological half-life of xyl-ATP was 5.1 hr, significantly longer than the congener analogue, 9-beta-D-arabinofuranosyladenine 5'-triphosphate, in the same cell line. These results demonstrate in a single cell line that xyl-A does not produce cytotoxicity as a free nucleoside; phosphorylation to the nucleoside 5'-triphosphate, an activating pathway initiated by adenosine kinase, is required for activity of the compound.

Submitted on November 11, 1980
Accepted on March 2, 1981




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