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Effects of IMP dehydrogenase inhibitors on the phosphorylation of ganciclovir in MOLT-4 cells before and after herpes simplex virus thymidine kinase gene transduction

R Agbaria, CA Mullen, NR Hartman, DA Cooney, Z Hao, RM Blaese and DG Johns

Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.

We have undertaken to characterize the role of cytoplasmic 5'- nucleotidase (EC 3.1.3.5) in the phosphorylation of the anti-herpes simplex virus and anti-human cytomegalovirus agent ganciclovir (GCV) in MOLT-4 cells, a human T cell line adapted to grow in suspension culture. The rate of formation of GCV triphosphate was found to be approximately doubled by preincubation of nontransfected MOLT-4 cells with agents that cause the accumulation of IMP, such as ribavirin (20 microM) and mycophenolic acid (1 microM), and the reaction rate was found to be unaffected by high levels of thymidine (100 microM). With herpes simplex virus-1 thymidine kinase (HStk) gene-transduced MOLT-4 cells, the rate of GCV phosphorylation was approximately 40-fold faster than that in uninfected cells and, in marked contrast to uninfected cells, the reaction was significantly inhibited both by IMP dehydrogenase inhibitors and by thymidine. These latter effects appear to be the result of 1) the accumulation of high levels of dTTP in IMP dehydrogenase inhibitor-treated cells, with consequent feedback inhibition of HStk, and 2) direct competitive substrate inhibition by thymidine of the HStk-catalyzed phosphorylation of GCV. Thus, agents that enhance 5'-nucleotidase-catalyzed phosphorylation of GCV in uninfected cells do not play a similar role in HStk-transfected cells, a consequence of the quantitative predominance of the viral thymidine kinase-catalyzed reaction over that attributable to endogenous cytoplasmic 5'-nucleotidase.

Volume 45, Issue 4, pp. 777-782, 04/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics




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Copyright © 1994 by the American Society for Pharmacology and Experimental Therapeutics