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Variation in human thymidylate synthase is associated with resistance to 5-fluoro-2'-deoxyuridine

ST Davis and SH Berger

Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of South Carolina, Columbia 29208.

Two human colorectal tumor cell lines are differentially sensitive to growth inhibition by 5-fluorodeoxyuridine (FdUrd); cell line RCA is less sensitive to FdUrd than is cell line C. Thymidylate synthase (TS), a target of FdUrd, has been purified to homogeneity from both cell lines. Because of differences in the avidity for a folate ligand affinity matrix, TS forms from the cells were purified by two different procedures. Relative to the enzyme from C cells, the enzyme from RCA cells demonstrated higher Km values for the substrates deoxyuridylate and 5,10-methylene-tetrahydrofolate, a lower rate of association of the inhibitor 5-fluorodeoxyuridylate (FdUMP), a similar rate of FdUMP dissociation, and lower enhancement of covalent FdUMP binding by folate derivatives. The activities of the enzymes in situ and the catalytic efficiencies of the purified enzymes were similar. Thus, a cell line that is naturally resistant to FdUrd has been identified that expresses a TS with reduced affinity for FdUMP and 5,10- methylenetetrahydrofolate, relative to the enzyme expressed in a FdUrd- sensitive cell line.

Volume 43, Issue 5, pp. 702-708, 05/01/1993
Copyright © 1993 by American Society for Pharmacology and Experimental Therapeutics




This article has been cited by other articles:


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M. M. Davies, P. G. Johnston, S. Kaur, and T. G. Allen-Mersh
Colorectal Liver Metastasis Thymidylate Synthase Staining Correlates with Response to Hepatic Arterial Floxuridine
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D. M. Landis and L. A. Loeb
Random Sequence Mutagenesis and Resistance to 5-Fluorouridine in Human Thymidylate Synthases
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Copyright © 1993 by the American Society for Pharmacology and Experimental Therapeutics