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Role of Folylpolyglutamates in Biochemical Modulation of Fluoropyrimidines by Leucovorin¹

Department of Molecular Pharmacology [A. R., J. T. L., J. R. B.] and Division of Biostatistics [D. N.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021, and Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425 [M. B., D. G. P.]

The growth-inhibitory effect of fluoropyrimidines combined with a short-term exposure to leucovorin and the pattern of polyglutamylation of folates were compared between parental CCRF-CEM cells and a cell line with impaired ability to form polyglutamates (CCRF-CEM/P). The combination of leucovorin with 5-fluorouracil or 5-fluorodeoxyuridine increased the growth inhibition of CCRF-CEM cells compared to the fluoropyrimidine alone in the parent cell line but not in CCRF-CEM/P cells. In addition, leucovorin produced a significant increase in the inhibition of intracellular thymidylate synthase activity caused by 5-fluorouracil or 5-fluorodeoxyuridine as compared to these drugs alone in CCRF-CEM cells, but no increase in inhibition over that produced by the single drugs alone was observed in CCRF-CEM/P cells. Although levels of 5,10-methylene tetrahydrofolate after leucovorin administration were similar in both cell lines, polyglutamylation of this coenzyme was decreased in the CCRF-CEM/P cell line. The inability of CCRF-CEM/P cells to form significant levels of polyglutamates of N⁵,N¹⁰-methylenetetrahydrofolate, may be responsible for the lack of enhanced cell kill observed when a short exposure to leucovorin is used with fluoropyrimidines.

¹ Supported by the USPHS (Grants CA 08010 and CA 22754).

² Fellow of the Associazione Italiana per la Ricerca sul Cancro, Milan, and Istituto Nazionale per lo Studio e la Cura dei Tumori, Genova, Italy.

³ Norman and Rosita Winston Foundation Clinical Scholar.

⁴ American Cancer Society Professor. To whom requests for reprints should be addressed.

Received 6/11/90. Accepted 11/15/90.

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