Role of folylpolyglutamates in biochemical modulation of fluoropyrimidines by leucovorin

Cancer Res. 1991 Feb 1;51(3):789-93.

Abstract

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-methylenete-trahydrofolate, may be responsible for the lack of enhanced cell kill observed when a short exposure to leucovorin is used with fluoropyrimidines.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cell Division / drug effects
  • Dose-Response Relationship, Drug
  • Drug Resistance
  • Drug Synergism
  • Fluorouracil / pharmacology*
  • Humans
  • Leucovorin / pharmacology*
  • Methotrexate
  • Pteroylpolyglutamic Acids / metabolism*
  • T-Lymphocytes / cytology
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / metabolism*
  • Thymidylate Synthase / biosynthesis*
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism

Substances

  • Pteroylpolyglutamic Acids
  • Thymidylate Synthase
  • Leucovorin
  • Fluorouracil
  • Methotrexate