Role of folylpolyglutamates in biochemical modulation of fluoropyrimidines by leucovorin.
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.
Romanini
A
A
Department of Molecular Pharmacology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
Lin
J T
JT
Niedzwiecki
D
D
Bunni
M
M
Priest
D G
DG
Bertino
J R
JR
D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D004357:Drug Synergism; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D002955:Leucovorin / Q000494:pharmacology*; D008727:Methotrexate; D011624:Pteroylpolyglutamic Acids / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D013940:Thymidylate Synthase / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D011624:Pteroylpolyglutamic Acids; D013940:Thymidylate Synthase; D002955:Leucovorin; D005472:Fluorouracil; D008727:Methotrexate