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Fluorouracil

(5-Fluorouracil; abbr. 5-FU).

Fluorouracil is a substrate for thymidylate synthase, an enzyme which catalyses the conversion of deoxyuridine monophosphate (dUMP) to thymidine monophosphate (TMP) and thus plays a key role in the biosynthesis of pyrimidine bases.

Thymidylate synthase converts Fluorouracil into to 5-fluorodeoxyuridylate in vivo. Fluorouracil is a so-called suicide inhibitor of thymidylate synthase, i.e., a substrate which the enzyme converts into a reactive irreversible inhibitor that immediately inactivates its catalytic activity. Fluorouracil is, therefore, an antimetabolite of nucleic acid synthesis. The compound can be converted also into 5-fluorouridine diphosphate or triphosphate and can be incorporated into RNA.

Fluorouracil has been used extensively in research on cytokines because, after systemic or local administration in vivo or treatment of cells in vitro, it has a temporary inhibitory effect on mouse bone marrow progenitor cells, killing most of them (see also: hematopoiesis).

Fluorouracil mainly affects multilineage colonies (see also: Colony formation assay) containing immature hematopoietic precursor cells known as CFU-GEMM. Fluorouracil has been shown to spare mainly non-cycling hematopoietic stem cells (see also: Cell cycle, quiescent cells). In addition, these surviving stem cells are more primitive than the average normal stem cells and also have a greater self-renewal potential and a high capacity to generate other hematopoietic cell types. Treatment with this compound, therefore, is one way to obtain cell populations with highly enriched primitive hematopoietic stem cell.

Treatment with Fluorouracil or other compounds (see: 4-HC, Hydroperoxycyclophosphamide) can be used also to study the types of hematopoietic progenitor cells developing from protected stem cells.

Cells surviving treatment with Fluorouracil can be assayed in long-term BMC (bone marrow culture), by Limiting dilution analysis, Colony formation assay, or by their ability to repopulate the bone marrow of lethally irradiated recipient mice (see: MRA, marrow repopulating ability).

Such experiments demonstrate that populations of hematopoietic stem cells are heterogeneous with respect to self-renewal capacity, that the cell types differ in their expression of cell surface markers, and that they differ also in their requirements for the presence of certain cytokines.

Cytoreductive treatment in vivo with Fluorouracil can be employed also to study the effects of cytokines and/or other compounds with respect to their protective and/or stimulatory effects on regenerating bone marrow cells and to study the differential toxicity for individual hematopoietic cell lineages.

For other entries pertaining to hematopoiesis see also the Hematology Dictionary section of this encyclopedia.

See REFERENCES for entry Fluorouracil

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