LEFLUNOMIDE INTERFERES WITH PYRIMIDINE NUCLEOTIDE BIOSYNTHESIS

Leflunomide is an anti-inflammatory and immunosuppressive agent which blocks proliferation of transformed cells and mitogen stimulated norma l lymphocytes but does not block T cell signalling mechanisms at antip roliferative concentrations. These properties are consistent with a me chanism involving interference with nucleotide metabolism. Leflunomide had anti-proliferative activity against all cells tested here. The an ti-proliferative activities could be reversed by addition of uridine o r cytidine to the cultures although some species and cellular differen ces were observed. Purine nucleosides had no effect. Measurements of n ucleotide pools in a human T cell line and mitogen stimulated rat sple en cells treated with leflunomide showed that leflunomide preferential ly reduces pyrimidine nucleotide levels. These results indicate that i nhibition of pyrimidine biosynthesis is responsible for the anti-proli ferative effects of leflunomide.