PMID: 7529314Jan 1, 1995Paper

The immunosuppressant leflunomide inhibits lymphocyte progression through cell cycle by a novel mechanism

The Journal of Pharmacology and Experimental Therapeutics
H M CherwinskiJ T Ransom

Abstract

Leflunomide is a novel and effective immunosuppressant that holds promise as a therapeutic agent, but the mechanism of action is unknown. Here we provide evidence that leflunomide is a general cytostatic agent for a wide range of cells. The IC50 for proliferation in transformed cell lines ranged from 2 to 16 microM. The mean IC50 for proliferation of mitogen-stimulated rat lymphocytes (86 nM) was much lower than for mouse (3.5 microM) or human (12.5 microM) lymphocytes. Initial signal transduction events (epidermal growth factor receptor-stimulated phosphotyrosine formation and phytohemagglutinin-stimulated Ca++ mobilization) were unaffected by antiproliferative concentrations of leflunomide. Leflunomide was equally as effective against mitogenic stimuli that bypass initial signaling events as it was against surface receptor-mediated mitogens. Leflunomide was fully potent when added 8 hr after the mitogenic stimulus. Cytokine dependent T-cell growth also was blocked by leflunomide. Leflunomide caused only partial reductions of autocrine cytokine production or cytokine receptor expression. Leflunomide blocked completely the progression of rat lymphocytes beyond early S-phase of cell cycle and inhibited entry of human T-cells int...Continue Reading

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