RT Journal Article
SR Electronic
T1 The immunosuppressant leflunomide inhibits lymphocyte progression through cell cycle by a novel mechanism.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 460
OP 468
VO 272
IS 1
A1 H M Cherwinski
A1 D McCarley
A1 R Schatzman
A1 B Devens
A1 J T Ransom
YR 1995
UL http://jpet.aspetjournals.org/content/272/1/460.abstract
AB 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 into the G2 and M-phases without causing cell death. Inhibition of proliferation could not be reversed by purine nucleosides. The results suggest that leflunomide's mechanism of action differs from that of other immunosuppressive agents such as corticosteroids, Cyclosporine A, rapamycin or mycophenolic acid.