Antimetabolites

Metabolic toxins that kill proliferating T cells are used in combination with other drugs to treat graft rejection.

These agents inhibit the proliferation of lymphocyte precursors during their maturation and also kill proliferating mature T cells that have been stimulated by alloantigens. The first such drug to be developed for the prevention and treatment of rejection was azathioprine. This drug is still used, but it is toxic to precursors of leukocytes in the bone marrow and enterocytes in the gut. The most widely used drug in this class is mycophenolate mofetil (MMF). MMF is metabolized to mycophenolic acid, which blocks a lymphocyte-specific isoform of inosine monophosphate dehydrogenase, an enzyme required for de novo synthesis of guanine nucleotides. Because MMF selectively inhibits the lymphocyte-specific isoform of this enzyme, it has relatively few toxic effects on other cells. MMF is now routinely used, often in combination with cyclosporine or FK506, to prevent acute allograft rejection.

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