ABSTRACT
Sirolimus (Rapamycin; Rapamune® Wyeth Laboratories) is a naturally occurring macrocyclic lactone with a potent immunosuppressive action, which was discovered in the 1970s and approved by the US Food and Drug Administration for use in renal transplant recipients in September 1999. Sirolimus is a highly lipophilic, low-molecular weight agent that inhibits cellular proliferation by blocking cell cycle progression at the G1 to S transition (Figure 1.4). Its action is mediated by binding to an intracellular receptor, the FK506 binding protein (FKBP12), which has been shown to be upregulated after vascular injury, such as stent implantation. The complex sirolimus-FKBP12 then binds a key regulatory kinase denominated mammalian Target Of Rapamycin (mTOR). The sirolimus-FKBP12-mTOR complex has
its capacity of preventing mitogen-induced downregulation of the cyclindependent kinase inhibitor p27Kip1.9,10 In an alternative way, however, sirolimus may also lead to neointimal inhibition through a pathway that is independent of p27Kip1, a mechanism that was recently suggested by the demonstration that sirolimus reduces smooth muscle cell proliferation in p27Kip1(–/–) knockout mice.9 As a result of these complex actions, sirolimus holds the cell cycle in late G1 phase (G1/S transition). In addition to its antiproliferative actions on smooth muscle cells, sirolimus has been shown to inhibit cytokine-driven (IL-2, IL-4, IL-7 and IL-15) T-cell proliferation and to interfere with macrophage function, actions that confer an anti-inflammatory effect to sirolimus (Figure 1.4).
