Rapamycin: Biological and therapeutic effects, binding by immunophilins and molecular targets of action

Summary

Rapamycin has been demonstrated to be a potent antiproliferative agent. In vitro, it has been instrumental in further defining intracellular signaling pathways associated with mitogenic stimuli. While the direct intracellular target of rapamycin-FKBP complexes remains elusive, its use in the analysis of the regulation of cell cycle progression and proliferation has led to a greater understanding of the complexity of cell growth control. The potential clinical utility of rapamycin is beginning to be appreciated. Whether it will be efficacious as an antifungal or an antitumor drug remains uncertain; it is likely to be useful as a potent immunosuppressive agent. It has clear efficacy in a number of animal models of allogeneic transplantation, and may be useful in the treatment of autoimmune disease. Its unique mechanism of action complements that of CsA, and it appears to be largely nonoverlapping for toxicity. Several in vivo models have shown that the combination of rapamycin and CsA is synergistic, and this approach may allow treatment with doses of each drug which are individually less toxic. However, human trials with rapamycin have not yet been reported, and the spectrum of toxicity is therefore incompletely defined. Nevertheless, rapamycin is likely to be useful in the treatment of autoimmune disease and graft rejection and to be an effective agent used alone or in combination with other immunosuppressive agents.