mTOR inhibitors: an overview.
Inhibitors of the mammalian target of rapamycin are a new class of immunosuppressants. In contrast to other macrolides, such as tacrolimus and cyclosporine A, they do not inhibit calcineurin and thus signal I of T-cell activation. By inhibiting signal III, the mechanism of action and side effects of sirolimus (rapamycin) and its derivative RAD are distinct from other immunosuppressants. Reports of synergism with cyclosporine A and tacrolimus in preclinical and clinical studies, avoidance of nephrotoxicity, and possible treatment or prevention of chronic allograft rejection are leading to high expectations for this new class of immunosuppressants. Furthermore, studies evaluating tolerance induction are being conducted. This review summarizes preclinical and clinical results published to date and exploits the future value of sirolimus and RAD for clinical transplantation.
Neuhaus
P
P
Department of Surgery, Charité Virchow, Berlin, Germany. chirurgie@charite.de
Klupp
J
J
Langrehr
J M
JM
D000818:Animals; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D000068338:Everolimus; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D016030:Kidney Transplantation / Q000276:immunology; D016031:Liver Transplantation / Q000276:immunology; D016377:Organ Transplantation; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D015398:Signal Transduction; D020123:Sirolimus / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D058570:TOR Serine-Threonine Kinases
D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D047428:Protein Kinase Inhibitors; D000068338:Everolimus; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus