Use of mTOR inhibitors in human organ transplantation.
The mammalian target of rapamycin (mTOR) inhibitor drugs rapamycin (sirolimus) and everolimus have undergone extensive clinical trials for a variety of organ grafts and have been licensed for use in human transplantation. Uniquely, they block the function of a master chemical switch, the protein kinase mTOR, which integrates the multiple biochemical pathways that are necessary for growth factors to induce cell proliferation. Many of these pathways are abnormal in tumorigenesis, and the role of mTOR and its inhibitors in cancer treatment is undergoing intense investigation. There are pharmacokinetic differences between the rapamycins, however, in all major respects, their actions are the same. They show synergy with the calcineurin inhibitors in antirejection effects but also augment the nephrotoxicity of both cyclosporine and tacrolimus. They allow marked reduction in calcineurin inhibitor drug doses, which also reduces the nephrotoxicity of the combinations. In clinical trials in kidney, heart, lung, small bowel, pancreas, islet and liver transplantation in combination with cyclosporine and tacrolimus, rejection rates are equivalent or superior to those achieved with mycophenolate mofetil combinations. Despite this, its clinical usage remains limited. The side-effect profile, especially elevations in serum lipids and nephrotoxicity when administered in combination with calcineurin inhibitors, are the major factors. However, these drugs are finding an increasing place in other areas of medicine, including incorporation into endovascular coronary artery and peripheral arterial stents and in cancer therapy. Their ability to reduce fibrosis and neovascularization suggests other areas of potential use.
Macdonald
Allan S
AS
Dalhousie University, Halifax, Nova Scotia, Canada. allan.macdonald@dal.ca