Sirolimus: Its role in nephrology (Review Article)

Abstract

SUMMARY:Sirolimus (Rapamycin, Wyeth Pharmaceuticals Australia Pty Ltd, Baulkham Hills, NSW, Australia) (SRL) has received increasing attention as an immunosuppressant in renal and other solid organ transplantation. Sirolimus is the first marketed agent in a new class of drugs with a novel mechanism of action. Sirolimus binds, like tacrolimus, to a member of the FK binding protein (FKBP) family. The SRL/FKBP complex binds to the protein kinase mTOR. Binding to mTOR blocks activation of signal transduction pathways causing arrest of the cell cycle in the G1 phase. It is now known that mTOR is a central regulator of cell growth and proliferation. The immunosuppressive properties of SRL are due primarily to blockade of interleukin-2 (IL-2)-induced proliferation of T cells. There is still much to be learnt about how best to use the drug. The key advantage over the current choice of immunosuppressive agents is the ability to preserve renal function and pathology while producing excellent rejection-free, graft survival rates. Thus, SRL may find its pivotal role as a calcineurin inhibitors replacement in patients whose grafts are affected by chronic allograft nephropathy. A second major driver for use may prove to be the impact of SRL on cancer incidence and prognosis. Studies still need to be performed to evaluate the best timing for commencement of SRL and the optimal dosage to minimize side-effects.

Autophagy in kidney transplants of sirolimus treated recipients

“…In the experimental setting, pharmaceutical inhibition of mTOR by sirolimus (rapamycin) or its derivative, everolimus, prevents the formation of mTORC1 and thus triggers the initiation of autophagic processes (1). mTOR inhibitors are used as immunosuppressive agents in transplantation medicine as they also block cytokine receptor-dependent signal transduction and thereby inhibit the activation of T lymphocytes (5). …”

Why Sick Cells Produce Tumors: The Protective Role of Autophagy

“…28 The mTOR inhibitor rapamycin is an example of a widely used drug that is also an activator of autophagy, currently under phase III clinical trials for gliomas and advanced renal carcinomas. 32,33 It will be of interest to directly test if part of the anti-tumor activity of mTOR inhibitors derives from the ability to stimulate autophagy.…”

Molecule-targeted agents in endometrial cancer

“…Rapamycin has a high oral bioavailability and was approved in 1990 by the Food and Drug Administration (FDA) as immunosuppressant after kidney transplantation. The oral administration is associated with class-specific side effects such as hypertension, oedema, hyperlipidaemia and gastrointestinal symptoms [45]. The first hints of antitumour activity were reported in 15 patients with cutaneous Kaposi's sarcoma after kidney transplantation in whom the replacement of cyclosphorine with rapamycin resulted in complete disappearance of the tumour within 3 months [46].…”