|Systematic (IUPAC) name|
|Mol. mass||914.172 g/mol|
|Bioavailability||20%, less after eating food rich in fat|
|Half life||57–63 hours|
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Sirolimus (INN) is a relatively new immunosuppressant drug used to prevent rejection in organ transplantation, and is especially useful in kidney transplants. It is also known as rapamycin. Sirolimus is a macrolide ("-mycin") first discovered as a product of the bacterium Streptomyces hygroscopicus in a soil sample from an island called Rapa Nui, better known as Easter Island. It is marketed under the trade name Rapamune by Wyeth.
Interestingly, sirolimus was originally developed as an antifungal agent. However, this was abandoned when it was discovered that it had potent immunosuppressive and antiproliferative properties.
Mechanism of action
Despite its similar name, it is not a calcineurin inhibitor like tacrolimus or cyclosporin. However, it has a similar suppressive effect on the immune system. Sirolimus inhibits the response to interleukin-2 (IL-2) and thereby blocks activation of T- and B-cells. In contrast, tacrolimus and cyclosporine inhibit the production of IL-2.
The mode of action of sirolimus is to bind the cytosolic protein FK-binding protein 12 (FKBP12) in a manner similar to tacrolimus. However, unlike the tacrolimus-FKBP12 complex which inhibits calcineurin (PP2B), the sirolimus-FKBP12 complex inhibits the mammalian target of rapamycin (mTOR) pathway through directly binding the mTOR Complex1 (mTORC1). mTOR is also called FRAP (FKBP-rapamycin associated protein) or RAFT (rapamycin and FKBP target). FRAP and RAFT are actually more accurate names since they reflect the fact that rapamycin must bind FKBP12 first, and only the FKBP12-rapamycin complex can bind FRAP/RAFT/mTOR.
Use in transplant
The chief advantage sirolimus has over calcineurin inhibitors is that it is not toxic to kidneys. Transplant patients maintained on calcineurin inhibitors long-term tend to develop impaired kidney function or even chronic renal failure, and this can be prevented by use of sirolimus instead. It is particularly advantageous in patients with kidney transplants for hemolytic-uremic syndrome as this disease is likely to recur in the transplanted kidney if a calcineurin-inhibitor is used.
Sirolimus can also be used alone or in conjunction with calcineurin inhibitors and/or mycophenolate mofetil, to provide steroid-free immunosuppression regimes. As impaired wound healing is a possible side effect of sirolimus, some transplant centres prefer not to use it immediately after the transplant operation, and start to give it after a period of weeks or months. Its optimal role in immunosuppression has not yet been determined and is the subject of a number of ongoing clinical trials.
The anti-proliferative effect of sirolimus has also been used in conjunction with coronary stents to prevent restenosis in coronary arteries following balloon angioplasty. The sirolimus is formulated in a polymer coating that affords controlled release through the healing period following coronary intervention. Several large clinical studies have demonstrated lower restenosis rates in patients treated with sirolimus eluting stents when compared to bare metal stents, resulting in fewer repeat procedures. A sirolimus eluting coronary stent is marketed by Cordis, a division of Johnson & Johnson, under the tradename Cypher. It has been proposed, however, that such stents may increase the risk of vascular thrombosis.
The anti-proliferative effects of sirolimus may have a role in treating cancer. Recently, it was shown that sirolimus inhibited the progression of dermal Kaposi's sarcoma in patients with renal transplants. Other mTOR inhibitors such as temsirolimus (CCI-779) or everolimus (RAD001) are being tested for use in cancers such as glioblastoma multiforme and mantle cell lymphoma.
Combination therapy of doxorubicin and sirolimus has been shown to drive AKT-positive lymphomas into remission in mice. Akt signalling promotes cell survival in Akt-positive lymphomas and acts to prevent the cytotoxic effects of chemotherapy drugs like doxorubicin or cyclophosphamide. Sirolimus blocks Akt signalling and the cells lose their resistance to the chemotherapy. Bcl-2-positive lymphomas were completely resistant to the therapy; nor are eIF4E expressing lymphomas sensitive to sirolimus. Rapamycin showed no effect on its own.
As with all immunosuppressive medications, rapamycin decreases the body's inherent anti-cancer activity and allows some cancers which would have been naturally destroyed to proliferate. Patients on immunosuppressive medications have a 10- to 100-fold increased risk of cancer compared to the general population. Furthermore, people who currently have or have already been treated for cancer have a higher rate of tumor progression and recurrence than patients with an intact immune system.
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