Introduction to rapamycin

Rapamycin (RAPA, RPM), also known as Sirolimus, is a macrolide antibiotic, similar to the structure of FK506.

Rapamycin was first studied as a low-toxicity antifungal agents, in 1977 found that rapamycin has immunosuppressive effect, in 1989 began to RAPA as a treatment of organ transplant rejection of new drugs for trial 2010 RAPA I, Phase II clinical trials are over and Phase III clinical trials are in progress.

Rapamycin is a novel macrolide immunosuppressant. Rapamycin through different cytokine receptors block the signal transduction, blocking T lymphocytes and other cells from G1 to S phase of the process, which play an immunosuppressive effect.

The history of rapamycin

In 1964, Stanley Scolina of McGill University in Canada collected a soil sample on Easter Island. He gave the sample to the Wyeth Pharmaceutical Laboratories to seek out new antibiotics.

In 1972, the researchers screened a fungus-inhibiting substance that was expected to be used to treat yeast infections. But after the cell culture experiments, it will hinder the proliferation of immune cells.

80 years of the 20th century, the research found that rapamycin can inhibit tumor growth.

In 1999, the US Food and Drug Administration approved rapamycin as an immunosuppressive agent for kidney transplantation.

Since 2007, two derivatives of rapamycin have been developed for the treatment of cancer, divided into tamoxifen for Pfizer and everolimus for Novartis.

In 2009, Randy Strong Lab of the Bashap Longevity and Aging Institute, David E. Harrison Group of Jackson Laboratories, and Richard A. Miller Laboratory of the University of Michigan Ann Arbor Joint reports of rapamycin can extend the life of mice.

Clinical application of rapamycin

Prevention of rejection

The advantages of rapamycin compared to calcineurin inhibitors are lower renal toxicity. Organ transplant recipients with long-term calcium-dependent phosphatase inhibitors will tend to develop impaired renal function, even with chronic renal failure, whereas rapamycin can be avoided. Rapamycin is particularly useful for patients with renal transplantation due to hemolytic uremia, and the use of calcineurin inhibitors may cause recurrence of the disease. But on October 7, 2008, the US Food and Drug Administration approved a change in the safety label of rapamycin to warn of the risk of declining renal function associated with its use.

Coronary stent coating

The antiproliferative effect of rapamycin can be used for the coating of the coronary stent to prevent the possible formation of restenosis of the coronary balloon angioplasty. Rapamycin formulated in the polymer coating in the controlled release, can be used for coronary intervention treatment of healing. Several large clinical trials have demonstrated that patients with sirolimus-eluting stents have a lower rate of restenosis compared with patients who use bare-metal stents, thereby reducing the probability of repeat surgery. A rapamycin eluting coronary stent has been marketed by Johnson & Johnson's affiliates. But the stent may increase the risk of vascular thrombosis.

In March 2010, according to foreign media reports, scientists recently found it another use: can be used to treat Alzheimer's disease.

Side effects of rapamycin

Rapamycin has similar side effects as FK506. In a large number of clinical trials found its side effects in a dose-dependent, and for the reversible, the therapeutic dose of rapamycin has not yet found a significant nephrotoxicity, no gingival hyperplasia.

The main side effects include: headache, nausea, dizziness, epistaxis, joint pain. Hyperlipidemia, hyperglycemia, elevated liver enzymes (SGOT, SGPT), elevated lactate dehydrogenase, hypokalemia, hypercholesterolemia, hypercholesterolemia, hypercholesterolemia, hypercholesterolemia, Hypomagnesemia and so on. It has also been reported that taking rapamycin can produce edema of the eyelids, and the reason for the lower plasma phosphate level is considered to be the extension of excretion of phosphate from transplanted kidneys with rapamycin-based immunosuppressive therapy. As with other immunosuppressive agents, RAPA has increased the chance of infection, there are reports that there is a tendency to increase the incidence of pneumonia, but other opportunistic infections and CsA no significant difference.

Mechanism of rapamycin action

Rapamycin blocks the signaling of T lymphocytes and other cells from G1 phase to S phase through different cytokine receptors. Rapamycin blocks the calcium dependence of T lymphocytes and B lymphocytes And non-calcium-dependent signaling pathways. Rapamycin, like FK506, binds to the same immunophilin FKBP12 to form RAPA-FKBP12 complexes that do not bind to calmodulin, and rapamycin does not inhibit T cells Of the early activation or direct reduction of cytokine synthesis. The target protein of this complex was first identified in yeast, known as TOR1 and TOR2.

Rapamycin can reduce the activity of cell cycle-dependent kinase (cdk) and cyclin complex kinase. The whole process of cell cycle requires uninterrupted activation of cdk and cyclin complexes. Rapamycin had no effect on the protein levels of cdk2, cdk4, cyclinD and cyclinE, but reduced the kinase activity of the cdk4-cyclinD and cdk2-cyclinE complexes. In the middle and late stages of G1, the activity of these kinases involves the removal of the cyclin-dependent kinase inhibitor p27kip1 from the cyclin-cdk complex, which inhibits cyclin-cdk complex kinase activity, thereby preventing p27 , Blocking the activation of the cdk4-cyclinD and cdk2-cyclinE complexes, resulting in subsequent cellular processes being inhibited: the hyperphosphorylation of the retinoblastoma protein (Rb) and the separation of the Rb-E2F complex. Decreased activation of the E2F transcription factor results in the down-regulation of the cyclin cdc2, cyclin A, and serine / threonine kinases required for transcriptional activity.

Rapamycin inhibits the transcription of the oncogene Bcl-2, which plays a critical role in the cell cycle. The decrease of Bcl-2 expression may induce apoptosis of activated lymphocytes. Rapamycin also prevents CD-28-mediated down-regulation of IKB [alpha] and inhibits nuclear translocation of c-rel. C-rel is a CD-28 response element regulator binding factor that down-regulates IL-2 gene expression.