Rapamycin inhibitors

Sirolimus, a target of rapamycin inhibitor, works by decreasing the ability of T cells to respond to IL-2. The major adverse events associated with sirolimus are decreased wound healing, hyperlipidemia, and myelosuppression. This agent appears to have promising effects because it may allow calcineurin inhibitor withdrawal in some patients. 

Del Bufalo D, Ciuffreda L, TriscinogUo D, Desideri M, Cognetti F, Zupi G Milella M. (2006) Antiangiogenic potential of the mammalian target of rapamycin inhibitor temsirohmus. Cancer Res 66 5549-5554. 

Mita MM, Mita AC, Chu QS, Rowinsky EK, Eetterly GJ, Goldston M, Patnaik A, Mathews L, Ricart AD, Mays T, Knowles H, Rivera VM, Kreisberg J, Bedrosian CL, Tolcher AW. (2008) Phase Itrial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573 MK-8669)... 

Webster AC, Lee VW, Chapman JR, Craig JC. Target of rapamycin inhibitors (sirolimus and everolimus) for primary immunosuppression of kidney transplant recipients a systematic review and meta-analysis of randomized trials. Transplantation 2006 81(9) 1234-48. 

The molecular targets of rapamycin inhibitors (mTOR), siroiimus and everoiimus, have a distinct mechanism of immunosuppressive action different from the calcineurin inhibitors cyclosporine and TAC. As such, they are expected to be minimally nephrotoxic per se. 

Wu L, Birle DC, Tannock IF. Effects of the mammalian tatget of rapamycin inhibitor CCI-779 used alone or with chemothetapy on human prostate cancer cells and xenografts. Cancer Res. 2005 65 2825. 

Pantuck AJ, Thomas G, Belldegrun AS, Figlin RA. Mammalian target of rapamycin inhibitors in renal cell carcinoma current status and future applications. Semin Oncol. 2006 33 607. 

Monoclonal and polyclonal antibodies directed at reactive T cells are important adjunct therapies and provide a unique opportunity to target specifically immune-reactive cells. Finally, newer small molecules and antibodies have expanded the arsenal of immunosuppressives. In particular, mTOR (mammalian target of rapamycin) inhibitors (sirolimus, everolimus) and anti-CD25 (interleukin [IL]-2 receptor) antibodies (basiliximab, daclizumab) target growth factor pathways, substantially limiting clonal expansion and potentially promoting tolerance. 

Shi Y, Yan H, Frost P, Gera J, Lichtenstein A. Mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by up-regulating the insulin-like growth factor receptor/insulin receptor substrate 1/phosphatidyl-inositol 3-kinase cascade. Mol Cancer Ther 2005 4 1533-1540... 

Temsirolimus is an mTOR (mammalian target of rapamycin) inhibitor. mTOR has multiple downstream targets, including cell translational machinery. Temsirolimus demonstrated clinical efficacy with significantly increased survival of renal cancer patients. In a clinical trial, 626 patients were randomized to one of three arms interferon alfa (IFN) alone ( = 207) temsirolimus 25 mg alone n = 209) or the combination of temsirolimus 15 mg and IFN ( = 210 Hudes et al. 2007). Temsirolimus was associated with a statistically significant improvement in overall survival when compared with IFN. The median OS was 10.9 months on the temsirolimus arm and 7.3 months on the IFN arm. Progression-free survival was 5.5 months on the temsirolimus arm and 3.1 months on the IFN arm. The combination of temsirolimus 15 mg and IFN did not increase survival over temsirolimus alone but was associated with increased toxicity. 

Balagula Y, Rosen A, Tan BH, Busam KJ, Pulitzer MP, Motzer RJ, et al. Clinical and histopathologic characteristics of rash in cancer patients treated with mammalian target of rapamycin inhibitors. Cancer October 15,2012 118(20) 5078-83. PubMed PMID 22437824. Epub 2012/03/23. eng. 

Gomez-Fernandez C, Garden BC, Wu S, Feldman DR, Lacouture ME. The risk of skin rash and stomatitis with the mammalian target of rapamycin inhibitor temsirolimus a systematic review of the literature and meta-analysis. Eur J Cancer February 2012 48(3) 340-6. PubMed PMID 22206873. Epub 2011/12/31. eng. 

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