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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/05/28 03:58:28」(JST)

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Everolimus (RAD-001) is the 40-O-(2-hydroxyethyl) derivative of sirolimus and works similarly to sirolimus as an inhibitor of mammalian target of rapamycin (mTOR).

It is currently used as an immunosuppressant to prevent rejection of organ transplants and treatment of renal cell cancer and other tumours. Much research has also been conducted on everolimus and other mTOR inhibitors for use in a number of cancers.

It is marketed by Novartis under the tradenames Zortress (USA) and Certican (Europe and other countries) in transplantation medicine, and Afinitor in oncology.

Approvals and indications [edit]

Everolimus is approved for various conditions:

Advanced kidney cancer (approved in March 2009)^[2]
Prevention of organ rejection after renal transplant(April 2010)^[3]
Subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TS) in patients who are not suitable for surgical intervention (October 2010)^[4]
Progressive or metastatic pancreatic neuroendocrine tumors not surgically removable (May 2011)^[5]
Breast cancer in post-menopausal women with advanced hormone-receptor positive, HER2-negative type cancer, in conjunction with exemestane (July 2012)^[6]

Clinical trials [edit]

As of October 2010^[update], Phase III trials are under way in gastric cancer, hepatocellular carcinoma and lymphoma.^[7] The use of everolimus in refractory chronic graft-versus-host disease has been reported in 2012.^[8]

Interim phase III trial results in 2011 showed that adding Afinitor (everolimus) to exemestane therapy against advanced breast cancer can significantly improve progression-free survival compared with exemestane therapy alone.^[9] However, everolimus increases mortality in cancer patients.^[10]

Mechanism [edit]

In a similar fashion to other mTOR inhibitors its effect is solely on the mTORC1 protein and not on the mTORC2 protein. This can lead to a hyper-activation of the kinase AKT via inhibition on the mTORC1 negative feedback loop while not inhibiting the mTORC2 positive feedback to AKT. This AKT elevation can lead to longer survival in some cell types.?

Role in heart transplantation [edit]

Everolimus may have a role in heart transplantation as it has been shown to reduce chronic allograft vasculopathy in such transplants. It also may have a similar role to sirolimus in kidney and other transplants.^[11]

Because hypercholesterolemia and hypertriglyceridemia have been reported, monitoring of blood lipid level is recommended.

Use in vascular stents [edit]

Everolimus is used in drug-eluting coronary stents as an immunosuppressant to prevent restenosis. Abbott Vascular produces an everolimus-eluting stent called the Xience V. It utilizes the Multi-Link Vision cobalt chromium stent platform and Novartis' everolimus. The product is also currently in use in the United States and as an investigational device in Japan. It is also available under a private-label version called the PROMUS Everolimus-Eluting Coronary Stent System and it is currently available in most major European and Asia-Pacific markets.

See also [edit]

Everolimus
Systematic (IUPAC) name
	dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]propan-2-yl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone
Clinical data
Licence data	US FDA:link
Pregnancy cat.	D (US)
Legal status	℞ Prescription only
Routes	Oral
Pharmacokinetic data
Half-life	~30 hours
Identifiers
CAS number	159351-69-6
ATC code	L01XE10 L04AA18
PubChem	CID 6442177
DrugBank	DB01590
ChemSpider	21106307
UNII	9HW64Q8G6G
KEGG	D02714
ChEMBL	CHEMBL1201755
Synonyms	42-O-(2-hydroxyethyl)rapamycin
Chemical data
Formula	C53H83NO14
Mol. mass	958.224 g/mol
	SMILES OCCO[C@@H]1CC[C@H](C[C@H]1OC)C[C@@H](C)[C@@H]4CC(=O)[C@H](C)/C=C(\C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)\C=C\C=C\C=C(/C)[C@@H](OC)C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N3CCCC[C@H]3C(=O)O4;
	InChI InChI=1S/C53H83NO14/c1-32-16-12-11-13-17-33(2)44(63-8)30-40-21-19-38(7)53(62,68-40)50(59)51(60)54-23-15-14-18-41(54)52(61)67-45(35(4)28-39-20-22-43(66-25-24-55)46(29-39)64-9)31-42(56)34(3)27-37(6)48(58)49(65-10)47(57)36(5)26-32/h11-13,16-17,27,32,34-36,38-41,43-46,48-49,55,58,62H,14-15,18-26,28-31H2,1-10H3/b13-11+,16-12+,33-17+,37-27+/t32-,34-,35-,36-,38-,39+,40+,41+,43-,44+,45+,46-,48-,49+,53-/m1/s1 ; Key:HKVAMNSJSFKALM-GKUWKFKPSA-N ;
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Discovery and development of mTOR inhibitors

References [edit]

^ R.N Formica Jra, K.M Lorberb, A.L Friedmanb, M.J Biaa, F Lakkisa, J.D Smitha, M.I Lorber (March 2004). "The evolving experience using everolimus in clinical transplantation". Elsevier 36 (2): S495–S499.
^ "Afinitor approved in US as first treatment for patients with advanced kidney cancer after failure of either sunitinib or sorafenib" (Press release). Novartis. 2009-03-30. Retrieved April 6, 2009.
^ "Novartis receives US FDA approval for Zortress (everolimus) to prevent organ rejection in adult kidney transplant recipients" (Press release). Novartis. 2010-04-22. Retrieved April 26, 2010.
^ "Novartis’ Afinitor Cleared by FDA for Treating SEGA Tumors in Tuberous Sclerosis". 1 Nov 2010.
^ http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm254350.htm
^ "US FDA approves Novartis drug Afinitor for breast cancer". 20 Jul 2012.
^ http://www.genengnews.com/gen-news-highlights/novartis-afinitor-cleared-by-fda-for-treating-sega-tumors-in-tuberous-sclerosis/81244159/
^ Lutz M, Kapp M, Grigoleit GU, Stuhler G, Einsele H, Mielke S (April 2012). "Salvage therapy with everolimus improves quality of life in patients with refractory chronic graft-versus-host disease". Bone Marrow Transplant 47 (S1): S410–S411.
^ "Positive Trial Data Leads Novartis to Plan Breast Cancer Filing for Afinitor by Year End". 2011.
^ Fatal AEs Higher with mTOR Drugs in Cancer. Med Page Today
^ Eisen HJ, Tuzcu EM, Dorent R, et al. (August 2003). "Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients". N. Engl. J. Med. 349 (9): 847–58. doi:10.1056/NEJMoa022171. PMID 12944570.

External links [edit]

Sedrani R, Cottens S, Kallen J, Schuler W (August 1998). "Chemical modification of rapamycin: the discovery of SDZ RAD". Transplant. Proc. 30 (5): 2192–4. doi:10.1016/S0041-1345(98)00587-9. PMID 9723437.

English Journal

Noninfectious pneumonitis with the use of mTOR inhibitors in breast cancer.

Peddi PF, Shatsky RA, Hurvitz SA.Author information Department of Medicine, Division of Hematology-Oncology, University of California, Los Angeles, CA 90404, USA. Electronic address: ppeddi@mednet.ucla.edu.AbstractThe mammalian target of rapamycin (mTOR) inhibitor class of drugs represents the newest addition to the armamentarium of therapies for hormonally driven breast cancer. It has recently been shown that the addition of mTOR inhibitor everolimus to aromatase inhibitors in hormone receptor-positive breast cancers improves progression-free survival. However, a clinically significant toxicity associated with this class of drugs is the development of noninfectious pneumonitis (NIP). Although generally mild and manageable, everolimus-induced NIP requires prompt diagnosis and management. This article will provide a brief overview of data relating to dysregulation of the phosphatidylinositol-3-kinase/protein kinase B/mTOR pathway in breast cancer; review the literature relating to the efficacy and safety of mTOR inhibitors in breast cancer; and evaluate the incidence, severity, and optimal management of mTOR inhibitor-related NIP in breast cancer.
Cancer treatment reviews.Cancer Treat Rev.2014 Mar;40(2):320-6. doi: 10.1016/j.ctrv.2013.08.004. Epub 2013 Aug 14.
The mammalian target of rapamycin (mTOR) inhibitor class of drugs represents the newest addition to the armamentarium of therapies for hormonally driven breast cancer. It has recently been shown that the addition of mTOR inhibitor everolimus to aromatase inhibitors in hormone receptor-positive breas
PMID 24011786

Co-targeting estrogen receptor and HER2 pathways in breast cancer.

Mehta A1, Tripathy D2.Author information 1University of Southern California, Keck School of Medicine, USA; USC, Norris Comprehensive Cancer and Department of Medicine, USA.2USC, Norris Comprehensive Cancer and Department of Medicine, USA; USC, Norris Comprehensive Cancer and Department of Medicine, USA. Electronic address: tripathy@usc.edu.AbstractThe estrogen steroid hormone receptor (ER) and human epithelial growth factor receptor 2 membrane tyrosine kinase growth factor receptor (HER2) are the mediators of two key pathways involved in breast carcinogenesis, invasive behavior and cell growth. Co-expression of these receptors results in specific biological features that are not fully understood, but include relative resistance to hormonal therapy and chemotherapy as well as better long-term outcome imparted by ER and worse outcome by HER2 expression. The ER and HER2 signaling pathways interact with each other as do many biological networks, and this creates opportunities for therapeutic co-targeting with agents that modulate these respective pathways. However, relatively few studies have been conducted to test concurrent manipulation of ER and HER2. The avoidance of chemotherapy side effects is an attractive feature that has further spurred explorations in this strategy. Still, the only dually targeted strategy approved by some regulatory agencies is the combination of hormonal therapy using aromatase inhibition and the HER2 kinase inhibitor lapatinib. Other dual combinations have also demonstrated a benefit, although most of the testing has compared hormonal therapy with or without HER2-directed agents and not the other way around, limiting the applicability of this concept in routine clinical practice, especially when chemotherapy is also used. Newer generation signal transduction inhibitors can augment the efficacy of hormonal therapy, with one such example of mTOR blockade using everolimus now in the clinic. The logical extension of ER and HER2 co-targeting is the discovery and clinical testing of "synthetic lethal" combinations attacking diverse pathways that produce quantum improvements over either therapy alone. Molecular annotation of human cancers can further inform personalized combinatorial regimens based on the unique circuitry of an individual patient's tumor, with the potential to yield much more than incremental gains in survival.
Breast (Edinburgh, Scotland).Breast.2014 Feb;23(1):2-9. doi: 10.1016/j.breast.2013.09.006. Epub 2013 Oct 28.
The estrogen steroid hormone receptor (ER) and human epithelial growth factor receptor 2 membrane tyrosine kinase growth factor receptor (HER2) are the mediators of two key pathways involved in breast carcinogenesis, invasive behavior and cell growth. Co-expression of these receptors results in spec
PMID 24176518

Metabolic complications with the use of mTOR inhibitors for cancer therapy.

Sivendran S, Agarwal N, Gartrell B, Ying J, Boucher KM, Choueiri TK, Sonpavde G, Oh WK, Galsky MD.Author information Hematology/Oncology Medical Specialists, Lancaster General Health, Lancaster, PA, United States.AbstractBACKGROUND: mTOR inhibitors are now approved by regulatory agencies for the treatment of a variety of malignancies. The risk of metabolic complications with these agents is not well characterized.
Cancer treatment reviews.Cancer Treat Rev.2014 Feb;40(1):190-6. doi: 10.1016/j.ctrv.2013.04.005. Epub 2013 May 16.
BACKGROUND: mTOR inhibitors are now approved by regulatory agencies for the treatment of a variety of malignancies. The risk of metabolic complications with these agents is not well characterized.METHODS: PubMed was searched for articles published from 2001 until 2011. Eligible studies included pros
PMID 23684373

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