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EVEROLIMUS: TEARING mTOR PATHWAYS

by Selleckchem | May 03 2012

EVEROLIMUS:
Mammalian target of Rapamycin abbreviated as mTOR is a serine/threonine protein kinase enzyme encoded by the FRAP1 gene involving in different transcriptional events, regulation of aging, and in cell invasion, survival and proliferation pathways. In cancers, the Dysregulation of mTOR cascade is a very common event that makes it a promising and attractive target for the anti-tumor therapies [1]. Among those many inhibiting drugs tried for the sake of treating cancers, Everolimus mTOR inhibitor is one of the best [2]. The trade name of this inhibiting drug is Afinitor Everolimus and is marketed by the company Novartis. It is an orally administered medicine and is a derivative of 40-O-(2-hydroxyethyl). Everolimus IC50 is found to be around 1 nM. In Everolimus structure a 2-hydroxyethyl chain at 40th Oxygen molecule improves its pharmacokinetic properties. Everolimus sulobility is best in DMSO (100 mg/ml) and ethanol as it is an oral drug but is also achievable in water. Everolimus price is about $60 for 5 mg vial and the Everolimus suppliers distribute it in the dry ice.

EVEROLIMUS: MECHANISM OF ACTION
Everolimus works as an immunosuppressant in case of renal, cardiac and some other transplants and apart from these functions this drug is also effective for the treatment of various types of tumors [4] due to its potential of specifically inhibiting the mTOR1 that leads to activation of Akt cascade and spares the downstream pathway of mTOR2.
Due to this specific mode of action, Everolimus has enjoyed a great success rate in treatment of cancer of colon either as alone [5] or as a combinational therapy with Octreotide in case of tumor cells in neuroendocrine where it was found to be jamming the Akt-mTOR-p70S6 kinase cascade [6] hence leading to the apoptotic death of cancerous cells. A recent research has enlisted Everolimus successes in treatment of renal tumors [7]. After a clinical assessment of Everolimus pharmacokinetic properties made it concerning for further use [8] hence inviting further research on this drug to make its efficacy better.

EVEROLIMUS AS AN ELUTING STENTS:
Everolimus is being used in cardiac diseases as a stent for example diseases in coronary artery and ischemia. It has been reported in many clinical research studies that Everolimus is preferable over the other traditional methods where a comparison was made between Everolimus eluting stents with stents of Paclitaxel etc [9-10]. To modify the Everolimus eluting stents making them bioabsorbable has led to its widespread use in diseases of coronary arteries [11].

EVEROLIMUS: CLINICAL STUDIES
Although various mTOR inhibitors are being used in clinical assays as anti-tumors agents but very few have enjoyed a remarkable success that Everolimus mTOR inhibitor tasted when treating various kinds of cancers. It has shown very promising apoptotic results against the breast carcinoma cell lines in vitro [12] after that Everolimus was applied in research to generate a good promising clinical data [13] and since it has been used either alone in clinical trials phase II [15] or in combination with other drugs in trials of phase I on cases of repeated breast cancer [15] or also as part of combinational therapy for the patients that are hormone receptor-positive [16].
The researchers have used in vivo models to check anti-cancer effects of Everolimus gastric cancer effects of Everolimus in combination with other agents on gastric cancer [17]. Its promising results made it recommended further for advanced cases of gastric cancer [18] the success of that further more led to commencement of the clinical trials of phase II for patients of gastric cancer [19]. It has been commonly used as an immunosuppressant molecule and also as a therapeutic agent in cases of renal transplantations [20]. Another study involving the use of Everolimus, patients suffering from renal cancer has revealed better results as compared to Azathioprine [21] that was widely used for kidney transplants.
Besides these cancers, since the mTOR inhibition was found to consider an attractive therapy in case of carcinoids treatment [22], a clinical study of phase II in neuroendocrine cancer experienced the use of Everolimus combined with Octreotide [23]. In the therapy involving Everolimus, regression of carcinoids occurs hence the success of this drug hailed it well as a novel therapeutic agent against carcinoids [24] that led to further clinical trials of Everolimus for reporting its good results.

REFERENCES:
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