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EVEROLIMUS-AN INHIBITOR OF mTOR PATHWAY

by Selleckchem | Jun 29 2012

EVEROLIMUS: INTRODUCTION
mTOR pathway is among the different vital regulators of cell cycle which are involved in its regulatory activities likecell proliferation, growth, migration and activities related to transcription and translation. mTOR is the translational product of FRAP1 gene which phosphorylates threonine/serine residues in protein. Defected or dysregulated mTOR pathway is a common reason of developing cancerous cells. Therefore, these proteins are also targeted while looking for an effective anti-cancer therapy [1]. Everolimus mTOR inhibitor is among the efficientinhibitors that have been searched so far [2]. Afinitor Everolimus is the brand name of inhibitor and developed by Novartis. Everolimus structure contains 40-O-(2-hydroxyethyl) derivative and properties related to ispharmacokinetics are found to be improved by the presence of oxygen at position 40. Everolimus IC50 for mTOR is around 1nM. Everolimus solubility is 100mg per ml of DMSO while it is also soluble in ethanol and water. It is administered orally and Everolimus price $60 in packaging of 5mg.It is distributed in dry ice.

EVEROLIMUS: MECHANISM OF ACTION
One of the properties of Everolimus is its immunosuppressant property in case of cardiac, renal and some of the other transplants, apart from these properties Everolimus is also used for the treatment of different tumors as an effective drug [4] because of its specific ability to check the mTOR1 which leads to stimulation of Akt cascade and inhibits the mTOR2 downstream pathway. When Everolimus is given alone it is found to act as apoptotic agent on colon cancer cells [5]or in combination with other drugs like Octreotide against the tumors of neuroendocrine cells where it seems to block Akt-mTOR-p70S6 kinase pathway [6]. Everolimus has also been recently used successfully against renal tumors [7]. The pharmacokinetic properties of the Everolimus have encouraged the scientists to do more research on the drug regarding its efficacy [8].

EVEROLIMUS AS STENTS
In therapy of ischemia and coronary artery disease Everolimus is being used as stents. A comparison study was done in which efficiency of Everolimus was compared to Paclitaxel which was used traditionally as stents [9-10]. Studies were also conducted to use Everolimus for coronary artery disease therapy as bio-absorbable stent[11].

CLINICAL TRIALSOF EVEROLIMUS
Everolimus is found to be more efficient and good as compared to other old mTOR inhibitors. The efficiency was checked in breast cancer cell lines [12]after which the drug was further encouraged to be researched in order to generate more data about the drug [13].The drug has been studied as a single agent in clinical trial of phase II [15] or as combinations with other chemotherapeutic agents in clinical trial phase I againstbreast cancer with repeated occurrence [15] or for the patients who are hormone receptor positive or HRP [16].
In different studies synergistic behavior of Everolimus with other drugs is being studied in vivo [17]. Fruitful results favored the use of Everolimus supported its use in advanced stages of gastrointestinal cancer [18] in clinical trials of phase II [19]. Everolimus has also been evaluated as an immunosuppressing agent after renal transplantations [20]. In a comparative study against renal cancer, Everolimus was proved better than Azathioprine [21], the drug used in kidney transplants.
Outstanding effects were shown by Everolimus in the therapy of carcinoids [22]. The medicine was used with Octreotide for therapy of neuroendocrine cancer in phase II trials [23]. It is found to be as a promising and therapeutic agent for cancer therapy [24] and hence a lot of studies are being carried out to develop more important drugs.

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