Everolimus (RAD001) (Synonyms: RAD001)

Everolimus (RAD001) is an orally active derivative of rapamycin that inhibits the Ser/Thr kinase, mTOR (mammalian target of rapamycin).^[1]

In vitro activity of everolimus it displayed that the dose-dependent inhibition of cell growth by everolimus using methylene blue staining after 96 hours of incubation in four different human tumor cell lines, which can be regarded as sensitive (HCT-15, A549) and insensitive (KB-31 and HCT-116).[1] In vitro efficacy test, antiproliferative concentrations of RAD001 resulted in total dephosphorylation of S6K1 and the substrate S6 and a shift in the mobility of 4E-BP1, with IC50 of 0.7 nmol/L and 1,778 nmol/L in both the sensitive murine B16/BL6 melanoma and the insensitive human cervical KB-31,respectively.^[2] In vitro study, combination gemcitabine (100 nM) with everolimus (0.05-2 μM) had significantly antiproliferative effect with an arrest of cell cycle at S phase.^[3]

In vivo experimental it shown that everolimus is very well tolerated with no obvious clinical signs of toxicity; even when treating for up to 60 mg/kg per day by oral gavage the maximum tolerated dosage was not reached. In vivo efficacy study, daily orally treatment with everolimus (0.5 or 2.5 mg/kg) dose-dependently inhibited growth, and using a higher dose of 5 mg/kg once or twice per week also showed similar antitumor efficacy in the rat CA20498 model.^[1] In vivo, treatment with 0.1-10 mg/kg/d RAD001 dose-dependently increased the hemoglobin content but reduced the Tie-2 content and this was significant for VEGF stimulation but not bFGF stimulation.^[2]

References:
[1].O'Reilly T, McSheehy PM. Biomarker Development for the Clinical Activity of the mTOR Inhibitor Everolimus (RAD001): Processes, Limitations, and Further Proposals. Transl Oncol. 2010 Apr;3(2):65-79.
[2].Lane HA, et al. mTOR inhibitor RAD001 (everolimus) has antiangiogenic/vascular properties distinct from a VEGFR tyrosine kinase inhibitor. Clin Cancer Res. 2009 Mar 1;15(5):1612-22.
[3].Pinto-Leite R, et al. Everolimus enhances gemcitabine-induced cytotoxicity in bladder-cancer cell lines. J Toxicol Environ Health A. 2012;75(13-15):788-99.