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  • Everolimus (RAD001)
Everolimus (RAD001)的可视化放大

Everolimus (RAD001)

A rapamycin derivative

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¥637-3312
价格
510-2650
Everolimus (RAD001)的二维码

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  • 货号: ajci11444
  • CAS: 159351-69-6
  • 别名: 依维莫司; RAD001; SDZ-RAD
  • 分子式: C53H83NO14
  • 分子量: 958.22
  • 纯度: >98%
  • 溶解度: ≥ 47.911mg/mL in DMSO, ≥ 122 mg/mL in EtOH
  • 储存: Store at -20°C
  • 库存: 现货

Background

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]

参考文献:
[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.


依维莫司 (RAD001) 是一种具有口服活性的雷帕霉素衍生物,可抑制 Ser/Thr 激酶 mTOR(雷帕霉素的哺乳动物靶标)。[1]


依维莫司的体外活性显示,在四种不同的人类肿瘤细胞系中孵育 96 小时后,使用亚甲蓝染色依维莫司对细胞生长的剂量依赖性抑制,可视为敏感(HCT-15、A549 ) 和不敏感(KB-31 和 HCT-116)。[1]在体外功效测试中,抗增殖浓度的 RAD001 导致 S6K1 和底物 S6 的完全去磷酸化以及 4E-BP1 的迁移率发生变化,在敏感小鼠 B16/BL6 中的 IC50 分别为 0.7 nmol/L 和 1,778 nmol/L分别对黑色素瘤和不敏感的人宫颈 KB-31。[2] 体外研究表明,吉西他滨 (100 nM) 与依维莫司 (0.05-2 μM) 的组合具有显着的抗增殖作用,并可阻滞细胞周期在S期。[3]


体内实验表明,依维莫司的耐受性非常好,没有明显的临床毒性迹象;即使通过口服强饲法以每天高达 60 mg/kg 的剂量进行治疗,也未达到最大耐受剂量。体内功效研究表明,每日口服依维莫司(0.5 或 2.5 mg/kg)剂量依赖性地抑制生长,每周一次或两次使用更高剂量的 5 mg/kg 在大鼠 CA20498 模型中也显示出相似的抗肿瘤功效。 [1] 在体内,用 0.1-10 mg/kg/d RAD001 剂量依赖性地增加血红蛋白含量但降低 Tie-2 含量,这对 VEGF 刺激有显着意义,但对 bFGF 刺激没有意义。 [2]

Protocol

Cell experiment [1]:

Cell lines

MTC cell

Preparation Method

The effects of everolimus and IGF-I on MTC cell viability in vitro were assessed by ATPlite assay on the Wallac Victor? 1420 Multilabel Counter. Cells were treated after 24?h with or without 10?nM–1?μM everolimus and/or 50?nM IGF-I. Treatments were renewed after the first 24?h of incubation. Cell viability was assessed after 48?h. Results were obtained by determining the mean value of six replicates.

Reaction Conditions

10?nM–1?μM, 24h

Applications

Everolimus dose-dependently reduced cell viability, from –19% at 10?nM to –31% vs. control at 1?μM. In the E-NR MTCs, everolimus did not significantly modify cell viability.

Animal experiment [2]:

Animal models

5‐week‐old NOD/SCID mice

Preparation Method

Everolimus or AZD8055 was dissolved in 30% (w/v) Captisol and given orally to mice at a dose of 5 mg/kg (everolimus) or 20 mg/kg (AZD8055) per day on weekdays from day 2 to day 20. The control mice received the vehicle only.

Dosage form

5 mg/kg, p.o.

Applications

AZD8055 more significantly inhibited the in vivo growth of the ATL‐cell xenografts than did everolimus.

参考文献:

[1]. Gentilin E, et al. Igf-I influences everolimus activity in medullary thyroid carcinoma. Front Endocrinol (Lausanne). 2015 May 5;6:63.


[2].Kawata T, et al, Takaori-Kondo A. Dual inhibition of the mTORC1 and mTORC2 signaling pathways is a promising therapeutic target for adult T-cell leukemia. Cancer Sci. 2018 Jan;109(1):103-111.

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