生物活性

• 描述mTOR is a serine-threonine kinase that interacts with several proteins to form two distinct complexes, mTORC1 and mTORC2, which show different sensitivities to rapamycin^[3]. Temsirolimus (CCI-779, NSC 683864) is a specific mTOR inhibitor with IC50 of 1.76 μM in a cell-free assay. Temsirolimus treatment at nanomolar concentrations (10 nM to <5 μM) displays a modest and selective antiproliferative activity via FKBP12-dependent mechanism but can completely inhibit the proliferation of a broad panel of tumor cells at low micromolar concentrations (5-15 μM), involving FKBP12-independent suppression of mTOR signaling. Temsirolimus treatment at micromolar but not nanomolar concentrations (20 μM) causes a marked decline in global protein synthesis and disassembly of polyribosomes, accompanied by rapid increase in the phosphorylation of translation elongation factor eEF2 and the translation initiation factor eIF2A^[7]. Temsirolimus inhibits the phosphorylation of ribosomal protein S6, more potently in PTEN-positive DU145 cells than in PTEN-negative PC-3 cells, and inhibits cell growth and clonogenic survival of both cells in a concentration-dependent manner^[2]. Administration of Temsirolimus (20 mg/kg i.p. 5 days/week) significantly delays the growth of DAOY xenografts by 160% after 1 week and 240% after 2 weeks, compared with controls. Single high-dose of Temsirolimus (100 mg/kg i.p) treatment induces 37% regression of tumor volume within 1 week. Temsirolimus treatment for 2 weeks also delays the growth of rapamycin-resistant U251 xenografts by 148%^[5]. In a phase 2 study, 25 mg temsirolimus was intravenously (IV) conducted once per week and the VEGF-A monoclonal antibody bevacizumab 10 mg/kg IV once every 2 weeks in 58 patients with differentiated PNETs and progressive disease by RECIST, results showed response rate (RR) was 41% (23 of 56 patients). PFS at 6 months was 79% (44 of 56). Median PFS was 13.2 months (95%CI,11.2to16.6).Median overall survival was 34 months (95% CI, 27.1 to not reached). For evaluable patients, the most common grade 3 to 4 adverse events attributed to therapy were hypertension (21%), fatigue (16%), lymphopenia (14%), and hyperglycemia (14%), suggesting substantial activity and reasonable tolerability of this drug^[6].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  human 697 cell	-	Growth inhibition assay	-	Inhibition of human 697 cell growth in a cell viability assay, IC50=1.7 nM	SANGER
  human A2780 cell	-	Growth inhibition assay	-	Inhibition of human A2780 cell growth in a cell viability assay, IC50=5.88 nM	SANGER
  human A3-KAW cell	-	Growth inhibition assay	-	Inhibition of human A3-KAW cell growth in a cell viability assay, IC50=10.43 nM	SANGER

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• 动物研究
  剂量	Mice: 2 mg/kg, 10 mg/kg[3] (i.v.); 0.6 mg/kg[4] (i.p.), 5 mg/kg - 50 mg/kg[2] (i.p.)
  给药途径	i.v., i.p.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT03629847	Neuroendocrine Tumors	Phase 1 Phase 2	Recruiting	December 2018	Saudi Arabia ... more >> Oncology Centre, King Faisal Specialist Hospital & Research Center Recruiting Riyadh, Saudi Arabia, 11211 Contact: Ali Aljubran, MD    966-1-4647272 ext 32084    ajubran@kfshrc.edu.sa    Contact: Lani Cabangon, RN    966-1-4647272 ext 32089    lcabangon06@kfshrc.edu.sa    Sub-Investigator: Hussein Raef          Sub-Investigator: Nora Alkahtani, MD          Sub-Investigator: Shouki Bazarbashi, MD          Sub-Investigator: Ahmed Alzahrani, MD          Sub-Investigator: Mohamed Alsubayel, MD          Sub-Investigator: Monther Kabbani, MD          Sub-Investigator: Hamad Albahli, MD          Sub-Investigator: Hadeel Almana, MD Collapse <<
  NCT01184326	Solid Tumor K... more >>idney Cancer Collapse <<	Phase 1	Completed	-	United States, Massachusetts ... more >> Beth Israel Deaconess Medical Center Boston, Massachusetts, United States, 02115 Dana-Farber Cancer Institute Boston, Massachusetts, United States, 02115 Collapse <<
  NCT01184326	-	-	Completed	-	-

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