Stracke S, Ramudo L, Keller F, Henne-Bruns D, Mayer J M
Division of Nephrology, University Hospital Ulm, Ulm, Germany.
Transplant Proc. 2006 Apr;38(3):766-70. doi: 10.1016/j.transproceed.2006.01.030.
Everolimus inhibits the growth of several tumor cell lines in vitro as well as tumor growth in a rat model. Mycophenolate mofetil (MMF) inhibits growth of a Walker sarcoma in a rat model in vivo. Herein we tested the in vitro antiproliferative capacity of everolimus and MMF on a pancreatic tumor cell line Panc-1 and on a small cell lung cancer cell line ScLc.
Cells were cultured under standardized conditions. Everolimus was added in increasing doses from 0.005 to 500 microg/mL; MMF was used from 0.05 to 5000 microg/mL. For co-incubation experiments, we combined everolimus (0.005 microg/mL and 0.05 microg/mL) with five concentrations of MMF; and MMF (0.5 microg/mL and 5 microg/mL) with five concentrations of everolimus. The antiproliferative capacity was assessed by a BrdU incorporation assay.
Everolimus and MMF inhibited BrdU incorporation into Panc-1 and ScLc in a dose-dependent fashion. A 50% inhibition was seen in Panc-1 only at 50 microg/mL everolimus, but in ScLc at 5 microg/mL everolimus. MMF was clearly more potent in Panc-1: 50% inhibition was observed at 5 microg/L. In ScLc, 40% inhibition of BrdU incorporation was seen only at 50 microg/L MMF. In co-incubation, an effective combination for both Panc-1 and ScLc was 5 microg/mL MMF with 0.005 microg/mL everolimus resulting in 50% inhibition of BrdU incorporation (P < .001).
Everolimus and MMF showed dose-dependent antiproliferative effects in tumor cell lines in vitro both alone and in combination. The combined use of everolimus and MMF showed supra-additive effects at concentrations used for therapeutic immunosuppression in patients.
依维莫司在体外可抑制多种肿瘤细胞系的生长,在大鼠模型中也能抑制肿瘤生长。霉酚酸酯(MMF)在体内大鼠模型中可抑制沃克肉瘤的生长。在此,我们测试了依维莫司和MMF对胰腺肿瘤细胞系Panc-1和小细胞肺癌细胞系ScLc的体外抗增殖能力。
细胞在标准化条件下培养。依维莫司以0.005至500微克/毫升的递增剂量添加;MMF的使用浓度为0.05至5000微克/毫升。在共孵育实验中,我们将依维莫司(0.005微克/毫升和0.05微克/毫升)与五种浓度的MMF联合使用;以及将MMF(0.5微克/毫升和5微克/毫升)与五种浓度的依维莫司联合使用。通过BrdU掺入试验评估抗增殖能力。
依维莫司和MMF以剂量依赖方式抑制BrdU掺入Panc-1和ScLc细胞。仅在依维莫司浓度为50微克/毫升时,Panc-1细胞的BrdU掺入受到50%的抑制,但在依维莫司浓度为5微克/毫升时,ScLc细胞的BrdU掺入受到50%的抑制。MMF对Panc-1细胞的作用明显更强:在5微克/升时观察到50%的抑制。在ScLc细胞中,仅在MMF浓度为50微克/升时,BrdU掺入受到40%的抑制。在共孵育中,对Panc-1和ScLc细胞均有效的联合用药方案是5微克/毫升的MMF与0.005微克/毫升的依维莫司,导致BrdU掺入受到50%的抑制(P <.001)。
依维莫司和MMF在体外肿瘤细胞系中单独及联合使用均显示出剂量依赖性的抗增殖作用。在用于患者治疗性免疫抑制的浓度下,依维莫司和MMF联合使用显示出超相加效应。