Medizinische Klinik III, Hämatologie, Onkologie und Transfusionsmedizin, Charité Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany.
Invest New Drugs. 2012 Apr;30(2):480-9. doi: 10.1007/s10637-010-9576-2. Epub 2010 Nov 16.
The novel AKT inhibitor perifosine, a synthetic alkylphospholipid, is currently being investigated in clinical trials for the treatment of different hematological and oncological malignancies. The in vitro cytotoxicity of perifosine, bortezomib and lenalidomide against 6 cell lines derived from hematological malignancies was investigated using trypan blue staining, flow cytometry-based detection of activated caspases, Annexin V assays, immunohistochemistry studies (KI-67 and caspase-3 staining) and the immature-myeloid-information (IMI) technique. Perifosine and bortezomib induced concentration- and time-dependent cytotoxicity in all cell lines tested. Perifosine together with bortezomib largely exerted additive or synergistic effects with combination indices ranging from 1.13 to 0.22 for combined efficacies of 25% to 75% after 24-hour incubation. Lenalidomide-triggered cytotoxicity was low in all cell lines tested with any assay (less than 10% compared to the negative control). Finally, perifosine, but not bortezomib or lenalidomide, significantly increased the number of cells detected in the IMI channel. Perifosine and bortezomib- but not lenalidomide- trigger substantial cytotoxicity by caspase activation and mainly act additively or synergistically. The IMI technique might be a useful tool for studying cytotoxicity of agents like perifosine that interact mainly with the cellular membrane.
新型 AKT 抑制剂帕非司他是一种合成的烷基磷酸脂，目前正处于临床试验阶段，用于治疗多种血液系统和恶性肿瘤。本研究旨在评估帕非司他、硼替佐米和来那度胺对 6 种血液系统恶性肿瘤细胞株的体外细胞毒性作用，采用台盼蓝染色、流式细胞术检测激活的半胱天冬酶、Annexin V 检测、免疫组化研究（KI-67 和 caspase-3 染色）和幼稚髓样信息（IMI）技术。结果发现，帕非司他和硼替佐米在所有检测的细胞株中均诱导出浓度和时间依赖性的细胞毒性。帕非司他与硼替佐米联合应用时，在 24 小时孵育后，25%至 75%的联合疗效时的联合指数（CI）范围为 1.13 至 0.22，表现出相加或协同作用。在所有检测的细胞株中，来那度胺触发的细胞毒性均较低（与阴性对照相比，小于 10%）。最后，与硼替佐米或来那度胺不同，帕非司他显著增加了 IMI 通道中检测到的细胞数量。帕非司他和硼替佐米而非来那度胺通过半胱天冬酶激活诱导显著的细胞毒性，主要表现为相加或协同作用。IMI 技术可能是研究与细胞膜主要相互作用的药物（如帕非司他）的细胞毒性的有用工具。
