哌立福新(PERIFOSINE，KRX-0401)发表治疗肾细胞癌的实验数据Keryx Biopharma发表第二阶段实验数据，以KRX-0401 (perifosine)治疗初期恶性肾脏细胞癌症。 哌立福新(PERIFOSINE，KRX-0401) 31 口服活性烷基磷酯化合物，具有抗肿瘤活性。 perifosine（Akt inhibitor）is an alkylphospholipid exhibiting antitumor properties and is currently in phase II clinical trials for various types of cancer. The mechanisms by which perifosine exerts its antitumor effects, including the induction of apoptosis, are not well understood. The current study focused on the effects of perifosine on the induction of apoptosis and its underlying mechanisms in human non–small cell lung cancer (NSCLC) cells. Perifosine,atclinically achievable concentration ranges of 10 to 15 μmol/L, effectively inhibited the growth and induced apoptosis of NSCLC cells. Perifosine inhibited Akt phosphorylation and reduced the levels of total Akt. Importantly,enforcedactivation of Akt attenuated perifosine-induced apoptosis. These results indicate that Akt inhibition is necessary for perifosine-induced apoptosis. Despite the activation of both caspase-8 and caspase-9, perifosine strikingly induced the expression of the tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) receptor, death receptor 5, and down-regulated cellular FLICE-inhibitory protein (c-FLIP), anendogenousinhibitor of the extrinsic apoptotic pathway, with limited modulatory effects on the expression of other genes including Bcl-2, Bcl-XL, PUMA, and survivin. Silencing of either caspase-8 or death receptor 5 attenuated perifosine-induced apoptosis. Consistently, further down-regulation of c-FLIP expression with c-FLIP small interfering RNA sensitized cells to perifosine-induced apoptosis, whereas enforced overexpression of ectopic c-FLIP conferred resistance to perifosine. Collectively, these data indicate that activation oftheextrinsic apoptotic pathway plays acriticalroleinperifosine-induced apoptosis. Moreover, perifosine cooperates with TRAIL to enhance the induction of apoptosis in human NSCLC cells, thus warranting future in vivo and clinical evaluation of perifosine in combination with TRAIL in the treatment of NSCLC.An orally active alkyl-phosphocholine compound with potential antineoplastic activity. Targetingcellularmembranes,perifosinemodulatesmembranepermeability,membranelipidcomposition,phospholipidmetabolism,andmitogenicsignaltransduction, resulting in cell differentiation and inhibition of cell growth. This agent also inhibits the anti-apoptoticmitogen-activated protein kinase (MAPK) pathway and modulates the balance between the MAPK and pro-apoptotic stress-activated protein kinase (SAPK/JNK) pathways, thereby inducing apoptosis. Perifosine has a lower gastrointestinal toxicity profile than the related agent miltefosine. 哌立福新（perifosine） 哌立福新是一杂环的烷基磷酸胆碱，其结构与其他脂类相似，可与肿瘤细胞膜作用，从而影响肿瘤细胞间生长信号的传导。在体外，哌立福新对多种细胞型的生长均有抑制作用。但在2007年美国一研究小组的Ⅱ期临床试验中，哌立福新的应用由于一系列的不良反应而被终止。在10 例接受哌立福新治疗的患者中未发现明显疗效， 中位生存期仅为1.8 个月，因此Robert 等认为进展期胰腺癌患者不适合应用哌立福新。另外，研究发现其他一些单药化疗如铂类、蒽环类抗生素、异磷酰胺、链唑霉素等均未显示出对胰腺癌的疗效，故未应用于临床。 联合化疗 由于早期的研究结果显示5-FU 对于进展期胰腺癌有一定疗效，继而出现了基于5-FU 的联合化疗方案，如FAM[5-FU、阿霉素(ADM)、丝裂霉素C(MMC)联合]方案、SMF[链脲佐菌素(STZ)、MMC、5-FU 联合]方案等。但美国西南肿瘤协作组（Southwest OncologyGroup, SWOG）的一项Ⅱ期临床研究对比了5-FU 单药化疗与5-FU 联合ADM、MMC、STZ 化疗的疗效， 结果显示对于患者生存的影响2 组无显著差异。 现今， 临床研究的热点主要是以吉西他滨为基础的化疗以及一些新药的联合化疗和综合疗法。