Tipifarnib (IND 58359) is a nonpeptidomimetic quinolinone with potential antineoplastic activity. Tipifarnib binds to and inhibits the enzyme farnesyl protein transferase, an enzyme involved in protein processing (farnesylation) for signal transduction. By inhibiting the farnesylation of proteins, this agent prevents the activation of Ras oncogenes, inhibits cell growth, induces apoptosis, and inhibits angiogenesis.

FTase:0.6 nM

在健康捐献者的T细胞中，Tipifarnib能以时间依赖的方式减少IFNγ阳性细胞的比例。相较于DMSO，Tipifarnib能减少沉淀中活化Ras的量。[2] Tipifarnib对于MDS克隆性造血具有选择性的体外毒性，其浓度低于10 nM时效应尤为显著，主要表现在白细胞前体上。这一作用并非通过诱导凋亡实现，因为正常与MDS前体细胞在暴露于Tipifarnib后72小时内展现出相同的DiOC3和annexin V表达。[3] Tipifarnib与10 nM 4-OH-他莫昔芬联合使用，在E2存在下将IC50从400 nM降低到50 nM。[4] Tipifarnib诱导U937细胞凋亡。[5] 此外，Tipifarnib对分离的人类法尼酰转移酶对lamin B肽和K-RasB肽的抑制作用IC50分别为0.86 nM和7.9 nM。[6]

与单独使用他莫昔芬或Tipifarnib相比，他莫昔芬与Tipifarnib的组合显著降低了Ki-67（平均值为5%对比16.9%和67.3%）。[4]相反，各治疗组间的凋亡评分无显著差异。Tipifarnib单独使用也比对照组降低了CTI。他莫昔芬与Tipifarnib的组合，或Tipifarnib与E2撤退的联合使用，在降低CTI方面最为有效（分别为0.8和0.7），这可能是肿瘤体积减少的原因。[4]

MACS-selected CD34+ cells are seeded in Methocult 4435 'complete' 1% bovine serum albumin, 3 U/mL recombinant human (rh) erythropoietin, 0.1 mM 2-mercaptoethanol, 2 mM L-glutamine and the following cytokines: 50 ng/mL rh stem cell factor, 20 ng/mL rh GM-CSF, 20 ng/mL rh IL-3, 20 ng/mL rh IL-6 and 20 ng/mL h G-CSF. DMSO or Tipifarnib is added at the concentrations of 2.5, 10, 25 and 50 nM at day 1. All cultures are performed in duplicates and the numbers of colonies are scored after 14 days of incubation at 37 °C in a humidified incubator containing 5% CO2