Farnesyltransferase inhibitor tipifarnib is well tolerated, induces stabilization of disease, and inhibits farnesylation and oncogenic/tumor survival pathways in patients with advanced multiple myeloma
Farnesyltransferase inhibitor tipifarnib is well tolerated, induces stabilization of disease, and inhibits farnesylation and oncogenic/tumor survival pathways in patients with advanced multiple myeloma
复制标题
DOI：
10.1182/blood-2003-08-2764
复制
发表时间：
2004-05-01
期刊：
影响因子：
20.3
通讯作者：
Sebti, SM
中科院分区：
文献类型：
--
作者：
Alsina, M;Fonseca, R;Sebti, SM
RAS基因突变的多发性骨髓瘤(MM)患者对化疗的反应较小，生存时间较短。因此，靶向RAS法尼化可能是治疗MM的一种新方法。我们在2期试验中评估了法尼基转移酶(FTase)抑制剂tipifarnib(Zarnestra)的活性和耐受性，以及它抑制复发MM患者蛋白质法尼化和致癌途径的能力。43名患者(中位年龄，62岁[范围，33-82岁])进入了这项研究，他们的化疗方案中位数为4(范围，1-6)。Tipifarnib 300 mg，每日2次，每4周1次，疗程3周。最常见的毒性是66%的患者出现疲劳。其他毒性包括腹泻、恶心、神经病变、贫血和血小板减少。64%的患者病情稳定。替法尼布可抑制骨髓和外周血单个核细胞中的FTase(但不抑制香叶基香叶素转移酶1)，并抑制未分离的单个核细胞和纯化的骨髓瘤细胞中HDJ-2的法尼化。抑制法尼化与疾病稳定无关。替法尼布可降低骨髓细胞中磷酸化Akt和信号转导与转录激活子3(STAT3)的水平，但不降低ERK1/2(细胞外信号调节蛋白1和2)的水平。我们得出结论，替法尼布是耐受性的，可以诱导疾病稳定，并可以抑制法尼化和致癌/Turnor生存途径。(C)2004年，由美国血液病学会提供。
Patients with multiple myeloma (MM) with mutated RAS are less likely to respond to chemotherapy and have a shortened survival. Therefore, targeting RAS farnesylation may be a novel approach to treatment of MM. We evaluated the activity and tolerability of the farnesyltransferase (FTase) inhibitor tipifarnib (Zarnestra) in a phase 2 trial as well as its ability to inhibit protein farnesylation and oncogenic pathways in patients with relapsed MM. Forty-three patients (median age, 62 years [range, 33-82 years]) with a median of 4 (range, 1-6) chemotherapy regimens entered the study. Tipifarnib, 300 mg orally twice daily, was administered for 3 weeks every 4 weeks. The most common toxicity was fatigue occurring in 66% of patients. Other toxicities included diarrhea, nausea, neuropathy, anemia, and thrombocytopenia. Sixty-four percent of the patients had disease stabilization. Treatment with tipifarnib suppressed FTase (but not geranylgeranyltransferase 1) in bone marrow and peripheral blood mononuclear cells and also inhibited the farnesylation of HDJ-2 in unfractionated mononuclear cells and purified myeloma cells. Inhibition of farnesylation did not correlate with disease stabilization. Finally, tipifarnib decreased the levels of phosphorylated Akt and STAT3 (signal transducer and activator of transcription 3) but not Erk1/2 (extracellular signal regulated kinase 1 and 2) in bone marrow cells. We conclude that tipifarnib is tolerable, can induce disease stabilization, and can inhibit farnesylation and oncogenic/turnor survival pathways. (C) 2004 by The American Society of Hematology.