Phase I dose-escalation study of F60008, a novel apoptosis inducer, in patients with advanced solid tumours
Phase I dose-escalation study of F60008, a novel apoptosis inducer, in patients with advanced solid tumours
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DOI：
10.1016/j.ejca.2009.01.026
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发表时间：
2009-07-01
影响因子：
8.4
通讯作者：
Verweij, J.
中科院分区：
文献类型：
--
作者：
Kitzen, J. J. E. M.;de Jonge, M. J. A.;Verweij, J.
癌细胞对细胞毒性疗法的抗性可由强抗凋亡效应物（例如NF-κ B）的活化引起。因此，抑制NF-κ B刺激的化合物可能克服化疗耐药性。F60008是雷公藤内酯醇的半合成衍生物，在体内转化为雷公藤内酯醇，并激活人类肿瘤细胞的凋亡。我们在晚期实体瘤患者中进行了一项F60008静脉给药的I期和药理学研究，每周输注一次，持续2周，每3周一次。入组了20例患者，共给药35个周期。最常见的血液学副作用是轻度1-2级贫血。非血液学毒性包括疲乏、恶心、呕吐、腹泻和便秘，均为1-2级。观察到两个致死性事件，其中可以看到单核细胞和中性粒细胞中caspase-3活性增加和明显的凋亡。药代动力学研究显示个体间变异性高，使F60008远离雷公藤甲素的最佳衍生物。(C)2009年爱思唯尔有限公司保留所有战斗。
Resistance of cancer cells to cytotoxic therapy can be caused by the activation of strong anti-apoptotic effectors, for example NF-kappa B. Therefore, compounds that inhibit NF-kappa B stimulation might overcome chemotherapy resistance. F60008, a semi-synthetic derivate of triptolide, is converted to triptolide in vivo and activates apoptosis in human tumour cells. We performed a phase I and pharmacological study of F60008 given intravenously as a weekly infusion for 2 weeks every 3 weeks in patients with advanced solid tumours. Twenty patients were enrolled, and a total of 35 cycles were administered. The most frequent haematological side-effect was mild grade 1-2 anaemia. Non-haematological toxicities included fatigue, nausea, vomiting, diarrhoea and constipation, all grade 1-2. Two lethal events were observed in which an increase in caspase-3 activity and overt apoptosis in monocytes and neutrophils could be seen. Pharmacokinetic studies showed high inter-individual variability and rendered F60008 a far from optimal derivate of triptolide. (C) 2009 Elsevier Ltd. All fights reserved.