Blockade of adaptive defensive changes in cholesterol uptake and synthesis in AME by the addition of pravastatin to idarubicin plus high-dose Ara-C: a phase 1 study
Blockade of adaptive defensive changes in cholesterol uptake and synthesis in AME by the addition of pravastatin to idarubicin plus high-dose Ara-C: a phase 1 study
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DOI：
10.1182/blood-2006-08-044446
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发表时间：
2007-04-01
期刊：
影响因子：
20.3
通讯作者：
Appelbaum, Frederick R.
中科院分区：
文献类型：
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作者：
Kornblau, Steven M.;Banker, Deborah E.;Appelbaum, Frederick R.
在暴露于细胞毒剂后，急性髓系白血病(AML)原始细胞在一种防御性适应中升高细胞胆固醇，从而增加了化疗耐药性，但用他汀类药物阻断HMG-CoA还原酶可在体外恢复化疗敏感性。这项第一阶段的研究评估了在伊达比星(IDA)中加入普伐他汀(PV)(40-1680 mg/天，第1-8天)([12 mg/(M-2)。天)，第4-6天])+大剂量阿糖胞苷(Ara-C；HDAC)[1.5g/(M-2.预后不良(n=26)或中度(n=10)预后不良(n=26)或中度(n=10)预后不良的初诊患者15例，抢救患者22例。与IDA-HDAC的历史经验相比，添加PV对中性粒细胞减少和血小板减少的持续时间和毒性曲线没有影响。在PV负荷期间(第0-4天)，几乎所有患者的血清甘油三酯、总胆固醇和低密度脂蛋白水平都有所下降。药代动力学研究表明，当PV剂量超过1280 mg/d时，血清PV水平更高、更持久。在15例新发患者中有11例获得了CR/CRP，其中10例细胞遗传学不良患者中有8例获得了CR/CRP，22例挽救患者中有9例获得了CR/CRP。未达到PV+IDA-HDAC的MTD。在IDA-HDAC中加入PV是安全的，令人鼓舞的应答率支持进行进一步的试验，评估胆固醇调节对AML反应的影响。
Following exposure to cytotoxic agents, acute myeloid leukemia (AML) blasts elevate cellular cholesterol in a defensive adaptation that increases chemoresistance, but blockade of HMG-CoA reductase with statins restores chemosensitivity in vitro. This phase 1 study evaluated adding pravastatin (PV) (40-1680 mg/day, days 1-8) to idarubicin (Ida) ([12 mg/ (M-2 . day), days 4-6]) + high-dose cytarabine (Ara-C; HDAC) [1.5 g/(M-2 . day) by Cl, days 4-7] in 15 newly diagnosed and 22 salvage patients with unfavorable (n = 26) or intermediate (n = 10) prognosis cytogenetics. Compared with historical experience with Ida-HDAC, the duration of neutropenia and throbmbocytopenia and the toxicity profile were unaffected by the addition of PV. During PV loading (day 0-4) serum triglyceride and total and LDL cholesterol levels decreased in nearly all patients. Pharmacokinetic studies demonstrated higher and more sustained serum PV levels with PV doses above 1280 mg/day. CR/CRp was obtained in 11 of 15 new patients, including 8 of 10 with unfavorable cytogenetics, and 9 of 22 salvage patients. An MTD for PV + Ida-HDAC was not reached. Addition of PV to Ida-HDAC was safe, and the encouraging response rates support conducting further trials evaluating the effect of cholesterol modulation on response in AML.