Burke Lillian P, Kukoly Cynthia A
Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.
Leuk Lymphoma. 2008 Feb;49(2):322-30. doi: 10.1080/10428190701760011.
HMG-CoA Reductase inhibitors (statins) induce apoptosis in acute myeloid leukemia (AML) cells in vitro; however, the concentrations associated with cell death in AML cells are higher than those clinically tolerated during prolonged therapy. We therefore wished to determine whether short exposures to lovastatin might induce cell death in AML cells at clinically attainable concentrations. The time and concentration dependence of HL60 and U937 cells was determined and showed that cell death was delayed. IC(50) values and IC(90) values determined on day 6 suggested that the sensitivity of AML cells to statins may occur at lower concentrations than previously reported. After 72 h, mevalonate did not rescue AML cells from cytotoxic concentrations of statins, suggesting that, although cell death was delayed, lovastatin induced lethal effects within 72 h. In conjunction with previously reported Phase I studies, the data presented here suggest that the high-dose, short course statins may be useful for the treatment of patients with AML.
3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂（他汀类药物）在体外可诱导急性髓系白血病（AML）细胞凋亡；然而，与AML细胞死亡相关的浓度高于长期治疗期间临床上所能耐受的浓度。因此，我们希望确定短期接触洛伐他汀是否能在临床上可达到的浓度下诱导AML细胞死亡。测定了HL60和U937细胞的时间和浓度依赖性，结果显示细胞死亡有所延迟。第6天测定的半数抑制浓度（IC50）值和90%抑制浓度（IC90）值表明，AML细胞对他汀类药物的敏感性可能在低于先前报道的浓度时出现。72小时后，甲羟戊酸不能使AML细胞从细胞毒性浓度的他汀类药物中解救出来，这表明，尽管细胞死亡有所延迟，但洛伐他汀在72小时内诱导了致命效应。结合先前报道的I期研究，本文所呈现的数据表明，高剂量、短疗程的他汀类药物可能对AML患者的治疗有用。
