Liesveld J L, Lancet J E, Rosell K E, Menon A, Lu C, McNair C, Abboud C N, Rosenblatt J D
James P Wilmot Cancer Center and the Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA.
Leukemia. 2003 Sep;17(9):1806-12. doi: 10.1038/sj.leu.2403063.
Patients with acute myelogenous leukemia or myelodysplastic syndrome may respond to farnesyl transferase inhibitors (FTIs) with partial or complete response rates noted in about 30% of such patients. FTIs prevent the attachment of a lipid farnesyl moiety to dependent proteins prior to their insertion into the plasma membrane and thereby prevent activity of these prenylation-dependent proteins, but their mechanism of tumor suppression remains unknown. Many patients receiving FTIs do experience myelosuppression. In this work, the in vitro effects of the FTI, R115777 on normal and leukemic hematopoiesis have been examined as have its effects on apoptosis induction and cell cycle profile in both leukemic blasts and normal CD34+ cells. R115777 was inhibitory to normal CD34+ cell proliferation and to leukemic blast cells, but did not affect long-term culture initiating cell frequency nor NOD-SCID reconstituting capacity. No induction of apoptosis or cell cycle changes were noted in AML blasts. These data suggest that myelosuppression with R115777 occurs largely at the intermediate to late progenitor stage of hematopoiesis and that cyclic use might avoid long-term marrow suppression.
急性髓性白血病或骨髓增生异常综合征患者可能对法尼基转移酶抑制剂（FTIs）有反应，约30%的此类患者有部分或完全缓解率。FTIs可防止脂质法尼基部分在相关蛋白插入质膜之前与之结合，从而阻止这些异戊二烯化依赖蛋白的活性，但其肿瘤抑制机制仍不清楚。许多接受FTIs治疗的患者确实会出现骨髓抑制。在这项研究中，研究了FTI R115777对正常和白血病造血的体外作用，以及其对白血病原始细胞和正常CD34+细胞凋亡诱导和细胞周期谱的影响。R115777抑制正常CD34+细胞增殖和白血病原始细胞，但不影响长期培养起始细胞频率和NOD-SCID重建能力。在急性髓性白血病原始细胞中未观察到凋亡诱导或细胞周期变化。这些数据表明，R115777引起的骨髓抑制主要发生在造血的中晚期祖细胞阶段，循环使用可能避免长期骨髓抑制。
