GÖ6976对慢性髓系白血病细胞增殖的影响及其毒性研究

Effect of GÖ6976 on Proliferation of Chronic Myeloid Leukemia Cells and Its Toxicity on Normal Cells and Mice

目的:研究GÖ6976对慢性髓系白血病(CML)细胞增殖的影响,及其对正常细胞及小鼠的毒性,为以后临床应用的有效性及安全性提供实验依据。方法:采用不同浓度的GÖ6976作用于CML急变期细胞株K562、人外周血单个核细胞(PBMNC)及小鼠正常BaF3细胞,MTT法检测其对细胞增殖的影响;选用BALB/C小鼠进行体内毒性研究,给药期间监测一般情况、体重及外周血白细胞数;给药前后摘眼球取血进行生化检查,同时对肝、肾及股骨进行病理学检查。结果:GÖ6976能明显抑制K562细胞的增殖,抑制效果随着剂量的增加而增加(r=0.9623),但对PBMNC及BaF3细胞无明显抑制作用。各组脏器的病理学检查均显示无炎症浸润等异常表现;高剂量组在外周血白细胞数变化率波动较大(P<0.05),这可能与细胞内蛋白激酶C被抑制有关。血液生化指标检测未见异常。低剂量组在外周血白细胞数、血液生化指标及组织病理学上与对照组比较无统计学差异。结论:GÖ6976对K562细胞增殖有明显抑制作用,且抑制效果随着剂量增加而增加。长期应用GÖ69765.0μmol/L及以下浓度对PBMNC、BaF3细胞没有明显的抑制作用。长期应用GÖ697610 mg/kg及以下浓度对BALB/c小鼠也没有明显的毒性作用。

Objective:To investigate the effect of GÖ6976 on the proliferation of chronic myeloid leukemia cells and its toxic effect on normal cells and mice,so as to provide experimental basis for the effectiveness and safety of its clinical application.Methods:Different concentrations of GÖ6976 were applied to the K562 cells,human peripheral blood mononuclear cells(PBMNC)and normal BaF3 cells,MTT assay was used to detect the effect on cell proliferation.BALB/C mice were used to investigate the toxicity in vivo.The general situation,body weight and the number of white blood cells in peripheral blood were monitored during administration,the blood collected from eyeballs before and after administration was used for biochemical examination,at the same time,the liver,kidney and femurs were examined pathologically.Results:GÖ6976 could significantly inhibit the proliferation of K562 cells,inhibition effect increased with increasing dose(r=0.9623).However,there was no significant change in the inhibitory effect on PBMNC and BaF3 cells.The pathological examination of organs in each group showed no abnormal manifestations such as inflammatory infiltration,while the change rate of leukocyte count in peripheral blood of high dose group fluctuated greatly(P<0.05),which might be related to the inhibition of intracellular protein kinase C,and no abnormality was observed in blood biochemical indexes.In the low dose group,there was no significant difference in peripheral blood leukocyte count,blood biochemical index and histopathology during administration drug as compared with the control group.Conclusion:GÖ6976 possesses a significant inhibitory effect on the proliferation of K562 cells,and the inhibitory effect increases with increasing dose.Long-term application of 5.0μmol/L and below concentrations of GÖ6976 shows no obvious inhibitory effect on PBMNC,BaF3 cells.Long-term application of 10 mg/kg and below concentrations of GÖ6976 shows no obvious toxic effect on BALB/c mice.