OBJECTIVE:Accumulating findings suggest that in acute myeloid leukemia (AML) patients, proinflammatory cytokines and growth factors play important roles in the proliferation and survival of AML cells in an autocrine and paracrine manner, leading to deterioration of AML. JTE-607 is a multiple cytokine inhibitor that potently suppresses production of proinflammatory cytokines. In the present study, we investigated the potency of JTE-607 as an antileukemic agent by exploiting a SCID mouse acute leukemia model. METHODS:SCID mice injected with anti-asialo-GM1 antibody were exposed to sublethal total-body irradiation at a dose of 3 Gy and then inoculated intravenously with AML cells. JTE-607 was administered using osmotic minipumps. The effects of JTE-607 on mouse survival time, human interleukin (IL)-8 levels in mouse plasma, and proportion of human CD45(+) cells in the bone marrow were studied. RESULTS:The survival time of the mice was strictly dependent on the number of U-937 cells proliferating in vivo. Administration of JTE-607 during the initial 7 days significantly prolonged survival of the mice, suggesting killing activity of JTE-607 against AML cells in vivo. Delayed administration of JTE-607 also prolonged the survival of mice bearing established leukemia with an effect comparable to the maximum tolerable dose of cytarabine. Flow cytometer analysis of bone marrow cells revealed decreased number of human CD45(+) cells. Human IL-8 level was also reduced by JTE-607. CONCLUSION:Our results indicate that JTE-607 has potential to be a new class of antileukemic drug that exerts inhibitory activities against both the proliferation and proinflammatory cytokine production of AML cells.

译文

目的:大量研究结果表明,在急性髓细胞性白血病(AML)患者中,促炎性细胞因子和生长因子以自分泌和旁分泌方式在AML细胞的增殖和存活中起重要作用,从而导致AML恶化。 JTE-607是一种多细胞因子抑制剂,可有效抑制促炎细胞因子的产生。在本研究中,我们通过利用SCID小鼠急性白血病模型研究了JTE-607作为抗白血病药物的效力。
方法:将注射了抗亚洲人GM1抗体的SCID小鼠暴露于3 Gy剂量的亚致死性全身照射下,然后静脉注射AML细胞。 JTE-607使用渗透微型泵给药。研究了JTE-607对小鼠存活时间,小鼠血浆中人白介素(IL)-8水平以及骨髓中人CD45()细胞比例的影响。
结果:小鼠的存活时间严格取决于体内增殖的U-937细胞数量。在最初的7天中施用JTE-607可以显着延长小鼠的存活期,表明JTE-607在体内对AML细胞具有杀伤活性。 JTE-607的延迟给药也延长了已确诊白血病的小鼠的存活,其作用与阿糖胞苷的最大耐受剂量相当。骨髓细胞的流式细胞仪分析显示人类CD45()细胞数量减少。 JTE-607也降低了人IL-8水平。
结论:我们的结果表明,JTE-607有潜力成为一类新型的抗白血病药物,对AML细胞的增殖和促炎性细胞因子产生均具有抑制活性。

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