Petrucci M T, De Felice L, Ricciardi M R, Ariola C, Mascolo M G, Fenu S, Tafuri A
Department of Human Biopathology, University La Sapienza, Roma, Italy.
Cytokines Mol Ther. 1996 Dec;2(4):225-30.
Management of acute lymphoblastic leukemia (ALL) patients may include growth factors (GFs) to reduce post-chemotherapy aplasia. A potential risk of GF administration is a stimulatory signal on the leukemic population. In the present study we investigated the proliferative and programmed cell death (PCD) effect of two cytokines that have recently entered clinical use, stem cell factor (SCF) and the granulocyte colony stimulating factor/IL-3 fusion molecule (PIXY-321), on 14 ALL samples. The activity of IL-7, a cytokine involved in the regulation of ALL cell proliferation, was also tested alone and in combination with these two cytokines. Using the acridine orange flow cytometric technique and the clonogenic assay, we showed that none of these cytokines was capable of significantly increasing the mean percentage of S-phase cells and CFU-L number. A mean decrease of G0 cells from 60.6% to 52.6% (p = 0.02), coupled by a significant increase of G1 cells from 28.2% to 37.9% (p = 0.003) was demonstrated in the presence of PIXY-321. IL-7 alone and in combination with either PIXY-321 or SCF induced similar changes in the percentage of cells in G0 and G1. SCF showed no activity on G0 depletion. When each individual samples was analyzed separately, some heterogeneity was observed. An increase of S phase was recorded in a proportion of cases after SCF and PIXY-321 exposure. However, none of the cytokines evaluated by a clonogenic assay following liquid culture was capable of maintaining or promoting self-renewal of leukemic precursors, as determined by plating fresh cells at time 0. Detection of cytokine effects of apoptosis showed that SCF and PIXY-321 did not significantly reduce the mean percentage of cells in PCD, whereas a significant protective effect was observed in the presence of IL-7 (p = 0.02). We conclude that PIXY-321 and, to a further extent, SCF fail to induce leukemic lymphoid cell proliferation, and do not protect cells from entering apoptosis. These in vitro findings may be useful for ALL clinical trial design.
急性淋巴细胞白血病（ALL）患者的治疗可能包括使用生长因子（GFs）以减少化疗后再生障碍。给予GFs的一个潜在风险是对白血病细胞群体产生刺激信号。在本研究中，我们调查了最近进入临床应用的两种细胞因子，即干细胞因子（SCF）和粒细胞集落刺激因子/白细胞介素-3融合分子（PIXY-321）对14例ALL样本的增殖和程序性细胞死亡（PCD）作用。还单独以及与这两种细胞因子联合测试了参与ALL细胞增殖调节的细胞因子白细胞介素-7（IL-7）的活性。使用吖啶橙流式细胞术和克隆形成试验，我们发现这些细胞因子均不能显著增加S期细胞的平均百分比和集落形成单位-白血病（CFU-L）数量。在存在PIXY-321的情况下，G0期细胞平均从60.6%降至52.6%（p = 0.02），同时G1期细胞从28.2%显著增加至37.9%（p = 0.003）。单独的IL-7以及与PIXY-321或SCF联合使用均在G0和G1期细胞百分比上诱导了类似变化。SCF对G0期细胞减少无活性。当分别分析每个个体样本时，观察到一些异质性。在一部分病例中，SCF和PIXY-321处理后记录到S期增加。然而，通过液体培养后的克隆形成试验评估，所检测的细胞因子均不能维持或促进白血病前体细胞的自我更新，这是通过在0时刻接种新鲜细胞来确定的。细胞凋亡的细胞因子效应检测表明，SCF和PIXY-321并未显著降低PCD中细胞的平均百分比，而在存在IL-7时观察到显著的保护作用（p = 0.02）。我们得出结论，PIXY-321以及在更大程度上SCF不能诱导白血病淋巴细胞增殖，也不能保护细胞免于进入凋亡。这些体外研究结果可能对ALL临床试验设计有用。
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