Tosi P, Visani G, Ottaviani E, Manfori S, Zinzani P L, Tura S
Institute of Hematology L. e A. Seràgnoli, University of Bologna, Italy.
Leukemia. 1994 Dec;8(12):2076-82.
It has been reported that the adenine nucleoside analogue fludarabine is able to increase the phosphorylation and the cytotoxicity of cytosine arabinoside (Ara-C) in different leukemic models, both in vitro and in vivo. In poor prognosis acute myeloid leukemia (AML), the combination of fludarabine with Ara-C and granulocyte colony-stimulating factor (G-CSF) has proven to be a highly effective regimen. In this study we aimed to further investigate the effects of this drug combination. In vitro, on fresh AML cells from ten patients, our results confirm an additive cytotoxic effect displayed by fludarabine + Ara-C, as demonstrated by isobologram analysis of the data. The addition of G-CSF significantly increased the efficacy of the drug combination. These effects appeared to be related to an increased incorporation of [3H]Ara-C into cellular DNA in the presence of fludarabine + G-CSF. Furthermore, the quantitative evaluation of programmed cell death (apoptosis) showed that fludarabine + Ara-C + G-CSF induce apoptosis to a higher degree than either compound alone. This finding suggests that cooperative induction of apoptosis could be the potential mechanism of action of this drug combination.
据报道，腺嘌呤核苷类似物氟达拉滨在不同的白血病模型中，无论体外还是体内，均能增强阿糖胞苷（Ara-C）的磷酸化作用及细胞毒性。在预后较差的急性髓系白血病（AML）中，氟达拉滨与阿糖胞苷及粒细胞集落刺激因子（G-CSF）联合使用已被证明是一种高效的治疗方案。在本研究中，我们旨在进一步探究这种药物组合的效果。在体外，针对来自10例患者的新鲜AML细胞，我们的结果证实了氟达拉滨+阿糖胞苷表现出相加的细胞毒性作用，数据的等效线图分析证明了这一点。添加G-CSF显著提高了药物组合的疗效。这些作用似乎与在氟达拉滨+G-CSF存在的情况下，[3H]阿糖胞苷更多地掺入细胞DNA有关。此外，对程序性细胞死亡（凋亡）的定量评估显示，氟达拉滨+阿糖胞苷+G-CSF诱导凋亡的程度高于单独使用任何一种化合物。这一发现表明，协同诱导凋亡可能是这种药物组合的潜在作用机制。
