Hubeek Isabelle, Litvinova Elena, Peters Godefridus J, Broekhuizen Richard, Haarman Eric G, Huismans Dieuwke R, Cloos Jacqueline, Zwaan Christian M, Fleischhack Gudrun, Creutzig Ursula, Kaspers Gertjan J L
Department of Pediatric Hematology/Oncology, VU University Medical Center, Amsterdam, The Netherlands.
Int J Oncol. 2004 Dec;25(6):1823-9.
The combination of fludarabine, cytarabine (ara-C) and G-CSF (FLAG) is routinely used in the treatment of acute myeloid leukemia (AML). In this study we characterized the interactions between fludarabine, ara-C and G-CSF in vitro using AML blasts. Exposure to G-CSF alone resulted in a higher leukemic cell survival (LCS), which might be indicative of increased proliferation. The LCS decreased significantly from 69.7 to 54.0% when blasts were exposed to G-CSF 21 h prior to incubation with ara-C (p=0.01). In contrast, LCS increased significantly (from 55.6 to 69.0%; p=0.04) after sequential exposure to G-CSF and fludarabine. Exposure to 4 combinations of fludarabine (4 h; 0.14 microM and 0.55 microM) and ara-C (96 h; 0.21 and 0.82 microM) (FLA) resulted in additive cytotoxicity. The triple combination (FLAG), 21 h 5 microM G-CSF followed by 4 h fludarabine (0.14 and 0.55 microM) and finally ara-C (0.21 and 0.82 microM) for 96 h also resulted in an additive cell kill. In conclusion, these data support the clinical use of G-CSF in combination with ara-C, and the combination of ara-C and FLA. Pre-exposure to G-CSF before FLA (FLAG) did not result in increased cytotoxicity in our experiments, indicative of similar anti-leukemic activity.
氟达拉滨、阿糖胞苷（ara-C）和粒细胞集落刺激因子（G-CSF）联合方案（FLAG）常用于治疗急性髓系白血病（AML）。在本研究中，我们利用AML原始细胞在体外对氟达拉滨、阿糖胞苷和G-CSF之间的相互作用进行了表征。单独使用G-CSF会导致白血病细胞存活率（LCS）升高，这可能表明增殖增加。当原始细胞在与阿糖胞苷孵育前21小时暴露于G-CSF时，LCS从69.7%显著降至54.0%（p=0.01）。相反，在先后暴露于G-CSF和氟达拉滨后，LCS显著升高（从55.6%升至69.0%；p=0.04）。暴露于氟达拉滨（4小时；0.14微摩尔/升和0.55微摩尔/升）和阿糖胞苷（96小时；0.21微摩尔/升和0.82微摩尔/升）的4种组合（FLA）会产生相加性细胞毒性。三联组合（FLAG），即先使用5微摩尔/升G-CSF 21小时，接着使用氟达拉滨（0.14微摩尔/升和0.55微摩尔/升）4小时，最后使用阿糖胞苷（0.21微摩尔/升和0.82微摩尔/升）96小时，也会产生相加性细胞杀伤作用。总之，这些数据支持G-CSF与阿糖胞苷联合以及阿糖胞苷与FLA联合的临床应用。在我们的实验中，在FLA（FLAG）之前预先暴露于G-CSF并未导致细胞毒性增加，这表明具有相似的抗白血病活性。
