Tafuri A, Lemoli R M, Chen R, Gulati S C, Clarkson B D, Andreeff M
Leukemia Cell Biology Laboratory, Memorial Sloan-Kettering Cancer Center, New York.
Leukemia. 1994 May;8(5):749-57.
Laboratory studies have suggested that hematopoietic growth factors (GF), combined with cytosine-arabinoside (Ara-C) can enhance cytotoxic effects of this agent against acute myeloid leukemia (AML) cells. While clinical trials based on this growth factor/chemotherapy combination (GF/CT) are progressing with discordant results, further information regarding the underlying mechanisms have been reported supporting this rationale and requiring additional investigation. To assess the role of cytokinetic changes in the GF/CT strategy and to evaluate if chemotherapeutic agents regimens other than Ara-C, when combined with GF, can enhance their cytotoxic effects, we have primed AML blasts with two cytokine combinations and then exposed these cells to the S-phase specific agent Ara-C as well as to the phase non-specific drug daunorubicin (DNR) and to the alkylating agent 4-hydroperoxycyclophosphamide (4-HC). The two cytokine combinations used for priming AML blasts were: (i) interleukin-3 (IL-3) + granulocyte-macrophage colony-stimulating factor (GM-CSF) + granulocyte colony-stimulating factor (G-CSF); and (ii) GM + G-CSF. Cytokinetic analysis in ten AML samples and clonogenic growth of leukemic colonies (CFU-L) in methylcellulose were used to detect proliferative and cytotoxic effects on AML samples. We report that in AML clonogenic cell growth can be stimulated by cytokines in 50% of the samples (4/8), and that Ara-C sensitization clearly occurs in two out of these four samples. Among the different cytokine combinations tested, the one containing IL-3 was the most effective through a cytokinetic mechanism consistent with recruitment (averaged G0 decrease p = 0.04; S-phase increase p = 0.005). Furthermore we observed increased cytotoxicity also to the phase non-specific drugs DNR and 4-HC, which may be mediated by other mechanisms recently described. We conclude that GF/CT combinations may also be beneficial in regimens containing drugs other than Ara-C, used for AML treatment, including bone marrow transplantation conditioning regimens.
实验室研究表明，造血生长因子（GF）与阿糖胞苷（Ara-C）联合使用可增强该药物对急性髓系白血病（AML）细胞的细胞毒性作用。虽然基于这种生长因子/化疗联合方案（GF/CT）的临床试验正在进行，但结果并不一致，有关潜在机制的进一步信息已被报道，支持这一基本原理并需要进一步研究。为了评估细胞动力学变化在GF/CT策略中的作用，并评估除Ara-C之外的其他化疗药物方案与GF联合使用时是否能增强其细胞毒性作用，我们用两种细胞因子组合预处理AML原始细胞，然后将这些细胞暴露于S期特异性药物阿糖胞苷以及非特异性药物柔红霉素（DNR）和烷化剂4-氢过氧环磷酰胺（4-HC）。用于预处理AML原始细胞的两种细胞因子组合为：（i）白细胞介素-3（IL-3）+粒细胞-巨噬细胞集落刺激因子（GM-CSF）+粒细胞集落刺激因子（G-CSF）；（ii）GM + G-CSF。对10个AML样本进行细胞动力学分析，并在甲基纤维素中检测白血病集落（CFU-L）的克隆生长，以检测对AML样本的增殖和细胞毒性作用。我们报告，在AML中，50%的样本（4/8）中细胞因子可刺激克隆细胞生长，并且在这4个样本中有2个明显出现了阿糖胞苷致敏。在测试的不同细胞因子组合中，含有IL-3的组合通过与募集一致的细胞动力学机制最为有效（平均G0期减少p = 0.04；S期增加p = 0.005）。此外，我们还观察到对非特异性药物DNR和4-HC的细胞毒性增加，这可能由最近描述的其他机制介导。我们得出结论，GF/CT组合在包含除Ara-C之外用于AML治疗的药物的方案中可能也是有益的，包括骨髓移植预处理方案。
