Kafka M, Dvilansky A, Nathan I
Hematology Laboratory, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Exp Hematol. 1990 Mar;18(3):153-8.
Exposure of HL-60 promyelocytic leukemia cells to a combination of interferon-gamma (IFN gamma) and 5-fluorouracil (5-FU), at concentrations ineffective by themselves, induced a significant differentiation into monocyte-like cells. This phenomenon was accompanied by a synergistic antiproliferative effect. Further characterization of these two activities of the IFN gamma/5-FU combination on HL-60 cells was carried out. Whereas a brief pretreatment of the cells with IFN gamma followed by 5-FU was sufficient to exert the synergistic antiproliferative action, the effect on differentiation was dependent on a prolonged concomitant exposure to both drugs. In an attempt to gain more insight into the biochemical mechanisms of these phenomena, we have examined the effects of RNA and protein synthesis inhibitors and of cytoskeleton disrupting agents on the actions of IFN gamma. Inhibition of RNA or protein synthesis by actinomycin D or cycloheximide did not prevent the antiproliferative action of IFN gamma nor the induction of monocytic differentiation, yet these two compounds blocked the priming effect of IFN gamma on the potentiation of 5-FU action. Actinomycin D synergistically potentiated the antiproliferative action of IFN gamma. Colchicine, vinblastine, and cytochalasin B, disrupting the microtubular and microfilament structure, did not interfere with the actions of IFN gamma; higher concentrations of the drugs even improved the priming effect. Exogenous thymidine, known to counteract the antiproliferative effect of 5-FU, also blocked the antigrowth action but not the differentiation induced by the IFN gamma/5-FU combination. The results suggest the existence of two different mechanisms of the IFN gamma/5-FU synergism: one governing the antiproliferative action via an effect on thymidine synthetase, inducible by a short-term IFN gamma pretreatment and dependent on de novo RNA and protein synthesis; and the other mediating the induction of differentiation requiring a long-term exposure of the cells to both drugs. From a clinical point of view, drug combinations such as IFN gamma and 5-FU, inducing differentiation as well as inhibiting proliferation, may suggest a new approach to the treatment of leukemia.
将人早幼粒白血病HL-60细胞暴露于γ-干扰素（IFNγ）和5-氟尿嘧啶（5-FU）的组合中，这两种药物单独使用时浓度无效，但联合使用可诱导细胞显著分化为单核细胞样细胞。这种现象伴随着协同的抗增殖作用。对IFNγ/5-FU组合对HL-60细胞的这两种活性进行了进一步表征。先用IFNγ短暂预处理细胞，然后再用5-FU处理，足以发挥协同抗增殖作用，而对分化的影响则取决于细胞长时间同时暴露于两种药物。为了更深入了解这些现象的生化机制，我们研究了RNA和蛋白质合成抑制剂以及细胞骨架破坏剂对IFNγ作用的影响。放线菌素D或环己酰亚胺抑制RNA或蛋白质合成并不能阻止IFNγ的抗增殖作用或单核细胞分化的诱导，但这两种化合物阻断了IFNγ对5-FU作用增强的启动效应。放线菌素D协同增强了IFNγ的抗增殖作用。秋水仙碱、长春碱和细胞松弛素B破坏微管和微丝结构，并不干扰IFNγ的作用；更高浓度的这些药物甚至改善了启动效应。已知外源性胸苷可抵消5-FU的抗增殖作用，它也阻断了IFNγ/5-FU组合诱导的生长抑制作用，但不影响分化。结果表明，IFNγ/5-FU协同作用存在两种不同机制：一种通过对胸苷合成酶的作用来控制抗增殖作用，这种作用可由IFNγ短期预处理诱导，并依赖于从头合成RNA和蛋白质；另一种介导分化诱导，需要细胞长期暴露于两种药物。从临床角度来看，IFNγ和5-FU等药物组合既能诱导分化又能抑制增殖，可能为白血病治疗提供一种新方法。
