Tosi P, Pellacani A, Zinzani P L, Magagnoli M, Visani G, Tura S
Istituto di Ematologia ed Oncologia Medica "L. e A. Seràgnoli", Policlinico S. Orsola, via Massarenti, 9, 40138 Bologna, Italy
Haematologica. 1999 Sep;84(9):794-8.
Fludarabine has shown a definite clinical activity in B-cell chronic lymphocytic leukemia (CLL). If the effects of this drug could be potentiated, it could be useful in order to obtain complete remissions. In this study we evaluated the effects of the combination of fludarabine and gemcitabine, a deoxycytidine analog that has shown both in vitro and in vivo activity against a variety of solid tumors.
CLL cells from 10 patients were cultured in vitro in the presence of fludarabine (0.5-1,000 microg/mL) and gemcitabine (0.1-5,000 microg/mL), both alone and in different combinations. Cytotoxic activity was tested by the XTT colorimetric assay. Furthermore we evaluated BCL-2 protein expression and, subsequently, the induction of apoptosis at baseline and after exposing cells to different concentrations of fludarabine and gemcitabine.
The IC(50) of fludarabine and gemcitabine on CLL cells was 550 and 1,100 microg/mL, respectively, in our series of samples; the cytotoxicity of either drug was not influenced by the percentage of BCL-2 positive cells in the same sample. The addition of gemcitabine increased fludarabine-induced cytotoxicity; however, isobologram analysis of the data showed synergism only when lower doses of gemcitabine were combined to fludarabine. Induction of apoptosis reflected this pattern of activity.
Gemcitabine was able to increase the activity of fludarabine only when low doses of the former were employed. As both compounds incorporate into DNA blocking chain elongation, our results could be explained by the drugs interfering at that level. The possibility of potentiating the effects of fludarabine with low doses of gemcitabine renders this combination promising in view of an in vivo use.
氟达拉滨在B细胞慢性淋巴细胞白血病（CLL）中已显示出明确的临床活性。如果这种药物的疗效能够增强，对于实现完全缓解可能会很有用。在本研究中，我们评估了氟达拉滨与吉西他滨联合使用的效果，吉西他滨是一种脱氧胞苷类似物，已显示出在体外和体内对多种实体瘤具有活性。
从10例患者中获取的CLL细胞在体外培养，分别加入氟达拉滨（0.5 - 1000μg/mL）和吉西他滨（0.1 - 5000μg/mL），单独使用及不同组合使用。通过XTT比色法检测细胞毒性活性。此外，我们评估了BCL - 2蛋白表达，并随后检测了在基线以及将细胞暴露于不同浓度的氟达拉滨和吉西他滨后凋亡的诱导情况。
在我们的一系列样本中，氟达拉滨和吉西他滨对CLL细胞的IC50分别为550和1100μg/mL；同一样本中任一药物的细胞毒性不受BCL - 2阳性细胞百分比的影响。加入吉西他滨可增加氟达拉滨诱导的细胞毒性；然而，对数据的等效线图分析表明，仅当低剂量的吉西他滨与氟达拉滨联合使用时才显示协同作用。凋亡诱导反映了这种活性模式。
仅当使用低剂量的吉西他滨时，它才能增加氟达拉滨的活性。由于这两种化合物都掺入DNA中阻断链延伸，我们的结果可以用药物在该水平的干扰来解释。鉴于在体内的应用，低剂量吉西他滨增强氟达拉滨效果的可能性使得这种联合用药前景广阔。
