De Witte T, Muus P, Haanen C, Van der Lely N, Koekman E, Van der Locht A, Blankenborg G, Wessels J
Department of Hematology, University Hospital Nijmegen, The Netherlands.
Behring Inst Mitt. 1988 Aug(83):301-7.
Leukemic clonogenic cells (CFU-L) and normal myeloid progenitor cells (CFU-GM) were exposed to Ara-C in the presence of crude CSF obtained from placentas (HPCM) or recombinant human GM-CSF for varying periods. The cytotoxicity of Ara-C to CFU-L increased considerably when the exposure time to Ara-C in the presence of HPCM was extended from 20 hours to 10 days. The ID50 of the CFU-L was 1.5 +/- 2.2 x 10(-8) M Ara-C compared to 5.5 +/- 2.9 x 10(-8) M Ara-C for the CFU-GM after an exposure to Ara-C for 10 days (p less than 0.05). Replacement of crude CSF from placenta conditioned medium by rh GM-CSF resulted in identical observations. Interesting was the observation that secondary leukemic colony forming cells were more or at least equally sensitive to Ara-C in the presence of GM-CSF when compared to the primary leukemic clonogenic cells. This contrasted the secondary normal CFU-GM, which were less sensitive to Ara-C than the primary CFU-GM. This indicates that GM-CSF induces leukemic clonogenic cells with selfrenewal capacity into proliferation, and in doing so, it may enhance the cytotoxicity of a cell cycle specific drug like Ara-C with sparing of the normal clonogenic cells.
将白血病克隆形成细胞（CFU-L）和正常髓系祖细胞（CFU-GM）在来自胎盘的粗制集落刺激因子（HPCM）或重组人粒细胞-巨噬细胞集落刺激因子（GM-CSF）存在的情况下，暴露于阿糖胞苷（Ara-C）不同时间。当在HPCM存在下阿糖胞苷的暴露时间从20小时延长至10天时，阿糖胞苷对CFU-L的细胞毒性显著增加。暴露于阿糖胞苷10天后，CFU-L的半数抑制浓度（ID50）为1.5±2.2×10⁻⁸M阿糖胞苷，而CFU-GM为5.5±2.9×10⁻⁸M阿糖胞苷（p＜0.05）。用重组人GM-CSF替代胎盘条件培养基中的粗制集落刺激因子得到相同的结果。有趣的是观察到，与原发性白血病克隆形成细胞相比，继发性白血病集落形成细胞在GM-CSF存在下对阿糖胞苷更敏感或至少同样敏感。这与继发性正常CFU-GM形成对比，继发性正常CFU-GM对阿糖胞苷的敏感性低于原发性CFU-GM。这表明GM-CSF诱导具有自我更新能力 的白血病克隆形成细胞增殖，在此过程中，它可能增强像阿糖胞苷这样的细胞周期特异性药物的细胞毒性，同时使正常克隆形成细胞免受影响。
