Gorodetsky R, Levdansky L, Ringel I, Vexler A
Sharett Institute of Oncology, Hadassah University Hospital, Jerusalem, Israel.
Radiat Res. 1998 Sep;150(3):283-91.
The cytotoxicity of paclitaxel (taxol) is associated mainly with block in G2/M phase, the most radiosensitive phase of the cell cycle. Nevertheless, taxol-induced modification of the effects of radiation may vary from clear sensitization to subadditivity. Therefore, this effect was studied in relation to drug-induced alterations in the distribution of cells in the phases of the cell cycle in tumor cells (EMT-6 and OV-1063) and normal skin fibroblasts. Cell survival was evaluated with two colorimetric assays. The cell cycle was evaluated by FACS analysis of doubly-labeled cells. The radiosensitivity of the different cells studied was similar, apart from the less radiosensitive human fibroblasts. However, their dose- and time-dependent sensitivity to taxol varied significantly. After 24 h exposure of EMT-6 cells to taxol (IC50 approximately 20 nM), the fraction of cells in G2/M phase increased, the fraction in S phase decreased, and the proportion of possibly apoptotic cells with subdiploid and subtetraploid DNA content increased; this coincided with radiosensitization. In OV-1063 cells (IC50 approximately 3 nM), the drug-induced G2/M-phase block was most pronounced, but the combined effect with radiation was merely additive. In human fibroblasts (IC50 approximately 35 nM), a minimal G2/M-phase block with no change in the S phase and a massive elevation of apoptotic cells with subdiploid DNA content was accompanied by a subadditive combined effect with radiation. Six hours of exposure to taxol increased the fraction of cells in S phase in both nonsynchronized and S-phase-synchronized human fibroblasts (G1 phase approximately 65%, S phase approximately 13%). This was accompanied by a pronounced subadditive effect of the combined treatment. However, in G1-phase synchronized human fibroblasts (G1 phase > or =90%, S phase approximately 3%), only the fraction of cells in G2/M phase was slightly elevated, with a merely additive response to the combined treatment. The differences in the response to the combined treatment between slowly and rapidly proliferating cells in relation to modifications in the cell cycle are discussed.
紫杉醇的细胞毒性主要与细胞周期中对辐射最敏感的G2/M期阻滞有关。然而，紫杉醇诱导的辐射效应改变可能从明显的增敏到亚相加性不等。因此，针对肿瘤细胞（EMT-6和OV-1063）及正常皮肤成纤维细胞中药物诱导的细胞周期各阶段细胞分布变化，对这种效应进行了研究。采用两种比色法评估细胞存活率。通过对双标记细胞进行流式细胞术分析来评估细胞周期。除了对辐射敏感性较低的人成纤维细胞外，所研究的不同细胞的放射敏感性相似。然而，它们对紫杉醇的剂量和时间依赖性敏感性差异显著。EMT-6细胞暴露于紫杉醇24小时后（IC50约为20 nM），G2/M期细胞比例增加，S期细胞比例下降，具有亚二倍体和亚四倍体DNA含量的可能凋亡细胞比例增加；这与放射增敏作用一致。在OV-1063细胞中（IC50约为3 nM），药物诱导的G2/M期阻滞最为明显，但与辐射的联合效应仅为相加性。在人成纤维细胞中（IC50约为35 nM），最小的G2/M期阻滞且S期无变化，同时具有亚二倍体DNA含量的凋亡细胞大量增加，与辐射的联合效应为亚相加性。暴露于紫杉醇6小时增加了非同步化和S期同步化的人成纤维细胞（G1期约65%，S期约13%）中S期细胞的比例。这伴随着联合治疗明显的亚相加效应。然而，在G1期同步化的人成纤维细胞中（G1期≥90%，S期约3%），仅G2/M期细胞比例略有升高，联合治疗的反应仅为相加性。讨论了缓慢增殖细胞和快速增殖细胞在细胞周期改变方面对联合治疗反应的差异。
