Radiosensitizing potential of gemcitabine (2′,2′-difluoro-2′-deoxycytidine) within the cell cycle in vitro
Radiosensitizing potential of gemcitabine (2′,2′-difluoro-2′-deoxycytidine) within the cell cycle in vitro
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DOI：
10.1016/s0360-3016(98)00105-9
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发表时间：
1998-07-01
影响因子：
7
通讯作者：
Weber, KJ
中科院分区：
文献类型：
--
作者：
Latz, D;Fleckenstein, K;Weber, KJ
目的：吉西他滨（2',2'-二氟脱氧胞苷；dFdCyd）是一种新型脱氧胞苷类似物，在体外具有显着的抗实体瘤活性和放射增敏特性。为了检查吉西他滨和放射联合治疗的细胞周期特异性效应，测量了来自对数期培养细胞、G1 和 S 期细胞的两种不同细胞系的体外克隆存活。方法和材料：中国仓鼠 (V79) 和人结肠癌细胞 (Widr) 细胞暴露于不同的放射剂量和相对于吉西他滨治疗的不同时间点 (2 小时)。还对有丝分裂选择（V79）或平台期细胞血清刺激（Widr）后获得的不同细胞周期群体进行了实验。根据LQ模型分析所得生存曲线，并根据生存曲线参数计算平均灭活剂量（MID）和细胞周期特异性增强比（ER）。 结果：对数期细胞联合治疗的有效性在吉西他滨暴露结束时照射细胞时最大[ER：1.28（V79），1.24（Widr）]。在去除药物后的后期，放射增敏作用下降，接近独立毒性。根据交互型损伤衰减的时间过程，得出 75 分钟 (V79) 和 92 分钟 (Widr) 的半衰期值。吉西他滨不会使来自 G1/S 边界的 G1 Widr 细胞或 V79 细胞放射增敏，但对 S 期细胞制剂观察到显着的放射增敏作用 [ER：1.45 (V79-lateS)、1.57 (Widr)]。结论：在照射前立即用吉西他滨处理细胞消除或至少大大减少了细胞周期期间放射敏感性的变化，具体表现为： S期的放射抗性。 S 相放射抗性的逆转可能意味着吉西他滨干扰了潜在的致命损伤修复/固定途径。已经采取了其他方法来克服 S 相放射抗性，例如热疗或高密度电离辐射，并且与 dFdCyd 的联合治疗可能被证明是补充这些努力的价值。 (C) 1998 爱思唯尔科学公司。
Purpose: Gemcitabine (2',2'-difluorodeoxycytidine; dFdCyd) is a new deoxycitidine analog which exhibits substantial activity against solid tumors and radiosensitizing properties in vitro. To examine cell cycle-specific effects of a combined treatment with gemcitabine and radiation, the in vitro clonogenic survival of two different cell lines was measured for cells from log-phase culture, G1 and S-phase cells.Methods and Materials: Chinese hamster (V79) and human colon carcinoma (Widr) cells were exposed to different radiation doses and for different points of time relative to gemcitabine treatment (2 h). Experiments were also tarried out with different cell-cycle populations obtained after mitotic selection (V79) or after serum stimulation of plateau-phase cells (Widr). The resulting survival curves were analyzed according to the LQ model, and mean inactivation doses (MID) and the cell cycle-specific enhancement ratios (ER) were calculated from the survival curve parameters.Results: Effectiveness of combined treatment of log-phase cells mas greatest when cells were irradiated at the end of the gemcitabine exposure [ER: 1.28 (V79), 1.24 (Widr)]. For later times after the removal of the drug, radiosensitization declined, approaching independent toxicity. From the time course of interactive-type damage decay half-life values of 75 min (V79) and 92 min (Widr) were derived. Gemcitabine did not radiosensitize G1 Widr cells or V79 cells from the G1/S border, but substantial radiosensitization was observed for the S-phase cell preparations [ER: 1.45 (V79-lateS), 1.57 (Widr)].Conclusions: Treatment of cells with gemcitabine immediately before irradiation eliminates, or at least greatly reduces, the variation in radiosensitivity during the cell cycle that is manifested by radioresistance during S phase. This reversal of S-phase radioresistance could imply that gemcitabine interferes with the potentially lethal damage repair/fixation pathway. Other approaches have been taken to overcome S-phase radioresistance, such as hyperthermia or densely ionizing radiation, and combined treatments with dFdCyd could prove of value to complement such efforts. (C) 1998 Elsevier Science Inc.