己酮可可碱对(E)-(2’)-脱氧-氟亚甲基胞苷的放射增敏和细胞周期的影响

Effect of pentoxifylline on (e)-2'-deoxy-2'-(fluoromethylene) cytidine induced-radiosensitization and cell cycle

目的 观察己酮可可碱 (PTX)在体外对 (E) (2’) 脱氧 氟亚甲基胞苷 (FMdC)的放射增敏作用和放射引起细胞周期再分布的影响。方法 在人结肠癌细胞系WiDr进行克隆形成分析检测放射增敏效应。常规照射剂量 2Gy时的放射增敏比 (SERSF2 )定义为 2Gy时对照组存活分数 (SF)和药物处理组SF之比。流式细胞仪应用于分析照射、FMdC和PTX对细胞周期分布的影响。结果 照射前用 30nmol/LFMdC处理WiDr细胞 48h或照射后立即单用 0 .5～ 1.0mmol/LPTX 14d均能观察到各自的放射增敏作用。 30nmol/LFMdC和 0 .2 5～ 1.0mmol/LPTX的SERSF2 分别为 1.0 9和 1.0 2～ 1.2 4。30nmol/LFMdC和 0 .5mmol/L或 1.0mmol/LPTX联合应用时 ,SERSF2 分别增加至 1.5 0和 1.6 6。PTX增强FMdC的放射敏感性。流式细胞仪分析表明 ,在非同步化WiDr细胞 ,放射引起G2 期阻滞和剂量有关。G2 +M期阻滞在照射后 6h可检测到 ,12h达高峰。照射前应用 30nmol/LFMdC能够使放射引起的G2 +M期阻滞增多 ,但PTX能显著去除G2 期阻滞。结论 己酮可可碱增强FMdC放射增敏作用和G2

Objective To investigate the effect of pentoxifylline (PTX) on (E) 2' deoxy 2' (fluoromethylene) cytidine (FMdC) induced radiosensitization and radiation induced cell cycle redistribution in vitro. Methods Clonogenic assay was used to evaluate the radiosensitizing effect of FMdC and pentoxifylline on a human colorectal cancer cell line WiDr. The change in radiosensitivity was quantified by calculating the sensitization enhancement ratio at a clinically relevant dose of 2?Gy (SER SF 2 ), defined as the mean survival fraction (SF) for control/mean SF for the drug. Flow cytometry was used to analyze the cell cycle distribution of radiation, FMdC and PTX. Results Pre irradiation exposure of exponentially growing WiDr cells to 30?nmol/L FMdC for 48 h or post irradiation to 0.5 1.0?mmol/L pentoxifylline alone for 14 days resulted in an increase in radiation induced cytotoxicity. The SER SF 2 was 1.09 for 30?nmol/L FMdC and 1.02 1.24 for 0.25 1.0?mmol/L PTX, respectively. Pentoxifylline enhanced the radiosensitizing effect of FMdC. The SER SF 2 of a combination of 30?nmol/L FMdC and 0.5?mmol/L or 1.0?mmol/L PTX was increased to 1.50 and 1.66, respectively. In asynchronous WiDr, flow cytometry analysis showed a dose dependent radiation induced G 2 arrest. This G 2 arrest was detectable at 6 h and peaked at 12 h after irradiation. Treatment with 30?nmol/L FMdC prior to radiation increased post irradiation induced G 2 arrest, and such a G 2 accumulation was significantly abrogated by PTX. Conclusions These results show that potentiation of FMdC radiosensitization by pentoxifylline is associated with abrogation of G 2 arrest in colorectal cancer cells.