裸鼠原位膀胱癌放射性核素内照射治疗的实验研究

The Experimental Study of Internal-radiation Therapy in Nude Mice Bearing Orthotopic Bladder Cancer

目的探讨膀胱内灌注125Ⅰ-脱氧尿嘧啶核苷(125IUdR)对裸鼠原位膀胱癌治疗的有效性与可行性。方法裸鼠原位膀胱癌模型设立对照组、MMC组、125IUdR组和联合组,通过流式细胞仪分析、实时定量PCR检测、病理学检查、caspase-3蛋白检测和生存分析比较各组的治疗情况。结果 MMC组、125IUdR组和联合组裸鼠的膀胱肿瘤重量均明显小于对照组,抑瘤率分别为33.45%、31.46%和50.27%;流式细胞仪检测显示125IUdR组和联合组肿瘤细胞的S期百分比较对照组明显降低,[分别为(3.9±0.7)%和(0.18±0.03)%],而凋亡指数明显高于对照组[分别为(3.367±1.629)%和(25.767±11.875)%];治疗组肿瘤细胞p21基因mRNA表达水平明显高于对照组;Caspase-3检测治疗组凋亡细胞数明显多于对照组;治疗组裸鼠的生存时间较对照组明显延长。结论膀胱内灌注125IUdR对裸鼠膀胱癌的治疗安全有效;125IUdR能选择性杀伤DNA合成S期的肿瘤细胞,显著抑制膀胱癌细胞的增殖,干扰膀胱癌细胞的DNA合成;氨甲喋呤联合125IUdR具有协同效应,可增强疗效。

Objective To investigate the efficacy and feasibility of intravesical instillation of 5-[125Ⅰ]iodo-2＇-deoxyuridine（125IUdR）in the treatment of orthotopic bladder cancer.Methods The model of orthotopic bladder cancer was established on BALB/nu/nu mice.The nude mice bearing orthotopic bladder cancer were randomly assigned to 4 groups：control group、MMC group、125IUdR group and combined group.The therapeutic effect in each group was compared through flow cytometry（FCM）、real time polymerase chain reaction（PCR）、pathological examination、caspase-3 and survival analysis.Results The bladder weight of mice bearing orthotopic bladder tumor were significantly lighter in MMC group、125IUdR group and combined group than in control group,and the inhibitory rate in in MMC group、125IUdR group and combined group was 33.45%、31.46% and 50.27% respectively.The S-phase percentage of tumor cells in 125IUdR group and combined group was significantly lower in therapeutic group[（3.9±0.7）%和（0.18±0.03）% separately] than in control group,on the other hand apoptotic index of tumor cell was obviously higher [（3.367±1.629）%和（25.767±11.875）% separately] than the latter.The messenger RNA level of p21 gene was strikingly higher in therapeutic group than in control group.The analysis of caspase-3 display that apoptosis cells were obviously higher in therapeutic group than in control group.The survival time of mice bearing orthotopic bladder cancer were much longer in therapeutic group than in control group.Conclusion 125IUdR can selectively kill S-phase tumor cells,suppressed tumor cell proliferation,obstructed the DNA synthesis of tumor cell.The combination of 125IUdR and MTX showed synergistic effect and enhanced therapeutic effect.