高压氧对非小细胞肺癌移植瘤裸鼠大分割放疗的增敏效应及其作用机制

Sensitization effect and mechanism of hyperbaric oxygen assisted hypofractionated radiation in treating non-small cell lung cancer

目的:应用18F-氟赤硝基咪唑(18F-FETNIM)正电子发射型计算机断层仪(PET)-CT,监测高压氧辅助大分割放疗(HFRT)过程中非小细胞肺癌(NSCLC)移植瘤裸鼠模型对放疗的增敏效应及其作用机制。方法:构建裸鼠NSCLC移植瘤裸鼠模型,按照随机数字表法分为单纯HFRT组、低氧辅助HFRT组和高压氧辅助HFRT组,每组40只。单纯HFRT组暴露模型荷瘤鼠左后肢肿瘤,使用6 MeV电子束单次大剂量照射,源皮距1 m、DT 20 Gy;低氧辅助HFRT组在上述相同的HFRT照射后,予以5 L/min、10.0%低氧的混合气体处理;高压氧辅助HFRT组在上述相同的HFRT照射后,予以高压氧处理。采用PET-CT动态评估18F-FETNIM代谢的变化,并计算移植瘤放射性最大标准化摄取值(SUVmax)。免疫组化法检测各组移植瘤组织中Ki-67及缺氧诱导因子-1α(HIF-1α)的阳性细胞表达情况,并分析其与放射性SUVmax的相关性。结果:18F-FETNIM PET-CT显像证实,与单纯HFRT组和低氧辅助HFRT组比较,高压氧辅助HFRT组移植瘤裸鼠荷瘤放射性SUVmax明显降低(P<0.01)。免疫组化结果显示,与单纯HFRT组和低氧辅助HFRT组比较,高压氧辅助HFRT组移植瘤裸鼠荷瘤组织中Ki-67阳性细胞比例明显降低,HIF-1α阳性细胞数明显减少,差异均有统计学意义(P<0.05)。放射性SUVmax与Ki-67表达水平呈正相关(r=0.677,P<0.01),SUVmax与HIF-1α表达水平也呈现正相关(r=0.445,P<0.05)。结论:高压氧联合HFRT处理对裸鼠NSCLC移植瘤组织具有放射增敏效应,其机制可能与抑制Ki-67、HIF-1α的阳性表达有关。

Objective To investigate the sensitization effect and mechanism of hyperbaric oxygen(HBO)assisted hypofractionated radiation(HFRT)in treating mice with non-small cell lung cancer(NSCLC),monitored by the PET/CT with fluorine-18 fluoroerythronitroimidazole(18F-FETNIM)as the marker.Methods The transplanted NSCLC tumor model was established in nude mice which were randomly divided into three groups:HFRT group(n=40),HBO-assisted HFRT group(n=40),and hypoxia-assisted HFRT group(n=40).In the HFRT group,the tumors on the left hind limbs of tumor-bearing mice were exposed to a high-dose-per-pulse of 6 MeV electron beam,with 1 m source-to-surface distance under 20 Gy.On the basis of the treatment in the HFRT group,the hypoxia-assisted HFRT group was given 10.0%hypoxic mixed gas at 5 L/min;while the HBO-assisted HFRT group was given HBO therapy.The PET/CT was used to dynamically evaluate the metabolic changes of 18F-FETNIM,and the maximum standardized uptake value(SUVmax)of the tumors was obtained.The expression levels of Ki-67 and hypoxia inducible factor-1α(HIF-1α)in tumor tissues of the three groups were detected by immunohistochemistry,and their correlations with SUVmax were analyzed.Results Compared with the HFRT group and hypoxia-assisted HFRT group,the radioactive SUVmax,the proportion of Ki-67 positive cells,and the number of HIF-1αpositive cells shown in the semi-quantitative analysis of the tumor-bearing mice in the HBO-assisted HFRT group decreased significantly,and all the differences were statistically significant(P<0.05 or P<0.01).Pearson test showed that the SUVmax was positively correlated with the expressions of Ki-67 and HIF-1α(r=0.677,P<0.01;r=0.445,P<0.05).Conclusion The PET-CT with 18F-FETNIM imaging shows that HBO can enhance the radiosensitivity of HFRT treatment on NSCLC transplanted tumor tissues in nude mice,and its mechanism might be related to the inhibition of Ki-67 and HIF-1αexpressions.