［18F］F-FMISO和［18F］F-FLT PET/CT双核素显像预测胰腺癌耐药性的体内研究

doi:10.3969/j.issn.1674-8115.2025.01.007

摘要/Abstract

摘要：

目的·［¹⁸F］氟代甲基咪唑（［¹⁸F］fluormisonidazole，［¹⁸F］F-FMISO）和［¹⁸F］氟代脱氧胸腺嘧啶核苷（［¹⁸F］fluorothymidine，［¹⁸F］F-FLT）分别是乏氧微环境及细胞增殖状态的特异性PET分子显像剂。该研究拟通过［¹⁸F］F-FMISO和［¹⁸F］F-FLT PET/CT双核素显像可视化监测胰腺癌耐药性对上述2种状态影响的变化规律，为临床转化提供理论依据。方法·采用CCK-8实验验证胰腺癌耐药细胞株PANC-1/R（PR）相对于亲代细胞株PANC-1（P）的耐药性。BALB/c雄性裸鼠左侧腋窝皮下接种胰腺癌细胞建立皮下移植瘤模型。设置亚组，分别为接种肿瘤细胞后第12天、第18天开始给予吉西他滨（gemcitabine，GEM）化疗（12D-G组和18D-G组）。于治疗前后同期行［¹⁸F］F-FMISO和［¹⁸F］F-FLT PET/CT显像，获得半定量指标（maximum standardized uptake value，SUV_max），计算ΔSUV_max=（第二次显像SUV_max－第一次显像SUV_max）/第一次显像SUV_max。通过勾画受试者工作特征曲线（receiver operating characteristic curve，ROC）获得各半定量参数判断胰腺癌耐药性的最佳阈值。结果·CCK-8实验证实PR具有对GEM的高度耐药性，耐药指数为4.24（n=5）。体内实验通过对比肿瘤生长速率和生存分析证实，亲代胰腺癌早期给予GEM化疗抑制肿瘤生长更显著，延长了生存时间（12D-G组，P=0.025），而耐药胰腺癌给予GEM化疗加速肿瘤生长，生存时间缩短（18D-G和12D-G，均P=0.025）。其次，非化疗组ΔSUV_max-FLT与生存时间呈负相关；化疗组ΔSUV_max-FMISO和ΔSUV_max-FLT与生存时间均呈负相关（P=0.050，P=0.006）；18D-G化疗组第二次显像P肿瘤的ΔSUV_max-FMISO和ΔSUV_max-FLT明显低于PR肿瘤（P=0.045，P=0.050）；12D-G化疗组第二次显像P肿瘤的ΔSUV_max-FLT略低于PR肿瘤（P=0.051）。ROC判断胰腺癌耐药性的最佳阈值：非化疗组ΔSUV_max-FLT=0.45时，灵敏度和特异度为100.00%、50.00%；化疗组ΔSUV_max-FMISO=0.37、ΔSUV_max-FLT=0.36时，灵敏度和特异度为100.00%、83.33%。结论·［¹⁸F］F-FMISO和［¹⁸F］F-FLT PET/CT双核素显像可用于评估胰腺癌耐药性，化疗前后比较［¹⁸F］F-FMISO与［¹⁸F］F-FLT PET差值对预测胰腺癌耐药性和生存时间的准确性最佳。

关键词: 胰腺癌, 耐药, ［¹⁸F］F-FMISO, 乏氧微环境, ［¹⁸F］F-FLT, 细胞增殖

Abstract:

Objective ·[¹⁸F]F-FMISO and [¹⁸F]F-FLT are specific PET imaging agents for detecting the hypoxia microenvironment and cell proliferation, respectively. This study aims to visualize and monitor the impact of drug resistance in pancreatic cancer on the hypoxia microenvironment and cell proliferation through [¹⁸F]F-FMISO and [¹⁸F]F-FLT PET/CT dual-nuclide imaging, with the goal of providing a theoretical basis for clinical application. Methods ·The CCK-8 assay was conducted to assess drug resistance in the PANC-1/R (PR) pancreatic cancer cell line compared to the parental PANC-1 (P) cell line. Subcutaneous xenograft models of pancreatic cancer were established by injecting male BALB/c nude mice with pancreatic cancer cells into the left axillary subcutaneous region. Subgroups were treated with gemcitabine (GEM) chemotherapy starting on day 18 (18D-G group) or day 12 (12D-G group) after inoculation of tumor cells. [¹⁸F] F-FMISO and [¹⁸F] F-FLT PET/CT imaging were performed before and after treatment to obtain semi-quantitative parameters (maximum standardized uptake value, SUV_max). ΔSUV_max was calculated by using the following equation: ΔSUV_max=(SUV_max of second imaging-SUV_max of first imaging)/ SUV_max of first imaging. Receiver operating characteristic (ROC) curves were used to determine the optimal threshold for the semi-quantitative parameters to assess pancreatic cancer drug resistance. Results ·The CCK-8 assay confirmed that the PR cells exhibited high resistance to GEM, with a resistance index of 4.24 (n=5). In vivo experiments showed that GEM chemotherapy significantly inhibited tumor growth and prolonged survival in the parental pancreatic cancer group (12D-G group, P=0.025), whereas GEM chemotherapy accelerated tumor growth and shortened survival (18D-G and 12D-G, P=0.025) in the drug-resistant pancreatic cancer group. In addition, in the non-chemotherapy group, ΔSUV_max-FLT might be negatively correlated with survival time, while in the chemotherapy group, both ΔSUV_max-FMISO and ΔSUV_max-FLT were negatively correlated with survival time (P=0.050, P=0.006). In the 18D-G and chemotherapy group, the second imaging showed significantly lower ΔSUV_max-FMISO and ΔSUV_max-FLT in P tumors compared to PR tumors (P=0.045, P=0.050). In the 12D-G and chemotherapy group, the second imaging showed slightly lower ΔSUV_max-FLT in P tumors compared to PR tumors (P=0.051). ROC analysis identified the optimal threshold for assessing pancreatic cancer drug resistance: when ΔSUV_max-FLT=0.45 in the non-chemotherapy group, the sensitivity and specificity were 100.00% and 50.00%, respectively; when ΔSUV_max-FMISO=0.37 and ΔSUV_max-FLT=0.36 in the chemotherapy group, the sensitivity and specificity were 100.00% and 83.33%, respectively. Conclusion ·[¹⁸F]F-FMISO and [¹⁸F]F-FLT PET/CT dual-nuclide imaging can be used to assess drug resistance in pancreatic cancer. The comparison of [¹⁸F]F-FMISO and [¹⁸F]F-FLT PET differences before and after chemotherapy provides the most accurate prediction of drug resistance and survival time.

Key words: pancreatic cancer, drug resistance, [¹⁸F]F-FMISO, hypoxia microenvironment, [¹⁸F]F-FLT, cell proliferation

中图分类号:

R735.9

孙晨玮, 海汪溪, 屈骞, 席云. ［¹⁸F］F-FMISO和［¹⁸F］F-FLT PET/CT双核素显像预测胰腺癌耐药性的体内研究[J]. 上海交通大学学报（医学版）, 2025, 45(1): 60-68.

SUN Chenwei, HAI Wangxi, QU Qian, XI Yun. [¹⁸F]F-FMISO and [¹⁸F]F-FLT PET/CT dual-nuclide imaging for in vivo prediction of drug resistance in pancreatic cancer[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(1): 60-68.

图/表 3

图1 实验流程Note： P—non-drug-resistant pancreatic cancer; PR—drug-resistant pancreatic cancer; GEM—gemcitabine. After inoculation of tumor cells, treatment was initiated on day 18 (18D-G) or day 12 (12D-G). Each subgroup, n=3.

Fig 1 Experimental flowchart

图2 裸鼠体质量与肿瘤体积追踪记录Note: After inoculation of tumor cells, treatment was initiated on day 18 (18D-G) or day 12 (12D-G). The GEM+ group received intraperitoneal injections of 1 μg/kg GEM every other day, while the GEM- group received intraperitoneal injections of 20 μl PBS every other day. The treatment was administered 6 times. The arrows indicate the time points of GEM administration. Each subgroup: n=3. ?—P<0.05; ??—P<0.01; ???—P<0.001.The purple circles indicate the statistical differences in weight of mice and volume of tumor before and after treatment in each group.Weight of mice?GEM+ group vs GEM- group: P<0.001 after the final treatment in 18D-G (P); P=0.001 after the final treatment in 18D-G (PR); P=0.002 after the final treatment in 12D-G (P); P=0.007 after the final treatment in 12D-G (PR). P group vs PR group: P=0.002 before treatment and P<0.001 after the final treatment in 18D-G (GEM-) and in 18D-G (GEM+); P=0.004 after the final treatment in 12D-G (GEM-); P=0.031 after the final treatment in 12D-G (GEM+).Volume of tumor?P group vs PR group: P=0.003 before treatment and P=0.036 after the final treatment in 18D-G (GEM-); P=0.010 before treatment in 18D-G (GEM+); P=0.024 before treatment and P=0.014 after the final treatment in 18D-G (GEM-); P=0.030 before treatment in 18D-G (GEM+).

Fig 2 Tracking record of nude mouse weight and tumor volume

图3 治疗前后双核素显像各半定量参数的ROC曲线Note： 1st Micro PET/CT was performed before treatment. 2nd Micro PET/CT was performed after the completion of treatment. The GEM+ group received intraperitoneal injections of 1 μg/kg GEM every other day, while the GEM- group received intraperitoneal injections of 20 μl PBS every other day. The treatment was administered 6 times. For the 1st Micro PET/CT, each subgroup n=12, while for the 2nd Micro PET/CT, each subgroup n=6. a? AUC≥0.90 (AUC of ΔSUVmax-FLT in the GEM- group=0.90, AUC of ΔSUVmax-FMISO in the GEM+ group=0.94, AUC of ΔSUVmax-FLT in the GEM+ group=0.97).

Fig 3 ROC curves of semi-quantitative parameters of dual-nuclide imaging before and after treatment

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［¹⁸F］F-FMISO和［¹⁸F］F-FLT PET/CT双核素显像预测胰腺癌耐药性的体内研究

[¹⁸F]F-FMISO and [¹⁸F]F-FLT PET/CT dual-nuclide imaging for in vivo prediction of drug resistance in pancreatic cancer

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