上海交通大学学报（医学版）

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2025 , Vol. 45 >Issue 1: 60 - 68

DOI: https://doi.org/10.3969/j.issn.1674-8115.2025.01.007

论著 · 临床研究

［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

  • 孙晨玮 ,
  • 海汪溪 ,
  • 屈骞 ,
  • 席云
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  • 上海交通大学医学院附属瑞金医院核医学科，上海 200025
孙晨玮（1984—），男，助理工程师，学士；电子信箱：poorpush@163.com。
席　云，副主任医师，博士；电子信箱：cloudylanhuit@163.com。

收稿日期: 2024-06-18

  录用日期: 2024-08-27

  网络出版日期: 2025-01-28

基金资助

国家自然科学基金(81801728)

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

  • SUN Chenwei ,
  • HAI Wangxi ,
  • QU Qian ,
  • XI Yun
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  • Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
XI Yun, E-mail: cloudylanhuit@163.com.

Received date: 2024-06-18

  Accepted date: 2024-08-27

  Online published: 2025-01-28

Supported by

National Natural Science Foundation of China(81801728)

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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，SUVmax），计算ΔSUVmax=（第二次显像SUVmax－第一次显像SUVmax）/第一次显像SUVmax。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ΔSUVmax-FLT与生存时间呈负相关；化疗组ΔSUVmax-FMISO和ΔSUVmax-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ΔSUVmax-FMISO和ΔSUVmax-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ΔSUVmax-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ΔSUVmax-FLT=0.45时，灵敏度和特异度为100.00%、50.00%；化疗组ΔSUVmax-FMISO=0.37、ΔSUVmax-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

本文引用格式

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 . DOI: 10.3969/j.issn.1674-8115.2025.01.007

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, SUVmax). ΔSUVmax was calculated by using the following equation: ΔSUVmax=(SUVmax of second imaging-SUVmax of first imaging)/ SUVmax 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, ΔSUVmax-FLT might be negatively correlated with survival time, while in the chemotherapy group, both ΔSUVmax-FMISO and ΔSUVmax-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 ΔSUVmax-FMISO and ΔSUVmax-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 ΔSUVmax-FLT in P tumors compared to PR tumors (P=0.051). ROC analysis identified the optimal threshold for assessing pancreatic cancer drug resistance: when ΔSUVmax-FLT=0.45 in the non-chemotherapy group, the sensitivity and specificity were 100.00% and 50.00%, respectively; when ΔSUVmax-FMISO=0.37 and ΔSUVmax-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

参考文献

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