Department of Nuclear Medicine, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China.
Department of Nuclear Medicine, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China.
Nucl Med Biol. 2023 May-Jun;120-121:108350. doi: 10.1016/j.nucmedbio.2023.108350. Epub 2023 May 8.
To use bifunctional target genes to increase the intracellular transport of gemcitabine (GEM) to reverse chemotherapy resistance and to simultaneously use reporter gene imaging to localize therapeutic genes. The therapeutic effect was evaluated by [F]FLT PET/CT to visualize the effect of gene therapy.
A viral gene vector containing the pancreatic cancer-targeting promoter MUC1 for specific transcription of equilibrative nucleoside transporter 1 (ENT1) and NIS (nuclide transport channel) was employed. [I]NaI uptake tests and [I]NaI SPECT imaging were performed to verify the function of NIS and the target function of MUC1. The correlation between [F]FLT uptake and GEM resistance were assessed, and the influence ENT1 and thymidine kinase 1 (TK1) expression on [F]FLT micro-PET/CT was measured, which provides a theoretical basis for the use of [F]FLT micro-PET/CT to evaluate the efficacy of gene therapy.
First, functions of gene therapy were confirmed: ENT1 reversed the drug resistance of GEM-resistant pancreatic cancer cells by increasing GEM intracellular transport; MUC1 drove NIS target gene expression in pancreatic cancer; and therapeutic genes could be localized using [I]NaI SPECT reporter gene imaging. Second, the [F]FLT uptake ratio was affected by drug resistance and GEM treatment. The mechanism underlying this effect was related to ENT1 and TK1. Increased expression of ENT1 inhibited the expression of TK1 after GEM chemotherapy to reduce the uptake of [F]FLT. Finally, micro-PET/CT indicated that the SUV of [F]FLT could predict survival time. SUV exhibited an increasing trend in resistant pancreatic cancer but a trend of inhibition after upregulation of ENT1, which was more significant after GEM treatment.
Bifunctional targeted genes can localize therapeutic genes through reporter gene imaging, reverse the drug resistance of GEM-resistant pancreatic cancer and be visually evaluated through [F]FLT micro-PET/CT.
利用双功能靶向基因增加吉西他滨（GEM）的细胞内转运，以逆转化疗耐药性，并同时利用报告基因成像来定位治疗基因。通过 [F]FLT PET/CT 可视化基因治疗效果来评估治疗效果。
使用含有胰腺癌细胞靶向启动子 MUC1 的病毒基因载体，用于特异性转录嘌呤核苷转运蛋白 1（ENT1）和 NIS（核素转运通道）。进行 [I]NaI 摄取试验和 [I]NaI SPECT 成像，以验证 NIS 的功能和 MUC1 的靶向功能。评估 [F]FLT 摄取与 GEM 耐药性之间的相关性，并测量 ENT1 和胸苷激酶 1（TK1）表达对 [F]FLT 微 PET/CT 的影响，为使用 [F]FLT 微 PET/CT 评估基因治疗效果提供理论依据。
首先，证实了基因治疗的功能：通过增加 GEM 细胞内转运，ENT1 逆转了 GEM 耐药胰腺癌细胞的耐药性；MUC1 驱动胰腺癌细胞中 NIS 靶基因表达；并且可以使用 [I]NaI SPECT 报告基因成像来定位治疗基因。其次，[F]FLT 摄取率受耐药性和 GEM 治疗的影响。这种影响的机制与 ENT1 和 TK1 有关。GEM 化疗后 ENT1 表达增加抑制了 TK1 的表达，从而减少了 [F]FLT 的摄取。最后，微 PET/CT 表明 [F]FLT 的 SUV 可以预测生存时间。在耐药性胰腺癌细胞中 SUV 呈上升趋势，但在 ENT1 上调后呈抑制趋势，在 GEM 治疗后更为明显。
双功能靶向基因可以通过报告基因成像定位治疗基因，逆转 GEM 耐药性胰腺癌细胞的耐药性，并通过 [F]FLT 微 PET/CT 进行可视化评估。
