Tippayamontri Thititip, Guérin Brigitte, Ouellet René, Sarrhini Otman, Rousseau Jacques, Lecomte Roger, Paquette Benoit, Sanche Léon
Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada.
Center of Radiotherapy Research, Faculty of Medicine and Health Sciences, Universite de Sherbrooke, Sherbrooke, QC, Canada.
EJNMMI Res. 2019 Apr 11;9(1):33. doi: 10.1186/s13550-019-0496-7.
The goal of targeted radiotherapy (TRT) is to administer radionuclides to tumor cells, while limiting radiation exposure to normal tissues. 3'-Deoxy-3'-[F]-fluorothymidine (F-FLT) is able to target tumor cells and emits a positron with energy appropriate for local (~ 1 mm range) radiotherapy. In the present work, we investigated the potential of TRT with a local administration of F-FLT alone or in combination with 5-fluorouracil (5FU), which acts as a chemotherapeutic agent and radiosensitizer. Treatment efficiency of F-FLT combined or not with 5FU was evaluated by intratumoral (i.t.) infusion into subcutaneous HCT116 colorectal tumors implanted in nu/nu mice. The tumor uptake and kinetics of F-FLT were determined and compared to 2-deoxy-2-[F]-fluoro-D-glucose (F-FDG) by dynamic positron emission tomography (PET) imaging following i.t. injection. The therapeutic responses of F-FLT alone and with 5FU were evaluated and compared with F-FDG and external beam radiotherapy (EBRT). The level of prostaglandin E (PGE) biosynthesis was measured by liquid chromatography/tandem mass spectrometry (LC/MS/MS) in order to determine the level of inflammation to healthy tissues surrounding the tumor, after i.t. injection of F-FLT, and compared to EBRT.
We found that i.t. administration of F-FLT offers (1) the highest tumor-to-muscle uptake ratio not only in the injected tumor, but also in distant tumors, suggesting potential for concurrent metastases treatment and (2) a sixfold gain in radiotherapeutic efficacy in the primary tumor relative to EBRT, which can be further enhanced with concurrent i.t. administration of the radiosensitizer 5FU. While EBRT stimulated PGE production in peritumoral tissues, no significant increase of PGE was measured in this area following i.t. administration of F-FLT.
Considering the biochemical stability of F-FLT and the physical properties of localized F, this study shows that TRT via intratumoral infusion of F-FLT and 5FU could provide a new effective treatment option for solid tumors. Using this approach in a colorectal tumor model, the tumor and its metastases could be efficiently irradiated locally with much lower doses absorbed by healthy tissues than with i.t. administration of F-FDG or conventional EBRT.
靶向放疗（TRT）的目标是将放射性核素输送到肿瘤细胞，同时限制对正常组织的辐射暴露。3'-脱氧-3'-[F]-氟胸苷（F-FLT）能够靶向肿瘤细胞，并发射出能量适合局部（~1毫米范围）放疗的正电子。在本研究中，我们研究了单独局部给予F-FLT或与作为化疗药物和放射增敏剂的5-氟尿嘧啶（5FU）联合使用进行TRT的潜力。通过向植入裸鼠的皮下HCT116结直肠癌肿瘤内（i.t.）注射，评估F-FLT联合或不联合5FU的治疗效果。在i.t.注射后，通过动态正电子发射断层扫描（PET）成像测定F-FLT的肿瘤摄取和动力学，并与2-脱氧-2-[F]-氟-D-葡萄糖（F-FDG）进行比较。评估F-FLT单独使用和与5FU联合使用的治疗反应，并与F-FDG和外照射放疗（EBRT）进行比较。通过液相色谱/串联质谱（LC/MS/MS）测量前列腺素E（PGE）生物合成水平，以确定在i.t.注射F-FLT后肿瘤周围健康组织的炎症水平，并与EBRT进行比较。
我们发现，i.t.给予F-FLT不仅在注射的肿瘤中，而且在远处肿瘤中都提供了（1）最高的肿瘤与肌肉摄取比，表明具有同时治疗转移灶的潜力；（2）相对于EBRT，原发性肿瘤的放射治疗效果提高了六倍，同时i.t.给予放射增敏剂5FU可进一步增强效果。虽然EBRT刺激肿瘤周围组织中PGE的产生，但在i.t.给予F-FLT后，该区域未检测到PGE的显著增加。
考虑到F-FLT的生化稳定性和局部F的物理性质，本研究表明，通过肿瘤内注射F-FLT和5FU进行TRT可为实体瘤提供一种新的有效治疗选择。在结直肠癌肿瘤模型中使用这种方法，可以用比i.t.给予F-FDG或传统EBRT低得多的健康组织吸收剂量对肿瘤及其转移灶进行局部有效照射。
