Tsuji Atsushi B, Sogawa Chizuru, Sugyo Aya, Sudo Hitomi, Toyohara Jun, Koizumi Mitsuru, Abe Masaaki, Hino Okio, Harada Yoshi-nobu, Furukawa Takako, Suzuki Kazutoshi, Saga Tsuneo
Diagnostic Imaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
Nucl Med Biol. 2009 May;36(4):379-88. doi: 10.1016/j.nucmedbio.2009.01.018. Epub 2009 Mar 26.
Malignant mesothelioma is a highly aggressive tumor originating in the pleura, peritoneum and pericardium, and the prognosis of patients undergoing current treatment remains poor. To develop new therapies, it is important to have a noninvasive imaging system for evaluating the efficacy of such prospective treatments. We have established clinically relevant mouse models and evaluated conventional and novel positron emission tomography (PET) tracers.
Epithelioid and sarcomatoid mesothelioma cells were inoculated subcutaneously and intrapleurally into nude mice. Biodistribution and PET imaging studies were conducted by injecting [(18)F]fluoro-2-deoxy-D-glucose (FDG), 3'-[(18)F]fluoro-3'-doxythymidine (FLT) or 4'-methyl-[(11)C]thiothymidine (S-dThd) into the mouse models. In vitro cellular uptake of [(14)C]FDG and [(3)H]FLT and thymidine kinase 1 (TK(1)) activity in both cell lines were measured. Expression of glucose transporter 1 (GLUT-1) and Ki-67 in xenografted tumors was evaluated by immunohistochemical staining.
In epithelioid mesothelioma models, biodistribution experiments showed that tumor uptake of [(11)C]S-dThd was significantly higher than that of [(18)F]FDG. On the other hand, in sarcomatoid models, [(18)F]FDG showed significantly higher accumulation than the other two tracers. These differential uptakes of the three tracers were confirmed by PET imaging. The cellular uptake of [(14)C]FDG and [(3)H]FLT and TK(1) activity in sarcomatoid cells were higher than those of epithelioid cells. GLUT-1 protein was strongly expressed in sarcomatoid but not in epithelioid tumor. We observed a high percentage of Ki-67-positive cells in both epithelioid and sarcomatoid tumors.
We established nude mouse models of epithelioid and sarcomatoid subtypes of mesothelioma. PET tracers applicable for the evaluation of epithelioid and sarcomatoid mesothelioma would vary: [(18)F]FLT and [(11)C]S-dThd seemed suitable for the epithelioid subtype and [(18)F]FDG seemed suitable for the sarcomatoid subtype in our mouse models. Our results indicated that cellular uptake and TK(1) activity in vitro are not always consistent with tracer uptake of [(18)F]FLT and [(11)C]S-dThd in vivo. These mouse models and PET imaging might be useful tools for evaluating new and effective treatments in mesothelioma.
恶性间皮瘤是一种起源于胸膜、腹膜和心包的高度侵袭性肿瘤，目前接受治疗的患者预后仍然很差。为了开发新的治疗方法，拥有一种用于评估此类前瞻性治疗效果的非侵入性成像系统非常重要。我们建立了与临床相关的小鼠模型，并评估了传统和新型正电子发射断层扫描（PET）示踪剂。
将上皮样和肉瘤样间皮瘤细胞皮下和胸膜内接种到裸鼠体内。通过向小鼠模型注射[（18）F]氟-2-脱氧-D-葡萄糖（FDG）、3'-[（18）F]氟-3'-脱氧胸苷（FLT）或4'-甲基-[（11）C]硫代胸苷（S-dThd）进行生物分布和PET成像研究。测量了两种细胞系中[（14）C]FDG和[（3）H]FLT的体外细胞摄取以及胸苷激酶1（TK（1））活性。通过免疫组织化学染色评估异种移植肿瘤中葡萄糖转运蛋白1（GLUT-1）和Ki-67的表达。
在上皮样间皮瘤模型中，生物分布实验表明，[（11）C]S-dThd的肿瘤摄取显著高于[（18）F]FDG。另一方面，在肉瘤样模型中，[（18）F]FDG的积聚显著高于其他两种示踪剂。PET成像证实了这三种示踪剂的不同摄取情况。肉瘤样细胞中[（14）C]FDG和[（3）H]FLT的细胞摄取以及TK（1）活性高于上皮样细胞。GLUT-1蛋白在肉瘤样肿瘤中强烈表达，但在上皮样肿瘤中不表达。我们在两种上皮样和肉瘤样肿瘤中均观察到高比例的Ki-67阳性细胞。
我们建立了间皮瘤上皮样和肉瘤样亚型的裸鼠模型。适用于评估上皮样和肉瘤样间皮瘤的PET示踪剂会有所不同：在我们的小鼠模型中，[（F）18]FLT和[（11）C]S-dThd似乎适用于上皮样亚型，而[（18）F]FDG似乎适用于肉瘤样亚型。我们的结果表明，体外细胞摄取和TK（1）活性并不总是与体内[（18）F]FLT和[（11）C]S-dThd的示踪剂摄取一致。这些小鼠模型和PET成像可能是评估间皮瘤新的有效治疗方法的有用工具。
