Comparison of conventional and novel PET tracers for imaging mesothelioma in nude mice with subcutaneous and intrapleural xenografts

Introduction: 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. Methods: Epithelioid and sarcomatoid mesothelioma cells were inoculated subcutaneously and intrapleurally into nude mice. Biodistribution and PET imaging studies were conducted by injecting [18F]fluoro-2-deoxy-D-glucose (FDG), 3'-[18F]fluoro-3'-doxythymidine (FLT) or 4'-methyl-[11C]thiothymidine (S-dThd) into the mouse models. In vitro cellular uptake of [14C]FDG and [3H]FLT and thymidine kinase 1 (TK1) 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. Results: In epithelioid mesothelioma models, biodistribution experiments showed that tumor uptake of [11C]S-dThd was significantly higher than that of [18F]FDG. On the other hand, in sarcomatoid models, [18F]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 [14C]FDG and [3H]FLT and TK1 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. Conclusions: 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: [18F]FLT and [11C]S-dThd seemed suitable for the epithelioid subtype and [18F]FDG seemed suitable for the sarcomatoid subtype in our mouse models. Our results indicated that cellular uptake and TK1 activity in vitro are not always consistent with tracer uptake of [18F]FLT and [11C]S-dThd in vivo. These mouse models and PET imaging might be useful tools for evaluating new and effective treatments in mesothelioma.