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

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

doi:10.1016/j.nucmedbio.2009.01.018

« Previous Next »Nuclear Medicine and Biology
Volume 36, Issue 4 , Pages 379-388, May 2009

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

Atsushi B. Tsuji
- Diagnostic Imaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan
Chizuru Sogawa
- Diagnostic Imaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan
Aya Sugyo
- Diagnostic Imaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan
Hitomi Sudo
- Diagnostic Imaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan
- Department of Pathology and Oncology, Juntendo University School of Medicine, Tokyo, 113-8421, Japan
Jun Toyohara
- Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, 206-8670, Japan
Mitsuru Koizumi
- Diagnostic Imaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan
Masaaki Abe
- Department of Pathology and Oncology, Juntendo University School of Medicine, Tokyo, 113-8421, Japan
Okio Hino
- Department of Pathology and Oncology, Juntendo University School of Medicine, Tokyo, 113-8421, Japan
Yoshi-nobu Harada
- Diagnostic Imaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan
Takako Furukawa
- Diagnostic Imaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan
Kazutoshi Suzuki
- Molecular Probe Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan
Tsuneo Saga
- Diagnostic Imaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan
- Corresponding author. Tel.: +81 43 206 3421; fax: +81 43 206 0818.

Received 27 November 2008; received in revised form 27 January 2009; accepted 31 January 2009. published online 31 March 2009.

Abstract

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.

Keywords: Positron emission tomography, Mesothelioma, Tumor mouse model, FDG, FLT, Thiothymidine