Rapid Cancer Fluorescence Imaging Using A γ-Glutamyltranspeptidase-Specific Probe For Primary Lung Cancer.
BACKGROUND
We set out to examine the activity of γ-glutamyltranspeptidase (GGT) in lung cancer and the validity of γ-glutamyl hydroxymethyl rhodamine green (gGlu-HMRG) for intraoperative imaging of primary lung cancer.


METHODS
GGT activities and mRNA expression levels of GGT1 (one of the GGT subtypes) in five human lung cancer cell lines were examined by fluorescence imaging and quantitative reverse transcription polymerase chain reaction. In vivo imaging of an orthotopic A549 xenograft model in nude mice was performed to confirm its applicability to intraoperative imaging. Furthermore, ex vivo imaging of 73 specimens from lung cancer patients were performed and analyzed to calculate the sensitivity/specificity of gGlu-HMRG for lung cancer diagnosis.


RESULTS
GGT activities and mRNA expression levels of GGT1 are diverse depending on cell type; A549, H441, and H460 showed relatively high GGT activities and expression levels, whereas H82 and H226 showed lower values. In the in vivo mouse model study, tiny pleural dissemination and hilar/mediastinal lymph node metastasis (less than 1 mm in diameter) were clearly detected 15 minutes after topical application of gGlu-HMRG. In the ex vivo study of specimens from patients, the sensitivity and specificity of gGlu-HMRG were calculated to be 43.8% (32/73) and 84.9% (62/73), respectively. When limited to female patients, never smokers, and adenocarcinomas, these values were 78.9% (15/19) and 73.7% (14/19), respectively.


CONCLUSIONS
Although GGT activity of lung cancer cells vary, gGlu-HMRG can serve as an intraoperative imaging tool to detect small foci of lung cancer when such cells have sufficient GGT activity.
Department of Thoracic Surgery, The University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. Electronic address: haruakihino@gmail.com.
Haruaki
H
Hino
Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan; PRESTO, Japan Science and Technology Agency, K's Gobancho 6F 7, Gobancho, Chiyoda-ku, Tokyo, 102-0076, Japan. Electronic address: mkamiya@m.u-tokyo.ac.jp.
Mako
M
Kamiya
Department of Thoracic Surgery, The University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. Electronic address: ken-tky@umin.net.
Kentaro
K
Kitano
Department of Materials Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan. Electronic address: mizuno@bmw.t.u-tokyo.ac.jp.
Kazue
K
Mizuno
Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. Electronic address: sayakatanaka-tky@umin.net.
Sayaka
S
Tanaka
Tokyo Institute of Technology, Chemical Resources Laboratory, 4259 Nagatsuta Midori-ku Yokohama-shi, Kanagawa, 226-8503, Japan. Electronic address: Nishiyama@res.titech.ac.jp.
Nobuhiro
N
Nishiyama
Department of Materials Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan. Electronic address: kataoka@bmw.t.u-tokyo.ac.jp.
Kazunori
K
Kataoka
Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan; Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan; CREST, Japan Agency for Medical Research and Development, 1-7-1 Otemachi, Chiyoda-ku, Tokyo, 100-0004, Japan. Electronic address: uranokun@m.u-tokyo.ac.jp.
Yasuteru
Y
Urano
Department of Thoracic Surgery, The University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. Electronic address: nakajima-tho@h.u-tokyo.ac.jp.
Jun
J
Nakajima