Fluorescence endoscopic detection of murine colitis-associated colon cancer by topically applied enzymatically rapid-activatable probe
- Makoto Mitsunaga1,
- Nobuyuki Kosaka1,
- Peter L Choyke1,
- Matthew R Young2,
- Christopher R Dextras2,
- Shakir M Saud2,3,
- Nancy H Colburn2,
- Masayo Sakabe4,
- Tetsuo Nagano4,
- Daisuke Asanuma5,
- Yasuteru Urano5,
- Hisataka Kobayashi1
- 1Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
- 2National Cancer Institute, Laboratory of Cancer Prevention, Frederick National Laboratory, Center for Cancer Research, National Cancer Institute-, Frederick, Maryland, USA
- 3National Cancer Institute, National Institute of Health, Nutritional Science Research Group, Division of Cancer Prevention, National Cancer Institute, Rockville, Maryland, USA
- 4Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
- 5Medicine, The University of Tokyo, Tokyo, Japan
- Correspondence to Dr Hisataka Kobayashi, Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room B3B69, MSC1088, Bethesda, MD 20892-1088, USA;
Contributors MM, NK and MRY conducted experiments, performed analyses and wrote the manuscript, CRD, SMS, NHC, MS, DA and YU conducted experiments and performed analysis. PLC and TN wrote the manuscript and supervised the project. HK planned and initiated the project, designed and conducted experiments, wrote the manuscript, and supervised the entire project.
- Revised 2 May 2012
- Accepted 4 May 2012
- Published Online First 14 June 2012
Objectives Screening colonoscopy to monitor for early colitis-associated colon cancer (CAC) is difficult due to the aberrant mucosal patterns associated with long-standing colitis. The aim of this study was to develop a rapid fluorescent detection method for use during colonoscopy for improving the detection of CAC utilising a topically applied enzymatically activatable probe (gGlu-HMRG) which fluoresces in the presence of γ-glutamyltranspeptidase (GGT), an enzyme associated with cancer.
Methods Expression of GGT in colon cell lines was examined with fluorescence microscopy and flow cytometry. A mouse model (azoxymethane/dextran sulphate sodium) of CAC was used and mice were examined with white light and fluorescence colonoscopy before and after topical gGlu-HMRG administration.
Results Expression of GGT, although variable, was higher in human colon cancer cells than normal human colon cells. Using fluorescence colonoscopy in mice, gGlu-HMRG fluorescent lesions were detected 5 min after topical administration and fluorescence persisted for at least 30 min. Fluorescence guided biopsy revealed all fluorescent lesions that contained cancer or dysplasia (n=16), whereas three out of 12 non-fluorescent lesions contained low grade dysplasia and others did not contain neoplastic histology. Microscopic inflammatory infiltration also had variable fluorescence but in general was much lower (∼10-fold) in signal than cancer. Repeat fluorescence endoscopy allowed individual tumours to be monitored.
Conclusion These results suggest that gGlu-HMRG can improve endoscopic detection of CAC with a higher target to background ratio than conventional white light colonoscopy. This could be of benefit to patients with long-standing colitis who must undergo repeated screening colonoscopies.
- Colitis-associated colon cancer
- fluorescence endoscopy
- optical molecular imaging
- activatable probe
- inflammatory bowel disease
- colorectal cancer
- liver metastases
- liver imaging
- colorectal metastases
- image analysis
- gastrointestinal endoscopy
Funding This research was supported by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.