Fluorescence endoscopic detection of murine colitis-associated colon cancer by topically applied enzymatically rapid-activatable probe

Gut. 2013 Aug;62(8):1179-86. doi: 10.1136/gutjnl-2011-301795. Epub 2012 Jun 14.

Abstract

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.

Keywords: Colitis-associated colon cancer; activatable probe; cancer; colorectal cancer; colorectal metastases; fluorescence endoscopy; gastrointestinal endoscopy; image analysis; imaging; inflammatory bowel disease; liver imaging; liver metastases; optical molecular imaging.

Publication types

  • Evaluation Study
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adenocarcinoma / diagnosis
  • Adenocarcinoma / enzymology
  • Adenocarcinoma / etiology
  • Administration, Topical
  • Animals
  • Biomarkers, Tumor / metabolism
  • Biopsy
  • Colitis / complications*
  • Colon / enzymology
  • Colonic Neoplasms / diagnosis*
  • Colonic Neoplasms / enzymology
  • Colonic Neoplasms / etiology*
  • Colonoscopy / methods
  • Disease Models, Animal
  • Early Detection of Cancer / methods
  • Fluorescent Dyes / administration & dosage
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Fluorescence / methods
  • Precancerous Conditions / diagnosis
  • Precancerous Conditions / enzymology
  • Precancerous Conditions / etiology
  • Tumor Cells, Cultured
  • gamma-Glutamyltransferase / metabolism

Substances

  • Biomarkers, Tumor
  • Fluorescent Dyes
  • gamma-Glutamyltransferase