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In vivo fluorescence imaging of gastrointestinal stromal tumors using fluorophore-conjugated anti-KIT antibody.

ABSTRACT: Gastrointestinal stromal tumors (GISTs) are frequently characterized by KIT overexpression. Tumor-free margins and complete cytoreduction of disease are mainstays of treatment. We hypothesized that fluorescently labeled anti-KIT antibodies can label GIST in vivo.KIT K641E(+/-) transgenic mice that spontaneously develop cecal GISTs were used in this study, with C57BL/6 mice serving as controls. Alexa 488 fluorophore-conjugated anti-KIT antibodies were delivered via the tail vein 24 h prior to fluorescence imaging. Following fluorescence laparoscopy, mice were sacrificed. The gastrointestinal tracts were grossly examined for tumors followed by fluorescence imaging. Tumors were harvested for histologic confirmation.KIT K641E(+/-) mice and C57BL/6 control mice received anti-KIT antibody or isotope control antibody. Fluorescence laparoscopy had a high tumor signal-to-background noise ratio. Upon blinded review of intravital fluorescence and bright light images, there were 2 false-positive and 0 false-negative results. The accuracy was 92 %. The sensitivity, specificity, positive and negative predictive values were 100, 87, 85, and 100 %, respectively, for the combined modalities.In this study, we present a method for in vivo fluorescence labeling of GIST in a murine model. Several translatable applications include: laparoscopic staging; visualization of peritoneal metastases; assessment of margin status; endoscopic differentiation of GISTs from other benign submucosal tumors; and longitudinal surveillance of disease response. This novel approach has clear clinical applications that warrant further research and development.

SUBMITTER: Metildi CA

PROVIDER: S-EPMC4127988 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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In vivo fluorescence imaging of gastrointestinal stromal tumors using fluorophore-conjugated anti-KIT antibody.

Metildi Cristina A CA Tang Chih-Min CM Kaushal Sharmeela S Leonard Stephanie Y SY Magistri Paolo P Tran Cao Hop S HS Hoffman Robert M RM Bouvet Michael M Sicklick Jason K JK

Annals of surgical oncology 20130814

<h4>Background</h4>Gastrointestinal stromal tumors (GISTs) are frequently characterized by KIT overexpression. Tumor-free margins and complete cytoreduction of disease are mainstays of treatment. We hypothesized that fluorescently labeled anti-KIT antibodies can label GIST in vivo.<h4>Methods</h4>KIT K641E(+/-) transgenic mice that spontaneously develop cecal GISTs were used in this study, with C57BL/6 mice serving as controls. Alexa 488 fluorophore-conjugated anti-KIT antibodies were delivered ...[more]

PMID: 23943029

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Project description:It is difficult to distinguish gastrointestinal stromal tumors (GISTs) from other types of submucosal tumors under conventional gastrointestinal endoscopy. We aimed to detect GISTs by molecular fluorescence imaging using a near-infrared (NIR) photosensitizer (IR700)-conjugated anti-c-KIT antibody and to treat GISTs by photoimmunotherapy with NIR irradiation as a non-invasive theranostic procedure. We also investigated the therapeutic mechanisms. Methods: Human GIST cell lines GIST-T1 and GIST-882M were incubated with IR700-conjugated anti-c-KIT antibody, IR700-12A8, and observed by confocal laser microscopy. Mice with GIST-T1 xenografts or rats with orthotopic xenografts were injected with IR700-12A8 or AF488-conjugated antibody, and observed under IVIS or autofluorescence imaging (AFI) endoscopy. GIST cells were treated with IR700-12A8 and NIR light in vitro and vivo, and cell viability, histology and apoptosis were evaluated. Results: Strong red fluorescence of IR700-12A8 was observed on the cell membrane of GIST cells and was gradually internalized into the cytoplasm. Tumor-specific accumulation of IR700-12A8 was observed in GIST-T1 xenografts in mice. Under AFI endoscopy, a strong fluorescence signal was observed in orthotopic GIST xenografts in rats through the normal mucosa covering the tumor. The percentage of dead cells significantly increased in a light-dose-dependent manner and both acute necrotic and late apoptotic cell death was observed with annexin/PI staining. Cleaved PARP expression was significantly increased after IR700-12A8-mediated NIR irradiation, which was almost completely reversed by NaN3. All xenograft tumors (7/7) immediately regressed and 4/7 tumors completely disappeared after IR700-12A8-mediated NIR irradiation. Histologic assessment and TUNEL staining revealed apoptosis in the tumors. Conclusion: NIR fluorescence imaging using IR700-12A8 and subsequent NIR irradiation could be a very effective theranostic technology for GIST, the underlying mechanism of which appears to involve acute necrosis and supposedly late apoptosis induced by singlet oxygen.

Dataset Information

In vivo fluorescence imaging of gastrointestinal stromal tumors using fluorophore-conjugated anti-KIT antibody.

Publications

In vivo fluorescence imaging of gastrointestinal stromal tumors using fluorophore-conjugated anti-KIT antibody.

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