Abstract |
The goal of the study was to assess the efficacy of combined extracellular matrix metalloprotease inducer ( EMMPRIN)- and death receptor 5 (DR5)-targeted therapy for pancreatic adenocarcinoma in orthotopic mouse models with multimodal imaging. Cytotoxicity of anti- EMMPRIN antibody and anti-DR5 antibody (TRA-8) in MIA PaCa-2 and PANC-1 cell lines was measured by ATPlite assay in vitro. The distributions of Cy5.5-labeled TRA-8 and Cy3-labeled anti- EMMPRIN antibody in the 2 cell lines were analyzed by fluorescence imaging in vitro. Groups 1 to 12 of severe combined immunodeficient mice bearing orthotopic MIA PaCa-2 (groups 1-8) or PANC-1 (groups 9-12) tumors were used for in vivo studies. Dynamic contrast-enhanced-MRI was applied in group 1 (untreated) or group 2 (anti- EMMPRIN antibody). The tumor uptake of Tc-99m-labeled TRA-8 was measured in group 3 (untreated) and group 4 (anti- EMMPRIN antibody). Positron emission tomography/computed tomography imaging with (18)F-FDG was applied in groups 5 to 12. Groups 5 to 8 (or groups 9 to 12) were untreated or treated with anti- EMMPRIN antibody, TRA-8, and combination, respectively. TRA-8 showed high killing efficacy for both MIA PaCa-2 and PANC-1 cells in vitro, but additional anti- EMMPRIN treatment did not improve the cytotoxicity. Cy5.5-TRA-8 formed cellular caps in both the cell lines, whereas the maximum signal intensity was correlated with TRA-8 cytotoxicity. Anti- EMMPRIN therapy significantly enhanced the tumor delivery of the MR contrast agent, but not Tc-99m-TRA-8. Tumor growth was significantly suppressed by the combination therapy, and the additive effect of the combination was shown in both MIA PaCa-2 and PANC-1 tumor models.
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Authors | Hyunki Kim, Guihua Zhai, Sharon L Samuel, Christopher J Rigell, Heidi R Umphrey, Samir Rana, Cecil R Stockard, Naomi S Fineberg, Kurt R Zinn |
Journal | Molecular cancer therapeutics
(Mol Cancer Ther)
Vol. 11
Issue 2
Pg. 405-15
(Feb 2012)
ISSN: 1538-8514 [Electronic] United States |
PMID | 22203731
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antibodies, Monoclonal
- CY5.5 cyanine dye
- Carbocyanines
- Receptors, TNF-Related Apoptosis-Inducing Ligand
- cyanine dye 3
- Fluorodeoxyglucose F18
- Basigin
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Topics |
- Adenocarcinoma
(drug therapy, metabolism, pathology)
- Animals
- Antibodies, Monoclonal
(chemistry, immunology, therapeutic use)
- Basigin
(immunology, metabolism)
- Carbocyanines
(chemistry)
- Cell Line, Tumor
- Cell Survival
(drug effects)
- Dose-Response Relationship, Drug
- Drug Synergism
- Drug Therapy, Combination
- Female
- Fluorodeoxyglucose F18
(pharmacokinetics)
- Humans
- Magnetic Resonance Imaging
- Mice
- Mice, Inbred BALB C
- Mice, SCID
- Microscopy, Fluorescence
(methods)
- Multimodal Imaging
(methods)
- Pancreatic Neoplasms
(drug therapy, metabolism, pathology)
- Positron-Emission Tomography
- Receptors, TNF-Related Apoptosis-Inducing Ligand
(immunology, metabolism)
- Tomography, X-Ray Computed
- Xenograft Model Antitumor Assays
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