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Dual combination therapy targeting DR5 and EMMPRIN in pancreatic adenocarcinoma.

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.
AuthorsHyunki Kim, Guihua Zhai, Sharon L Samuel, Christopher J Rigell, Heidi R Umphrey, Samir Rana, Cecil R Stockard, Naomi S Fineberg, Kurt R Zinn
JournalMolecular cancer therapeutics (Mol Cancer Ther) Vol. 11 Issue 2 Pg. 405-15 (Feb 2012) ISSN: 1538-8514 [Electronic] United States
PMID22203731 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Antibodies, Monoclonal
  • CY5.5 cyanine dye
  • Carbocyanines
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • cyanine dye 3
  • Fluorodeoxyglucose F18
  • Basigin
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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