Dual combination therapy targeting DR5 and EMMPRIN in pancreatic adenocarcinoma.
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.
Department of Radiology, University of Alabama at Birmingham, 1670 University Blvd, Birmingham, AL 35294, USA. Hyunki@uab.edu
Hyunki
H
Kim
Guihua
G
Zhai
Sharon L
SL
Samuel
Christopher J
CJ
Rigell
Heidi R
HR
Umphrey
Samir
S
Rana
Cecil R
CR
Stockard
Naomi S
NS
Fineberg
Kurt R
KR
Zinn
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*; D051926:Basigin / Q000276:immunology* / Q000378:metabolism; D002232:Carbocyanines / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics; D006801:Humans; D008279:Magnetic Resonance Imaging; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008856:Microscopy, Fluorescence / Q000379:methods; D064847:Multimodal Imaging / Q000379:methods; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049268:Positron-Emission Tomography; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology* / Q000378:metabolism; D014057:Tomography, X-Ray Computed; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; C098793:CY5.5 cyanine dye; D002232:Carbocyanines; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C089187:cyanine dye 3; D019788:Fluorodeoxyglucose F18; D051926:Basigin