EMAP II-based antiangiogenic-antiendothelial in vivo combination therapy of pancreatic cancer.
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) frequently resists conventional cytotoxic therapy. The antitumor effects of endothelial monocyte-activating polypeptide II (EMAP) have been attributed to its antiendothelial and antiangiogenic activities. We tested the hypothesis that a combination of EMAP with bevacizumab (Bev) and gemcitabine (Gem) targets different pathways of PDAC progression and represents more effective treatment.


METHODS
Proliferation of PDAC and endothelial cell lines was evaluated in vitro. In vivo tumor growth and survival PDAC xenograft experiments were performed with EMAP, Bev, and Gem, either alone or in combination. Intratumoral microvessel density and proliferative activity were analyzed by immunostaining with PECAM-1 and proliferating cell nuclear antigen antibodies, and apoptotic activity was measured by the TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) procedure.


RESULTS
Compared with controls, net reduction in tumor growth in EMAP, Bev, Gem, EMAP + Bev, EMAP + Gem, Bev + Gem, and EMAP + Bev + Gem groups was 58, 40, 40, 67, 68, 69, and 96%, respectively. Addition of EMAP to the Bev + Gem group statistically significantly improved survival at a median of >8 days while inducing long-term survival in some animals after maintenance therapy. Combination treatment of EMAP with Bev and Gem reduced proliferation of endothelial but not of PDAC cells. Addition of EMAP to Bev and Gem statistically significantly decreased proliferative activity while maintaining a comparable rate of microvessel density and apoptosis.


CONCLUSIONS
Addition of antiendothelial EMAP to a Bev and Gem regimen improves antitumor effects in a xenograft model of PDAC. This multitargeting strategy to prevent PDAC progression shows therapeutic promise and may overcome limitations by combinations of Gem with anti-vascular endothelial growth factor agents alone.
Schwarz
Roderich E
RE
Department of Surgery, Division of Surgical Oncology, UT Southwestern Medical Center, Dallas, TX, USA. Roderich.Schwarz@utsouthwestern.edu
Awasthi
Niranjan
N
Konduri
Srivani
S
Cafasso
Danielle
D
Schwarz
Margaret A
MA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D000068258:Bevacizumab; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000098:blood supply* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D007124:Immunoenzyme Techniques; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000008:administration & dosage; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000098:blood supply* / Q000473:pathology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000008:administration & dosage; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D016207:Cytokines; D009363:Neoplasm Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D016601:RNA-Binding Proteins; C077219:small inducible cytokine subfamily E, member 1; D003841:Deoxycytidine; D000068258:Bevacizumab; D000093542:Gemcitabine