An antiendothelial combination therapy strategy to increase survival in experimental pancreatic cancer

Background: Combination treatments in addition to gemcitabine have failed to improve outcomes in pancreatic cancer. We tested gemcitabine in combination with the antiendothelial agent endothelial monocyte-activating polypeptide II (EMAP II). Methods: Human pancreatic cancer cell line murine xenografts were treated with recombinant EMAP II (80 μg/kg), gemcitabine (100 mg/kg), or a combination, and survival and local tumor outcomes were studied. Results: Both EMAP II and gemcitabine inhibited tumor growth, but the combination of both was always more effective. EMAP II and gemcitabine also inhibited microvessel density, with the combination being more effective. Apoptotic activity was increased by factors of 3.2-, 2.7-, and 4.2-fold in EMAP II, gemcitabine, or their combination, respectively. There was a significant extension of survival after EMAP II and gemcitabine combination therapy compared with controls in 2 different pancreatic cancer cell line models at P = .0001 and P = .006, respectively. The median EMAP II survival contribution over gemcitabine was 16 days, from 35 to 51 days (P = .017). EMAP II had no impact on gemcitabine-induced antiproliferative effects against pancreatic cancer cells in vitro. Conclusion: The antiendothelial agent EMAP II enhanced gemcitabine-mediated tumor inhibition, pointing toward a promising strategy for improved combination treatment of pancreatic cancer.