title: Interferon-alpha in combination with chemotherapy has potent antiangiogenic properties in an orthotopic mouse model for pancreatic adenocarcinoma.
abstract: There are clinical data showing encouraging results for combining chemoradiotherapy with interferon (IFN)-alpha (CapRI scheme) for the treatment of pancreatic carcinoma. Here, it was tried to evaluate the antiangiogenic effect of IFN-alpha in combination with chemotherapy. Mice were inoculated with syngeneic pancreatic carcinoma cells in the pancreas. After 5 days, the animals were treated with 5-fluorouracil (5-FU)+/-IFN-alpha. Tumor growth, vascular endothelial growth factor (VEGF) serum levels and VEGF-R expression, real-time reverse transcription-polymerase chain reaction of mRNA coding for RGS-5, an angiogenic pericyte marker at sites of physiologic and pathologic angiogenesis and impact of IFN-alpha treatment on vessel density by CD31 stain and intravital microscopy were analyzed. The addition of IFN-alpha to 5-FU-treatment decreased tumor volume, reduced serum level of VEGF, and down-regulated the expression of VEGF-receptor significantly. Furthermore, the combination therapy revealed a decrease in vessel density and a down-regulation of RGS-5, which is a protein involved in angiogenic tumor vasculature. IFN-alpha significantly improves the outcome of 5-FU-therapy in treating pancreatic carcinoma. This is at least partly mediated by IFN-alpha antiangiogenic properties, which acts along with 5-FU on the VEGF system, vessel density, and RGS-5 expression in pericytes.
authors.affiliation: Department of Surgery, National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Igor
authors.initials: I
authors.lastname: Tibensky
authors.forename: Jan
authors.initials: J
authors.lastname: Schmidt
authors.forename: Thilo
authors.initials: T
authors.lastname: Hackert
authors.forename: Eduard
authors.initials: E
authors.lastname: Ryschich
authors.forename: Dirk
authors.initials: D
authors.lastname: Jäger
authors.forename: Markus W
authors.initials: MW
authors.lastname: Büchler
authors.forename: Angela
authors.initials: A
authors.lastname: Märten
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005472:Fluorouracil / Q000008:administration & dosage; D015870:Gene Expression / Q000187:drug effects; D007150:Immunohistochemistry; D016898:Interferon-alpha / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020710:RGS Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D020533:Angiogenesis Inhibitors; D016898:Interferon-alpha; D020710:RGS Proteins; D012333:RNA, Messenger; C105346:Rgs5 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D040262:Receptors, Vascular Endothelial Growth Factor; D005472:Fluorouracil