title: Antiangiogenic versus cytotoxic therapeutic approaches to human pancreas cancer: an experimental study with a vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor and gemcitabine.
abstract: Pancreatic adenocarcinoma is a leading cause of cancer death in the United States and represents a challenging chemotherapeutic problem. The pharmacological control of angiogenesis might represent a novel approach to the management of pancreas cancer, since the pathological development of vascular supply is a critical step for tumor growth and may affect its prognosis. In order to test this hypothesis, SU5416 ([3-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-1,3-dihydro-indol-2-one]) a selective inhibitor of the vascular endothelial growth factor receptor-2 tyrosine kinase, and gemcitabine (2', 2'-difluorodeoxycytidine) were tested on endothelial (HUVEC) and pancreatic tumor cells (MIA PaCa-2) in vitro and in vivo alone and in simultaneous association. SU5416 inhibited HUVEC cells stimulated to proliferate by vascular endothelial growth factor but not MIA PaCa-2 cells; the drug concentration that decreased cell growth by 50% (IC50) was 0.14 microM. Furthermore, SU5416 reduced the development of microvessels from placental explants (IC50, 0.23 microM). Gemcitabine inhibited the growth of both HUVEC and MIA PaCa-2 cells with an IC50 of 0.08 and 0.1 microM, respectively. A synergistic effect (combination index <1 and dose reduction index >1) on anti-proliferative and pro-apoptotic activity was calculated with the simultaneous combination of the two drugs on endothelial cells. A marked in vivo antitumor effect on MIA PaCa-2 xenografts was observed with SU5416 at a protracted schedules, as well as with gemcitabine; furthermore, the combination between the two drugs resulted in an almost complete suppression of tumor growth and relapse. In conclusion, the present results provide the evidence of an effective anti-endothelial/antitumor activity of protracted administration of SU5416 on human pancreas cancer xenografts, which is comparable with the one obtained by gemcitabine; moreover, the synergistic combination between these drugs on endothelial cells and the promising association in pancreatic cancer xenografts could be used in future studies and translated into the clinical setting.
authors.affiliation: Division of Pharmacology and Chemotherapy, Department of Oncology, Transplants and Advanced Technologies in Medicine, University of Pisa, Via Roma, 55, I-56126 Pisa, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Bocci
authors.forename: Romano
authors.initials: R
authors.lastname: Danesi
authors.forename: Gabriele
authors.initials: G
authors.lastname: Marangoni
authors.forename: Anna
authors.initials: A
authors.lastname: Fioravanti
authors.forename: Ugo
authors.initials: U
authors.lastname: Boggi
authors.forename: Irene
authors.initials: I
authors.lastname: Esposito
authors.forename: Alessandro
authors.initials: A
authors.lastname: Fasciani
authors.forename: Elena
authors.initials: E
authors.lastname: Boschi
authors.forename: Daniela
authors.initials: D
authors.lastname: Campani
authors.forename: Generoso
authors.initials: G
authors.lastname: Bevilacqua
authors.forename: Franco
authors.initials: F
authors.lastname: Mosca
authors.forename: Mario
authors.initials: M
authors.lastname: Del Tacca
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010920:Placenta / Q000098:blood supply / Q000187:drug effects; D011247:Pregnancy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors; D046509:Tissue Culture Techniques; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D020533:Angiogenesis Inhibitors; D000964:Antimetabolites, Antineoplastic; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D003841:Deoxycytidine; C116890:Semaxinib; D040301:Vascular Endothelial Growth Factor Receptor-2; D000093542:Gemcitabine