title: Differential therapeutic effects of anti-VEGF-A antibody in different tumor models: implications for choosing appropriate tumor models for drug testing.
abstract: We previously reported that the host response to certain chemotherapies can induce primary tumor regrowth, angiogenesis, and even metastases in mice, but the possible impact of anti-VEGF-A therapy in this context has not been fully explored. We, therefore, used combinations of anti-VEGF-A with chemotherapy on various tumor models in mice, including primary tumors, experimental lung metastases, and spontaneous lung metastases of 4T1-breast and CT26-colon murine cancer cell lines. Our results show that a combined treatment with anti-VEGF-A and folinic acid/5-fluorouracil/oxaliplatin (FOLFOX) but not with anti-VEGF-A and gemcitabine/cisplatinum (Gem/CDDP) enhances the treatment outcome partly due to reduced angiogenesis, in both primary tumors and experimental lung metastases models. However, neither treatment group exhibited an improved treatment outcome in the spontaneous lung metastases model, nor were changes in endothelial cell numbers found at metastatic sites. As chemotherapy has recently been shown to induce tumor cell invasion, we tested the invasion properties of tumor cells when exposed to plasma from FOLFOX-treated mice or patients with cancer. While plasma from FOLFOX-treated mice or patients induced invasion properties of tumor cells, the combination of anti-VEGF-A and FOLFOX abrogated these effects, despite the reduced plasma VEGF-A levels detected in FOLFOX-treated mice. These results suggest that the therapeutic impact of antiangiogenic drugs varies in different tumor models, and that anti-VEGF-A therapy can block the invasion properties of tumor cells in response to chemotherapy. These results may implicate an additional therapeutic role for anti-VEGF-A when combined with chemotherapy.
authors.affiliation: Corresponding Author: Yuval Shaked, Department of Molecular Pharmacology, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, 1 Efron St. Bat Galim, Haifa, Israel 31096. yshaked@tx.technion.ac.il.
authors.forename: Dror
authors.initials: D
authors.lastname: Alishekevitz
authors.forename: Rotem
authors.initials: R
authors.lastname: Bril
authors.forename: David
authors.initials: D
authors.lastname: Loven
authors.forename: Valeria
authors.initials: V
authors.lastname: Miller
authors.forename: Tali
authors.initials: T
authors.lastname: Voloshin
authors.forename: Svetlana
authors.initials: S
authors.lastname: Gingis-Velistki
authors.forename: Ella
authors.initials: E
authors.lastname: Fremder
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Scherer
authors.forename: Yuval
authors.initials: Y
authors.lastname: Shaked
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000008:administration & dosage; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols; D003131:Combined Modality Therapy; D005472:Fluorouracil; D006801:Humans; D007167:Immunotherapy; D002955:Leucovorin; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D009944:Organoplatinum Compounds; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage* / Q000276:immunology
chemical_list: D020533:Angiogenesis Inhibitors; D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D009944:Organoplatinum Compounds; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D002955:Leucovorin; D005472:Fluorouracil