title: Combination therapy of VEGF-trap and gemcitabine results in improved anti-tumor efficacy in a mouse lung cancer model.
abstract: BACKGROUND
  Angiogenesis is essential for the growth and metastasis of cancer. Although anti-angiogenic agents, particularly vascular endothelial growth factor (VEGF) inhibitors, have exhibited single-agent activity, there is considerable interest in combining these novel drugs with conventional chemotherapy reagents to achieve an optimal clinical efficacy. The objective of this study was to evaluate the benefits of the combination therapy of vascular endothelial growth factor trap (VEGF-Trap) with gemcitabine in a lung tumor model.
  
  
  METHODS
  A luciferase-expressing Lewis lung carcinoma (LLC) model was established in C57BL/6J mice and tumor-bearing mice were randomized into control, VEGF-Trap, gemcitabine and VEGF-Trap/gemcitabine combination groups. Tumor growth and animal survival were monitored. Tumor microvessel density and cell proliferation were evaluated by CD31 and Ki-67 immunohistochemical analysis. TUNEL assay was performed to detect apoptotic cells. The protein levels of Cyclin D1, Pro-Caspase-3, Bcl-2, MMP2 and MMP9 in tumor extracts were examined by western blot.
  
  
  RESULTS
  VEGF-Trap in combination with gemcitabine showed significantly enhanced inhibition of tumor growth and prolonged mouse survival compared to the VEGF-Trap or gemcitabine monotherapy. The VEGF-Trap/gemcitabine combination therapy not only potently inhibited tumor angiogenesis and cell proliferation, but also increased cellular apoptosis within tumor tissues. In addition, the combination treatment markedly down-regulated the expression of proliferation, anti-apoptosis and invasion related proteins.
  
  
  CONCLUSIONS
  Combination therapy using VEGF-Trap and gemcitabine resulted in improved anti-tumor efficacy in a lung cancer model and VEGF-Trap/gemcitabine combination might represent a promising strategy in the treatment of human lung cancer.
authors.affiliation: Department of Histology and Embryology, Tongji University School of Medicine, Shanghai, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhou
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Yaoqin
authors.initials: Y
authors.lastname: Yang
authors.forename: Huihong
authors.initials: H
authors.lastname: Tao
authors.forename: Dong
authors.initials: D
authors.lastname: Li
authors.forename: Junli
authors.initials: J
authors.lastname: Zhang
authors.forename: Gening
authors.initials: G
authors.lastname: Jiang
authors.forename: Jianmin
authors.initials: J
authors.lastname: Fang
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D017930:Genes, Reporter; D008175:Lung Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D040262:Receptors, Vascular Endothelial Growth Factor / Q000008:administration & dosage / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D000093542:Gemcitabine
chemical_list: D020533:Angiogenesis Inhibitors; D000964:Antimetabolites, Antineoplastic; D011993:Recombinant Fusion Proteins; D003841:Deoxycytidine; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor; D000093542:Gemcitabine