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PMID: 24176949 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

Combined blockade of HER2 and VEGF exerts greater growth inhibition of HER2-overexpressing gastric cancer xenografts than individual blockade.

Experimental & molecular medicine ·Vol. 45 ·2013-11-01 ·Pages e52

Singh R, Kim WJ, Kim PH, Hong HJ

Abstract

Gastric cancer overexpressing the human epidermal growth factor 2 (HER2) protein has a poor outcome, although a combination of chemotherapy and the anti-HER2 antibody trastuzumab has been approved for the treatment of advanced gastric cancer. Vascular endothelial growth factor (VEGF) expression in gastric cancer is correlated with recurrence and poor prognosis; however, the anti-VEGF antibody bevacizumab has shown limited efficacy against gastric cancer in clinical trials. In this study, we evaluated the antitumor effects of trastuzumab; VEGF-Trap binding to VEGF-A, VEGF-B and placental growth factor (PlGF); and a combination of trastuzumab and VEGF-Trap in a gastric cancer xenograft model. Although trastuzumab and VEGF-Trap each moderately inhibited tumor growth, the combination of these agents exerted greater inhibition compared with either agent alone. Immunohistochemical analyses indicated that the reduction in tumor growth was associated with decreased proliferation and increased apoptosis of tumor cells and decreased tumor vascular density. The combined treatment resulted in fewer proliferating tumor cells, more apoptotic cells and reduced tumor vascular density compared with treatment with trastuzumab or VEGF-Trap alone, indicating that trastuzumab and VEGF-Trap had additive inhibitory effects on the tumor growth and angiogenesis of the gastric cancer xenografts. These data suggest that trastuzumab in combination with VEGF-Trap may represent an effective approach to treating HER2-overexpressing gastric cancer.

MeSH Terms
Animals Antibodies, Monoclonal, Humanized/administration & dosage,therapeutic use Antineoplastic Combined Chemotherapy Protocols/therapeutic use Apoptosis Cell Line, Tumor Cell Proliferation Humans Mice Mice, Inbred BALB C Neovascularization, Pathologic/drug therapy Receptor, ErbB-2/antagonists & inhibitors Receptors, Vascular Endothelial Growth Factor/administration & dosage,therapeutic use Recombinant Fusion Proteins/administration & dosage,therapeutic use Stomach Neoplasms/drug therapy,pathology Trastuzumab Vascular Endothelial Growth Factor A/antagonists & inhibitors Xenograft Model Antitumor Assays
Chemicals
Antibodies, Monoclonal, Humanized Recombinant Fusion Proteins Vascular Endothelial Growth Factor A aflibercept ERBB2 protein, human Receptor, ErbB-2 Receptors, Vascular Endothelial Growth Factor Trastuzumab
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Singh Rohit
1] Department of Molecular Bioscience, College of Biomedical Science, Kangwon National University, Chuncheon, Korea [2] Institute of Antibody Research, Kangwon National University, Chuncheon, Korea.
Kim Woo Jin
Kim Pyeung-Hyeun
Hong Hyo Jeong
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Article Info
Journal
Experimental & molecular medicine
Abbr.
Exp Mol Med
ISSN
2092-6413
DOI
10.1038/emm.2013.111
Published
2013-11-01
Epub
2013-00-01
Pages
e52
Language
English
Region
United States
NLM ID
9607880
PMCID
PMC3849567
Subset
IM
External Links
PubMed source DOI: 10.1038/emm.2013.111 PMC Full Text View journal details
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