Exp Mol Med.  2013 Nov;45(11):e52.

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

• 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.

Keyword

combination treatment; gastric cancer; HER2; trastuzumab; VEGF-Trap

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
Vascular Endothelial Growth Factor A/antagonists & inhibitors
Xenograft Model Antitumor Assays
Antibodies, Monoclonal, Humanized
Recombinant Fusion Proteins
Vascular Endothelial Growth Factor A
Receptor, erbB-2
Receptors, Vascular Endothelial Growth Factor