Addition of bevacizumab enhances antitumor activity of erlotinib against non-small cell lung cancer xenografts depending on VEGF expression

Purpose Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), and bevacizumab, an anti-vascular endothelial growth factor (VEGF) agent, are promising therapies for advanced non-small cell lung cancer (NSCLC). Our study was aimed to determine whether there were condit...

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Bibliographic Details
Published in:Cancer chemotherapy and pharmacology 2014-12, Vol.74 (6), p.1297-1305
Main Authors: Li, Heyan, Takayama, Koichi, Wang, Shuo, Shiraishi, Yoshimasa, Gotanda, Keisuke, Harada, Taishi, Furuyama, Kazuto, Iwama, Eiji, Ieiri, Ichiro, Okamoto, Isamu, Nakanishi, Yoichi
Format: Article
Language:English
Subjects:
Animals
Antibodies, Monoclonal, Humanized - administration & dosage
Antineoplastic agents
Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics
Antineoplastic Combined Chemotherapy Protocols - pharmacology
Bevacizumab
Biological and medical sciences
Cancer Research
Carcinoma, Non-Small-Cell Lung - drug therapy
Carcinoma, Non-Small-Cell Lung - pathology
Cell Line, Tumor
Chromatography, High Pressure Liquid
Drug Resistance, Neoplasm
Enzyme-Linked Immunosorbent Assay
ErbB Receptors - antagonists & inhibitors
Erlotinib Hydrochloride
Female
Humans
Lung Neoplasms - drug therapy
Lung Neoplasms - pathology
Medical sciences
Medicine
Medicine & Public Health
Mice
Mice, Inbred BALB C
Mice, Nude
Multiple tumors. Solid tumors. Tumors in childhood (general aspects)
Oncology
Original
Original Article
Pharmacology. Drug treatments
Pharmacology/Toxicology
Pneumology
Quinazolines - administration & dosage
Tumors
Tumors of the respiratory system and mediastinum
Vascular Endothelial Growth Factor A - antagonists & inhibitors
Vascular Endothelial Growth Factor A - metabolism
Xenograft Model Antitumor Assays
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Summary:Purpose Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), and bevacizumab, an anti-vascular endothelial growth factor (VEGF) agent, are promising therapies for advanced non-small cell lung cancer (NSCLC). Our study was aimed to determine whether there were conditions under which the addition of bevacizumab would enhance the antitumor activity of erlotinib against NSCLC tumors in vitro and in vivo. Methods MTS was for NSCLC cell (PC9, 11–18, H1975, H157, H460 and A549) growth assay in vitro. ELISA was for VEGF protein assay in cells and tumor tissues. Mouse xenograft models were established with H157, H460 and A549 with primary resistance to erlotinib and treated with erlotinib plus bevacizumab or each agent alone. Erlotinib concentrations in tumors were determined by high-performance liquid chromatography. Results Bevacizumab alone did not inhibit NSCLC cell growth in vitro. In primarily erlotinib-resistant NSCLC cells, the levels of VEGF protein were highest in H157 cell followed in order by H460 and A549 cells. In vivo, bevacizumab alone significantly inhibited tumor growth only in xenograft models with high (H157) and/or moderate (H460) levels of VEGF protein. A combination of erlotinib and bevacizumab partially reversed resistance to erlotinib in H157 xenografts (high VEGF level) with increasing intratumoral erlotinib concentrations, but not in H460 (moderate) or A549 (low) xenografts. Conclusions These results support that combined with anti-VEGF therapy could enhance antitumor activity of anti-EGFR therapy and/or partially reverse resistance to EGFR TKI, by increasing EGFR TKI concentration in specific tumors that express high levels of VEGF protein.
ISSN:0344-5704
1432-0843
DOI:10.1007/s00280-014-2610-x