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

Heyan Li, Koichi Takayama, Shuo Wang, Yoshimasa Shiraishi, Keisuke Gotanda, Taishi Harada, Kazuto Furuyama, Eiji Iwama, Ichiro Ieiri, Isamu Okamoto, Yoichi Nakanishi

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)1297-1305
Number of pages9
JournalCancer chemotherapy and pharmacology
Volume74
Issue number6
DOIs
Publication statusPublished - Oct 9 2014

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Heterografts
Non-Small Cell Lung Carcinoma
Vascular Endothelial Growth Factor A
Cells
Tumors
Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Neoplasms
Assays
Proteins
Growth
Erlotinib Hydrochloride
Bevacizumab
High performance liquid chromatography
Cell growth
Therapeutics
Enzyme-Linked Immunosorbent Assay
High Pressure Liquid Chromatography
Tissue

All Science Journal Classification (ASJC) codes

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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Addition of bevacizumab enhances antitumor activity of erlotinib against non-small cell lung cancer xenografts depending on VEGF expression. / Li, Heyan; Takayama, Koichi; Wang, Shuo; Shiraishi, Yoshimasa; Gotanda, Keisuke; Harada, Taishi; Furuyama, Kazuto; Iwama, Eiji; Ieiri, Ichiro; Okamoto, Isamu; Nakanishi, Yoichi.

In: Cancer chemotherapy and pharmacology, Vol. 74, No. 6, 09.10.2014, p. 1297-1305.

Research output: Contribution to journalArticle

Li, Heyan ; Takayama, Koichi ; Wang, Shuo ; Shiraishi, Yoshimasa ; Gotanda, Keisuke ; Harada, Taishi ; Furuyama, Kazuto ; Iwama, Eiji ; Ieiri, Ichiro ; Okamoto, Isamu ; Nakanishi, Yoichi. / Addition of bevacizumab enhances antitumor activity of erlotinib against non-small cell lung cancer xenografts depending on VEGF expression. In: Cancer chemotherapy and pharmacology. 2014 ; Vol. 74, No. 6. pp. 1297-1305.
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T1 - Addition of bevacizumab enhances antitumor activity of erlotinib against non-small cell lung cancer xenografts depending on VEGF expression

AU - Li, Heyan

AU - Takayama, Koichi

AU - Wang, Shuo

AU - Shiraishi, Yoshimasa

AU - Gotanda, Keisuke

AU - Harada, Taishi

AU - Furuyama, Kazuto

AU - Iwama, Eiji

AU - Ieiri, Ichiro

AU - Okamoto, Isamu

AU - Nakanishi, Yoichi

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AB - 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.

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