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Enhanced anti-angiogenic effect of E7820 in combination with erlotinib in epidermal growth factor receptor-tyrosine kinase inhibitor-resistant non-small-cell lung cancer xenograft models.

Ito K, Semba T, Uenaka T, Wakabayashi T, Asada M, Funahashi Y - Cancer Sci. (2014)

Bottom Line: Treatment with E7820 (50 mg/kg) with erlotinib (60 mg/kg) showed a synergistic antitumor effect in three xenograft models.Immunohistochemical analysis indicated that combined treatment with E7820 and erlotinib significantly decreased microvessel density and increased apoptosis of tumor-associated endothelial cells compared with use of only one of the agents.This combination increased apoptosis in HUVECs through activation of both intrinsic and extrinsic apoptosis pathways in vitro.

View Article: PubMed Central - PubMed

Affiliation: Tsukuba Research Laboratory, Eisai Co., Ltd., Tsukuba, Japan.

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Combination treatment with E7820 and erlotinib (ERL) preferentially decreased microvessel density and enhanced apoptosis of tumor-associated endothelial cells in non-small-cell lung cancer xenograft models. Mice (n = 5, per group) were treated with vehicle, E7820 (50 mg/kg), and/or erlotinib (60 mg/kg) for 7 days. The tumors were resected and processed for immunohistochemical evaluation of CD31. (a) Columns indicate means of density of CD31-positive count. *P < 0.05 (b) Representative results are shown with CD31 staining in H1975. (c) Double immunofluorescence staining of CD31/TUNEL. Columns indicate means of apoptosis index in endothelial cells. *P < 0.05; **P < 0.01. (d) Representative results are shown with CD31/TUNEL staining in H1975. Endothelial cells (CD31+) stained with red fluorescence and apoptotic cells (TUNEL+) stained with green fluorescence. Colocalization of endothelial cells undergoing apoptosis yielded yellow fluorescence.
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fig02: Combination treatment with E7820 and erlotinib (ERL) preferentially decreased microvessel density and enhanced apoptosis of tumor-associated endothelial cells in non-small-cell lung cancer xenograft models. Mice (n = 5, per group) were treated with vehicle, E7820 (50 mg/kg), and/or erlotinib (60 mg/kg) for 7 days. The tumors were resected and processed for immunohistochemical evaluation of CD31. (a) Columns indicate means of density of CD31-positive count. *P < 0.05 (b) Representative results are shown with CD31 staining in H1975. (c) Double immunofluorescence staining of CD31/TUNEL. Columns indicate means of apoptosis index in endothelial cells. *P < 0.05; **P < 0.01. (d) Representative results are shown with CD31/TUNEL staining in H1975. Endothelial cells (CD31+) stained with red fluorescence and apoptotic cells (TUNEL+) stained with green fluorescence. Colocalization of endothelial cells undergoing apoptosis yielded yellow fluorescence.

Mentions: Because E7820 shows anti-angiogenic activity in xenografted human tumors in mice,(19,21) we examined MVD in human NSCLC A549, H1975, and H1650 xenograft models after treatment. Nude mice bearing A549, H1975, or H1650 xenografts were treated with E7820 (50 mg/kg), and/or erlotinib (60 mg/kg) for 7 days. Microvessel density in the tumor xenografts was determined by immunohistochemical staining against CD31. Treatment with E7820 or erlotinib alone did not decrease MVD in the A549 xenograft model (Fig. 2a,b). However, E7820 in combination with erlotinib did significantly decrease the number of CD31-positive cells in the A549 xenografted tumor (P < 0.05; Fig. 2a,b). We obtained similar results in the H1975 and H1650 xenograft model (P < 0.05; Fig. 2a,b).


Enhanced anti-angiogenic effect of E7820 in combination with erlotinib in epidermal growth factor receptor-tyrosine kinase inhibitor-resistant non-small-cell lung cancer xenograft models.

Ito K, Semba T, Uenaka T, Wakabayashi T, Asada M, Funahashi Y - Cancer Sci. (2014)

Combination treatment with E7820 and erlotinib (ERL) preferentially decreased microvessel density and enhanced apoptosis of tumor-associated endothelial cells in non-small-cell lung cancer xenograft models. Mice (n = 5, per group) were treated with vehicle, E7820 (50 mg/kg), and/or erlotinib (60 mg/kg) for 7 days. The tumors were resected and processed for immunohistochemical evaluation of CD31. (a) Columns indicate means of density of CD31-positive count. *P < 0.05 (b) Representative results are shown with CD31 staining in H1975. (c) Double immunofluorescence staining of CD31/TUNEL. Columns indicate means of apoptosis index in endothelial cells. *P < 0.05; **P < 0.01. (d) Representative results are shown with CD31/TUNEL staining in H1975. Endothelial cells (CD31+) stained with red fluorescence and apoptotic cells (TUNEL+) stained with green fluorescence. Colocalization of endothelial cells undergoing apoptosis yielded yellow fluorescence.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4317852&req=5

fig02: Combination treatment with E7820 and erlotinib (ERL) preferentially decreased microvessel density and enhanced apoptosis of tumor-associated endothelial cells in non-small-cell lung cancer xenograft models. Mice (n = 5, per group) were treated with vehicle, E7820 (50 mg/kg), and/or erlotinib (60 mg/kg) for 7 days. The tumors were resected and processed for immunohistochemical evaluation of CD31. (a) Columns indicate means of density of CD31-positive count. *P < 0.05 (b) Representative results are shown with CD31 staining in H1975. (c) Double immunofluorescence staining of CD31/TUNEL. Columns indicate means of apoptosis index in endothelial cells. *P < 0.05; **P < 0.01. (d) Representative results are shown with CD31/TUNEL staining in H1975. Endothelial cells (CD31+) stained with red fluorescence and apoptotic cells (TUNEL+) stained with green fluorescence. Colocalization of endothelial cells undergoing apoptosis yielded yellow fluorescence.
Mentions: Because E7820 shows anti-angiogenic activity in xenografted human tumors in mice,(19,21) we examined MVD in human NSCLC A549, H1975, and H1650 xenograft models after treatment. Nude mice bearing A549, H1975, or H1650 xenografts were treated with E7820 (50 mg/kg), and/or erlotinib (60 mg/kg) for 7 days. Microvessel density in the tumor xenografts was determined by immunohistochemical staining against CD31. Treatment with E7820 or erlotinib alone did not decrease MVD in the A549 xenograft model (Fig. 2a,b). However, E7820 in combination with erlotinib did significantly decrease the number of CD31-positive cells in the A549 xenografted tumor (P < 0.05; Fig. 2a,b). We obtained similar results in the H1975 and H1650 xenograft model (P < 0.05; Fig. 2a,b).

Bottom Line: Treatment with E7820 (50 mg/kg) with erlotinib (60 mg/kg) showed a synergistic antitumor effect in three xenograft models.Immunohistochemical analysis indicated that combined treatment with E7820 and erlotinib significantly decreased microvessel density and increased apoptosis of tumor-associated endothelial cells compared with use of only one of the agents.This combination increased apoptosis in HUVECs through activation of both intrinsic and extrinsic apoptosis pathways in vitro.

View Article: PubMed Central - PubMed

Affiliation: Tsukuba Research Laboratory, Eisai Co., Ltd., Tsukuba, Japan.

Show MeSH
Related in: MedlinePlus