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.
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.
Affiliation: Tsukuba Research Laboratory, Eisai Co., Ltd., Tsukuba, Japan.Show MeSH
Related in: MedlinePlus
Mentions: We next examined whether E7820 in combination with erlotinib resulted in the inhibition of tumor cell proliferation and enhancement of tumor cell apoptosis in tumor tissues. Nude mice bearing A549, H1975, or H1650 tumors were treated with E7820 (50 mg/kg) and/or erlotinib (60 mg/kg), for 7 days. Staining with PCNA was carried out to assess cell proliferation and TUNEL staining was used to assess apoptosis in the tumor cells. E7820 in combination with erlotinib significantly decreased the number of PCNA-positive cells compared with E7820 or erlotinib alone in three xenograft models (P < 0.05; Fig. 3a,b). Furthermore, combination treatments of these drugs significantly increased TUNEL-positive tumor cells compared with either E7820 or erlotinib alone in three xenograft models after 7 days of treatment (Fig. 3c,d). These results indicated that the superior antitumor activity of E7820 in combination with erlotinib was caused by decreased tumor cell proliferation and increased tumor cell apoptosis based on enhanced anti-angiogenesis activity.
Affiliation: Tsukuba Research Laboratory, Eisai Co., Ltd., Tsukuba, Japan.