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E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition
Author(s) -
Matsui Junji,
Yamamoto Yuji,
Funahashi Yasuhiro,
Tsuruoka Akihiko,
Watanabe Tatsuo,
Wakabayashi Toshiaki,
Uenaka Toshimitsu,
Asada Makoto
Publication year - 2007
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.23131
Subject(s) - angiogenesis , cancer research , stem cell factor , angiogenesis inhibitor , tyrosine kinase inhibitor , imatinib , receptor tyrosine kinase , tyrosine kinase , stromal cell , in vivo , biology , receptor , cancer , pharmacology , stem cell , medicine , progenitor cell , microbiology and biotechnology , myeloid leukemia
E7080 is an orally active inhibitor of multiple receptor tyrosine kinases including VEGF, FGF and SCF receptors. In this study, we show the inhibitory activity of E7080 against SCF‐induced angiogenesis in vitro and tumor growth of SCF‐producing human small cell lung carcinoma H146 cells in vivo . E7080 inhibits SCF‐driven tube formation of HUVEC, which express SCF receptor, KIT at the IC 50 value of 5.2 nM and it was almost identical for VEGF‐driven one (IC 50 = 5.1 nM). To assess the role of SCF/KIT signaling in tumor angiogenesis, we evaluated the effect of imatinib, a selective KIT kinase inhibitor, on tumor growth of H146 cells in nude mice. Imatinib did not show the potent antitumor activity in vitro (IC 50 = 2,200 nM), because H146 cells did not express KIT. However, oral administration of imatinib at 160 mg/kg clearly slowed tumor growth of H146 cells in nude mice, accompanied by decreased microvessel density. Oral administration of E7080 inhibited tumor growth of H146 cells at doses of 30 and 100 mg/kg in a dose‐dependent manner and caused tumor regression at 100 mg/kg. While anti‐VEGF antibody also slowed tumor growth, it did not cause tumor regression. These results indicate that KIT signaling has a role in tumor angiogenesis of SCF‐producing H146 cells, and E7080 causes regression of H146 tumors as a result of antiangiogenic activity mediated by inhibition of both KIT and VEGF receptor signaling. E7080 may provide therapeutic benefits in the treatment of SCF‐producing tumors. © 2007 Wiley‐Liss, Inc.