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Lenvatinib in combination with golvatinib overcomes hepatocyte growth factor pathway-induced resistance to vascular endothelial growth factor receptor inhibitor.

Nakagawa T, Matsushima T, Kawano S, Nakazawa Y, Kato Y, Adachi Y, Abe T, Semba T, Yokoi A, Matsui J, Tsuruoka A, Funahashi Y - Cancer Sci. (2014)

Bottom Line: Here, we explored the effect of the HGF/Met signaling pathway and its inhibitors on resistance to lenvatinib, a VEGFR inhibitor.Lenvatinib potently inhibited the growth of HUVECs induced by VEGF alone, but cells induced by VEGF plus HGF showed lenvatinib resistance.This HGF-induced resistance was cancelled when the Met inhibitor, golvatinib, was added with lenvatinib.

View Article: PubMed Central - PubMed

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

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Related in: MedlinePlus

Effect of combined lenvatinib and golvatinib treatment on tumor volume in hepatocyte growth factor (HGF)-expressing human cancer xenograft models in mice. Nude mice bearing SEKI (a), KP-4 (b), IM95m (c), or A2780 (d) tumors were treated orally with lenvatinib (10 mg/kg), golvatinib (100 mg/kg), or both, once daily. Tumor volume was measured using calipers on the indicated days. Data represent the means ± SD of six animals. *P < 0.05 versus vehicle control at the end of treatment. †Combination therapy demonstrated a synergistic effect (two-way anova analysis; P < 0.05).
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fig03: Effect of combined lenvatinib and golvatinib treatment on tumor volume in hepatocyte growth factor (HGF)-expressing human cancer xenograft models in mice. Nude mice bearing SEKI (a), KP-4 (b), IM95m (c), or A2780 (d) tumors were treated orally with lenvatinib (10 mg/kg), golvatinib (100 mg/kg), or both, once daily. Tumor volume was measured using calipers on the indicated days. Data represent the means ± SD of six animals. *P < 0.05 versus vehicle control at the end of treatment. †Combination therapy demonstrated a synergistic effect (two-way anova analysis; P < 0.05).

Mentions: We used the above cell lines to create mouse human tumor xenograft models to test the therapeutic effects of lenvatinib and golvatinib given alone or in combination (Fig.3). A clinically relevant dose of lenvatinib (10 mg/kg) showed significant but weak antitumor activity in all but the KP-4 model (Fig.3). Administration of a clinically relevant dose of golvatinib (100 mg/kg) showed similar antitumor activity to lenvatinib in the SEKI and IM95m models, but showed no antitumor activity in the KP-4 and A2780 models. In contrast, combined treatment with lenvatinib and golvatinib showed significant antitumor activities in all four models examined when compared with the control, and in all but the IM95m model when compared with treatment using each agent alone. The in vivo antitumor activities were synergistic in the SEKI, KP-4, and A2780 models, and additive in the IM95m model. Neither abnormal macroscopic findings nor body weight loss were evident in mice treated with either lenvatinib or golvatinib alone or in combination (Fig. S3).


Lenvatinib in combination with golvatinib overcomes hepatocyte growth factor pathway-induced resistance to vascular endothelial growth factor receptor inhibitor.

Nakagawa T, Matsushima T, Kawano S, Nakazawa Y, Kato Y, Adachi Y, Abe T, Semba T, Yokoi A, Matsui J, Tsuruoka A, Funahashi Y - Cancer Sci. (2014)

Effect of combined lenvatinib and golvatinib treatment on tumor volume in hepatocyte growth factor (HGF)-expressing human cancer xenograft models in mice. Nude mice bearing SEKI (a), KP-4 (b), IM95m (c), or A2780 (d) tumors were treated orally with lenvatinib (10 mg/kg), golvatinib (100 mg/kg), or both, once daily. Tumor volume was measured using calipers on the indicated days. Data represent the means ± SD of six animals. *P < 0.05 versus vehicle control at the end of treatment. †Combination therapy demonstrated a synergistic effect (two-way anova analysis; P < 0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4317894&req=5

fig03: Effect of combined lenvatinib and golvatinib treatment on tumor volume in hepatocyte growth factor (HGF)-expressing human cancer xenograft models in mice. Nude mice bearing SEKI (a), KP-4 (b), IM95m (c), or A2780 (d) tumors were treated orally with lenvatinib (10 mg/kg), golvatinib (100 mg/kg), or both, once daily. Tumor volume was measured using calipers on the indicated days. Data represent the means ± SD of six animals. *P < 0.05 versus vehicle control at the end of treatment. †Combination therapy demonstrated a synergistic effect (two-way anova analysis; P < 0.05).
Mentions: We used the above cell lines to create mouse human tumor xenograft models to test the therapeutic effects of lenvatinib and golvatinib given alone or in combination (Fig.3). A clinically relevant dose of lenvatinib (10 mg/kg) showed significant but weak antitumor activity in all but the KP-4 model (Fig.3). Administration of a clinically relevant dose of golvatinib (100 mg/kg) showed similar antitumor activity to lenvatinib in the SEKI and IM95m models, but showed no antitumor activity in the KP-4 and A2780 models. In contrast, combined treatment with lenvatinib and golvatinib showed significant antitumor activities in all four models examined when compared with the control, and in all but the IM95m model when compared with treatment using each agent alone. The in vivo antitumor activities were synergistic in the SEKI, KP-4, and A2780 models, and additive in the IM95m model. Neither abnormal macroscopic findings nor body weight loss were evident in mice treated with either lenvatinib or golvatinib alone or in combination (Fig. S3).

Bottom Line: Here, we explored the effect of the HGF/Met signaling pathway and its inhibitors on resistance to lenvatinib, a VEGFR inhibitor.Lenvatinib potently inhibited the growth of HUVECs induced by VEGF alone, but cells induced by VEGF plus HGF showed lenvatinib resistance.This HGF-induced resistance was cancelled when the Met inhibitor, golvatinib, was added with lenvatinib.

View Article: PubMed Central - PubMed

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

Show MeSH
Related in: MedlinePlus