Multi-Kinase Inhibitor E7080 Suppresses Lymph Node and Lung Metastases of Human Mammary Breast Tumor MDA-MB-231 via Inhibition of Vascular Endothelial Growth Factor-Receptor (VEGF-R) 2 and VEGF-R3 Kinase

Matsui, Junji; Funahashi, Yasuhiro; Uenaka, Toshimitsu; Watanabe, Tatsuo; Tsuruoka, Akihiko; Asada, Makoto

doi:10.1158/1078-0432.ccr-07-5270

Cited by 436 publications

(325 citation statements)

References 25 publications

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“…Apart from inhibiting angiogenesis by targeting endothelial cells [4][5][6][7], lenvatinib exerts a direct effect on tumor cells, by inhibiting their migration and invasion [8]. Promising antitumor effects of lenvatinib were observed in Phase I trials [9,10], leading to a number of disease-specific phase 2 and phase 3 trials with lenvatinib as a single agent or in combination with other anticancer agents.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and excretion of 14C-lenvatinib in patients with advanced solid tumors or lymphomas

et al. 2014

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Summary Lenvatinib is an orally available multi-targeted tyrosine kinase inhibitor with anti-angiogenic and antitumor activity. To get more insight into the disposition of lenvatinib, a mass balance study was performed in patients with advanced solid tumors. A single oral 24 mg (100 μCi) dose of 14 Clenvatinib was administered to six patients, followed by collection of blood, plasma, urine and feces for 7 to 10 days. The collected material was analyzed for total radioactivity, unchanged lenvatinib and selected metabolites. The safety and antitumor effect of a daily oral dose of 24 mg non-labeled lenvatinib were assessed in the extension phase of the study. Peak plasma concentrations of lenvatinib and total radioactivity were reached 1.6 and 1.4 h after administration, respectively, and their terminal phase half-lifes were 34.5 and 17.8 h, respectively. Unchanged lenvatinib systemic exposure accounted for 60 % of the total radioactivity in plasma. Peak concentrations of the analyzed metabolite were over 700-fold lower than the peak plasma concentration of lenvatinib. Ten days after the initial dose, the geometric mean (± CV) recovery of administered dose was 89 % ±10 %, with 64 % ±11 % recovered in feces and 25 % ±18 % in urine. Unchanged lenvatinib in urine and feces accounted for 2.5 % ±68 % of the administered dose, indicating a major role of metabolism in the elimination of lenvatinib. In conclusion, lenvatinib is rapidly absorbed and extensively metabolized, with subsequent excretion in urine and, more predominantly, in feces. Additionally, lenvatinib showed acceptable safety and preliminary antitumor activity.

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Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and excretion of 14C-lenvatinib in patients with advanced solid tumors or lymphomas

et al. 2014

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“…E7080 shows potent antitumor effects in xenograft models of various types of tumors by inhibiting angiogenesis, especially through VEGFR-2/3 suppression (16,17). We have tested the therapeutic efficacy of E7080 against lung cancer cell lines expressing wild-type EGFR, using in vivo experimental metastasis models.…”

Section: Introductionmentioning

confidence: 99%

E7080 Suppresses Hematogenous Multiple Organ Metastases of Lung Cancer Cells with Nonmutated Epidermal Growth Factor Receptor

Ogino

Hashimoto²,

Kakiuchi³

et al. 2011

Molecular Cancer Therapeutics

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While epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors improve the prognosis of patients with EGFR mutant lung cancer, the prognosis of patients with nonmutant EGFR lung cancer, especially those with metastases, is still extremely poor. We have assessed the therapeutic efficacy of E7080, an orally available inhibitor of multiple tyrosine kinases including VEGF receptor 2 (VEGFR-2) and VEGFR-3, in experimental multiple organ metastasis of lung cancer cell lines without EGFR mutations. E7080 markedly inhibited the in vitro proliferation of VEGF-stimulated microvascular endothelial cells. Intravenous inoculation into natural killer cell-depleted severe combined immunodeficient mice of the small cell lung cancer cell lines H1048 (producing low amounts of VEGF) and SBC-5 (producing intermediate amounts of VEGF) resulted in hematogenous metastases into multiple organs, including the liver, lungs, kidneys, and bones, whereas intravenous inoculation of PC14PE6, a non-small cell lung cancer cell line producing high amounts of VEGF, resulted in lung metastases followed by massive pleural effusion. Daily treatment with E7080 started after the establishment of micrometastases significantly reduced the number of large (>2 mm) metastatic nodules and the amount of pleural effusion, and prolonged mouse survival. Histologically, E7080 treatment reduced the numbers of endothelial and lymph endothelial cells and proliferating tumor cells and increased the number of apoptotic cells in metastatic nodules. These results suggest that E7080 has antiangiogenic and antilymphangiogenic activity and may be of potential therapeutic value in patients with nonmutant EGFR lung cancer and multiple organ metastases.

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“…12 Based on previous studies 8,9 and data presented here, 30-100 mg/kg daily may be considered optimal for E7080 in mice. The antitumour activity of E7080 was grossly maintained upon reduction of the dose to 10 mg/kg in two of the human xenograft models applied (ALSKX and MOX).…”

Section: Discussionmentioning

confidence: 85%

“…7 E7080 is an orally active inhibitor of multiple tyrosine kinases including receptors for a number of growth factors which have pro-angiogenic properties, such as VEGF, FGF, SCF and PDGF, and in vivo antitumour activity in SCLC and breast cancer based on angiogenesis inhibition have been demonstrated previously. 8,9 We undertook our study to evaluate the preclinical activity of this compound in human sarcomas. E7080 did not potently inhibit the viability of sarcoma cell lines but showed broad antitumour activity in a panel of human sarcoma xenografts, accompanied by reduction in the density of tumour microvessels.…”

mentioning

confidence: 99%

Antitumour activity of oral E7080, a novel inhibitor of multiple tyrosine kinases, in human sarcoma xenografts

Bruheim¹,

Kristian²,

Uenaka

et al. 2011

Intl Journal of Cancer

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E7080 is an inhibitor of multiple tyrosine kinases, several of which have pro-angiogenic properties, including receptors for VEGF, FGF, SCF and PDGF. We undertook our study to evaluate the preclinical activity of E7080 in human sarcomas. The antitumour activity of orally administered E7080 was tested in ten human tumour xenografts representing different sarcoma histotypes. Concomitant changes in microvessel density were assayed by immunohistochemistry to CD31. Immunohistochemistry was also used to assess the expression of kinases that E7080 is known to inhibit. The MTS assay was applied to determine effects on tumour cell viability in vitro. At the Q1D5 3 2 schedule, E7080 (30 mg/kg) was active (T/C<40%) in 7/10 xenografts. The effects were accompanied by marked decrease in microvessel densities. Given at the Q1D5 3 4 schedule, E7080 (30, 10, 3 mg/kg) showed antitumour activity in a dose dependent manner in two different xenografts. E7080 growth inhibition did not correlate with the expression of VEGFR1-3, PDGFRA, PDGFRB, FGFR1 or KIT on tumour cells but was significantly correlated with expression of VEGFR2 on tumour microvessels. In vitro E7080 did not show potent effects on tumour cell viability in four different sarcoma cell lines, with IC50 values !10 lM. In conclusion, E7080 showed broad in vivo antitumour activity in sarcoma, mainly attributable to angiogenesis inhibition. E7080 was also active in xenografts resistant to one or more clinically relevant reference drugs given at MTD (doxorubicin, cisplatin or ifosfamide). The present results encourage further investigation of a potential role of E7080 in sarcoma therapy in the clinic.

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Multi-Kinase Inhibitor E7080 Suppresses Lymph Node and Lung Metastases of Human Mammary Breast Tumor MDA-MB-231 via Inhibition of Vascular Endothelial Growth Factor-Receptor (VEGF-R) 2 and VEGF-R3 Kinase

Cited by 436 publications

References 25 publications

Pharmacokinetics and excretion of 14C-lenvatinib in patients with advanced solid tumors or lymphomas

Pharmacokinetics and excretion of 14C-lenvatinib in patients with advanced solid tumors or lymphomas

E7080 Suppresses Hematogenous Multiple Organ Metastases of Lung Cancer Cells with Nonmutated Epidermal Growth Factor Receptor

Antitumour activity of oral E7080, a novel inhibitor of multiple tyrosine kinases, in human sarcoma xenografts

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