Antitumor Vascular Strategy for Controlling Experimental Metastatic Spread of Human Small-Cell Lung Cancer Cells with ZD6474 in Natural Killer Cell–Depleted Severe Combined Immunodeficient Mice

Yano, Seiji; Muguruma, Hiroaki; Matsumori, Yuka; Goto, Hisatsugu; Nakataki, Emiko; Edakuni, Nobutaka; Tomimoto, Hideki; Kakiuchi, Soji; Yamamoto, Akihiko; Uehara, Hisanori; Ryan, Anderson J.; Sone, Saburo

doi:10.1158/1078-0432.ccr-05-0674

Cited by 43 publications

(32 citation statements)

References 32 publications

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“…The concentrations of E7080 required to inhibit endothelial proliferation was lower, as was the dose needed to show antimetastatic effects (10 vs. 50 mg/kg; refs. 25,37,38). Furthermore, we found that E7080 prolonged survival in mice bearing multiple organ metastases of SBC-5 cells those with pleural effusion caused by PC14PE6 cells, clearly indicating that E7080 is a highly active inhibitor of angiogenesis of lung cancers with nonmutant EGFR.…”

Section: Discussionmentioning

confidence: 67%

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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Section: Discussionmentioning

confidence: 67%

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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“…In this model, highly bone metastatic SBC-5 cells produced metastatic colonies predominantly into the liver, lung, and bone (10,18). SBC-5 cells transfected with FST gene developed significantly fewer metastases in the liver and lung compared with the parental cell or vector control clone ( Fig.…”

Section: Resultsmentioning

confidence: 89%

Follistatin Suppresses the Production of Experimental Multiple-Organ Metastasis by Small Cell Lung Cancer Cells in Natural Killer Cell–Depleted SCID Mice

Ogino¹,

Yano

Kakiuchi³

et al. 2008

Clinical Cancer Research

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Purpose: Follistatin (FST), an inhibitor of activin, regulates a variety of biological functions, including cell proliferation, differentiation, and apoptosis. However, the role of FST in cancer metastasis is still unknown. Previous research established a multiple-organ metastasis model of human small cell lung cancer in natural killer cell^depleted SCID mice. In this model, i.v. inoculated tumor cells produced metastatic colonies in multiple organs including the lung, liver, and bone. The purpose of this study is to determine the role of FST in multiple-organ metastasis using this model. Experimental Design: A human FST gene was transfected into the small cell lung cancer cell lines SBC-3 and SBC-5 and established transfectants secreting biologically active FST. The metastatic potential of the transfectants was evaluated using the metastasis model. Results: FST-gene transfection did not affect the cell proliferation, motility, invasion, or adhesion to endothelial cells in vitro. I.v. inoculated SBC-3 or SBC-5 cells produced metastatic colonies into multiple organs, including the lung, liver, and bone in the natural killer cell^depleted SCID mice. FST transfectants produced significantly fewer metastatic colonies in these organs when compared with their parental cells or vector control clones. Immunohistochemical analyses of the liver metastases revealed that the number of proliferating tumor cells and the tumor-associated microvessel density were significantly less in the lesions produced by FST transfectants. Conclusions: These results suggest that FST plays a critical role in the production of multipleorgan metastasis, predominantly by inhibiting the angiogenesis.This is the first report to show the role of FST in metastases.

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“…Vandetanib is a tyrosine kinase inhibitor of both VEGFR-2 and EGFR, and preclinical studies have confirmed its anti-tumour effects in a range of cancer types (Wedge et al, 2002;Ciardiello et al, 2004;Taguchi et al, 2004;Williams et al, 2004;Yano et al, 2005). Phase III clinical studies are now underway with vandetanib in non-small-cell lung cancer following promising results in phase I and II studies (Holden et al, 2005;Natale et al, 2006;Tamura et al, 2006;Heymach et al, 2007a, b).…”

Section: Discussionmentioning

confidence: 99%

“…In our model, EGFR inhibition contributed to the anti-metastatic effect of vandetanib. Moreover, angiogenesis is essential for the growth of tumours more than 1 -2 mm in diameter (Fidler and Ellis, 1994;Ellis and Fidler, 1996;Yano et al, 2005), and VEGF is necessary for the formation of metastatic tissues at the primary site (Küsters et al, 2007). It is possible that VEGFR inhibition at the primary site may reduce the hematogenic metastasis in cholangiocarcinoma.…”

Section: Anti-metastatic Effects Of Vandetanib In Vivomentioning

confidence: 99%

Vandetanib (ZD6474), an inhibitor of VEGFR and EGFR signalling, as a novel molecular-targeted therapy against cholangiocarcinoma

Yoshikawa

Ojima²,

Kokubu³

et al. 2009

Br J Cancer

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Cholangiocarcinoma is an intractable cancer, with no effective therapy other than surgical resection. Elevated vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) expressions are associated with the progression of cholangiocarcinoma. We therefore examined whether inhibition of VEGFR and EGFR could be a potential therapeutic target for cholangiocarcinoma. Vandetanib (ZD6474, ZACTIMA), a VEGFR-2/EGFR inhibitor, was evaluated. Four human cholangiocarcinoma cell lines were molecularly characterised and investigated for their response to vandetanib. In vitro, two cell lines (OZ and HuCCT1), both of which harboured KRAS mutation, were refractory to vandetanib, one cell line (TGBC24TKB) was somewhat resistant, and another cell line (TKKK) was sensitive. The most sensitive cell line (TKKK) had EGFR amplification. Vandetanib significantly inhibited the growth of TKKK xenografts at doses X12.5 mg kg À1 day À1 (Po0.05), but higher doses (50 mg kg À1 day À1 , Po0.05) of vandetanib were required to inhibit the growth of OZ xenografts. Vandetanib (25 mg kg À1 day À1 ) also significantly (P ¼ 0.006) prolonged the time to metastasis in an intravenous model of TKKK metastasis. Inhibiting both VEGFR and EGFR signalling appears a promising therapeutic approach for cholangiocarcinoma. The absence of KRAS mutation and the presence of EGFR amplification may be potential predictive molecular marker of sensitivity to EGFR-targeted therapy in cholangiocarcinoma.

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Antitumor Vascular Strategy for Controlling Experimental Metastatic Spread of Human Small-Cell Lung Cancer Cells with ZD6474 in Natural Killer Cell–Depleted Severe Combined Immunodeficient Mice

Cited by 43 publications

References 32 publications

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

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

Follistatin Suppresses the Production of Experimental Multiple-Organ Metastasis by Small Cell Lung Cancer Cells in Natural Killer Cell–Depleted SCID Mice

Vandetanib (ZD6474), an inhibitor of VEGFR and EGFR signalling, as a novel molecular-targeted therapy against cholangiocarcinoma

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