Antiangiogenic Therapy Using Sunitinib Combined with Rapamycin Retards Tumor Growth But Promotes Metastasis

doi:10.1016/j.tranon.2014.02.007

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Antiangiogenic Therapy Using Sunitinib Combined with Rapamycin Retards Tumor Growth But Promotes Metastasis

Translational Oncology2014doi:10.1016/j.tranon.2014.02.007

Abstract

Background This study investigated the synergistic effect of sunitinib and rapamycin on tumor growth and metastasis in murine breast cancer model.Methods The synergistic antitumor effect of sunitinib and rapamycin on tumor growth and metastasis was investigated. Myeloid-derived suppressor cells (MDSCs) in spleens and lungs were assessed. Tumor hypoxia, vessel density and micrometastasis were evaluated. Versican, indoleamine 2,3-dioxygenase (IDO), arginase 1, interleukin-6 (IL-6), IL-10, and transforming growth factor β (TGF-β) in the lungs and tumors were examined. IL-6 and TGF-β in the blood were evaluated.Results Synergism between sunitinib and rapamycin on tumor growth was observed. Sunitinib plus rapamycin reduced splenomegaly, MDSCs in spleens and lungs, and microvessel density in tumor microenvironment, while exacerbated hypoxia and promoted cancer lung metastasis. Sunitinib plus rapamycin markedly induced versican, IDO, arginase 1, IL-6, and TGF-β expression in the lungs, whereas it reduced IDO and IL-10 expression in the primary tumor tissues. IL-6 levels in the circulation were increased after rapamycin and combination therapies.Conclusions The combination of sunitinib plus rapamycin reduced the tumor growth but promoted tumor metastasis. This study warrants that further mTOR inhibition treatment should be closely watched in clinical setting, especially combined with antiangiogenic therapy.

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Tumor angiogenesis: molecular pathways and therapeutic targets

10.1038/nm.2537 · 2011

SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types

1999

Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis

10.1016/j.ccr.2009.01.027 · 2009

Hypoxia signalling in cancer and approaches to enforce tumour regression

10.1038/nature04871 · 2006

Overexpression of hypoxia-inducible factor 1α is a marker for an unfavorable prognosis in early- stage invasive cervical cancer

2000

Direct regulation of TWIST by HIF-1α promotes metastasis

10.1038/ncb1691 · 2008

Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis

10.1016/j.cell.2004.06.006 · 2004

In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/phar macodynamic relationship

2003

Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane

Antiangiogenic Therapy Using Sunitinib Combined with Rapamycin Retards Tumor Growth But Promotes Metastasis

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