Abstract
VEGF receptor blockage has been reported to increase serum VEGF. We hypothesized that mTOR inhibition by everolimus counteracts VEGF induction by sunitinib resulting in an improved anti-tumor activity of sunitinib. In vitro, sunitinib in combination with everolimus did not outperform the respective monotherapies. In vivo, monotherapies reduced tumor growth by 60%, whereas the combination of sunitinib and everolimus led to an almost complete tumor growth inhibition. This superior anti-tumor activity coincided with attenuation of VEGF peaks. In conclusion mTOR inhibition by everolimus counteracts VEGF induction by sunitinib and results in significant reduction of tumor burden and long-lasting tumor growth control.
2010 Elsevier Ireland Ltd. All rights reserved.
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology*
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Cell Line, Tumor
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Enzyme-Linked Immunosorbent Assay
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Everolimus
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Female
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Humans
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Immunohistochemistry
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Immunosuppressive Agents / therapeutic use*
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Indoles / pharmacology*
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Intracellular Signaling Peptides and Proteins / drug effects*
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Mice
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Mice, Nude
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Protein Serine-Threonine Kinases / drug effects*
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Pyrroles / pharmacology*
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Sirolimus / analogs & derivatives*
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Sirolimus / therapeutic use
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Stomach Neoplasms / drug therapy*
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Stomach Neoplasms / pathology
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Sunitinib
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TOR Serine-Threonine Kinases
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Transplantation, Heterologous
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Vascular Endothelial Growth Factor A / biosynthesis*
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Vascular Endothelial Growth Factor A / drug effects
Substances
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Antineoplastic Agents
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Immunosuppressive Agents
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Indoles
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Intracellular Signaling Peptides and Proteins
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Pyrroles
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Vascular Endothelial Growth Factor A
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Everolimus
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MTOR protein, human
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mTOR protein, mouse
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Protein Serine-Threonine Kinases
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TOR Serine-Threonine Kinases
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Sunitinib
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Sirolimus