Abstract
Functions of receptor tyrosine kinases implicated in angiogenesis were pharmacologically impaired in a mouse model of pancreatic islet cancer. An inhibitor targeting VEGFRs in endothelial cells (SU5416) is effective against early-stage angiogenic lesions, but not large, well-vascularized tumors. In contrast, a kinase inhibitor incorporating selectivity for PDGFRs (SU6668) is shown to block further growth of end-stage tumors, eliciting detachment of pericytes and disruption of tumor vascularity. Importantly, PDGFRs were expressed only in perivascular cells of this tumor type, suggesting that PDGFR(+) pericytes in tumors present a complimentary target to endothelial cells for efficacious antiangiogenic therapy. Therapeutic regimes combining the two kinase inhibitors (SU5416 and SU6668) were more efficacious against all stages of islet carcinogenesis than either single agent. Combination of the VEGFR inhibitor with another distinctive kinase inhibitor targeting PDGFR activity (Gleevec) was also able to regress late-stage tumors. Thus, combinatorial targeting of receptor tyrosine kinases shows promise for treating multiple stages in tumorigenesis, most notably the often-intractable late-stage solid tumor.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Angiogenesis Inhibitors / pharmacology*
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Angiogenesis Inhibitors / therapeutic use
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Animals
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Blood Vessels / pathology
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Blood Vessels / physiology
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Carcinoma, Islet Cell / blood supply*
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Carcinoma, Islet Cell / drug therapy*
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Carcinoma, Islet Cell / metabolism
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Carcinoma, Islet Cell / pathology
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Endothelium, Vascular / cytology
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Endothelium, Vascular / drug effects*
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Endothelium, Vascular / metabolism
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Female
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Indoles / pharmacology
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Indoles / therapeutic use
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Neovascularization, Pathologic
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Oxindoles
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Pericytes / drug effects*
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Pericytes / physiology
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Platelet-Derived Growth Factor / metabolism
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Propionates
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Pyrroles / pharmacology
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Pyrroles / therapeutic use
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Receptors, Platelet-Derived Growth Factor / antagonists & inhibitors
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Receptors, Platelet-Derived Growth Factor / genetics
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Receptors, Platelet-Derived Growth Factor / metabolism
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Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors
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Receptors, Vascular Endothelial Growth Factor / metabolism
Substances
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Angiogenesis Inhibitors
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Indoles
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Oxindoles
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Platelet-Derived Growth Factor
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Propionates
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Pyrroles
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Semaxinib
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orantinib
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Protein-Tyrosine Kinases
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Receptors, Platelet-Derived Growth Factor
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Receptors, Vascular Endothelial Growth Factor