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.
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Authors | Gabriele Bergers, Steven Song, Nicole Meyer-Morse, Emily Bergsland, Douglas Hanahan |
Journal | The Journal of clinical investigation
(J Clin Invest)
Vol. 111
Issue 9
Pg. 1287-95
(May 2003)
ISSN: 0021-9738 [Print] United States |
PMID | 12727920
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Angiogenesis Inhibitors
- Indoles
- Oxindoles
- Platelet-Derived Growth Factor
- Propionates
- Pyrroles
- Semaxinib
- orantinib
- Protein-Tyrosine Kinases
- Receptors, Platelet-Derived Growth Factor
- Receptors, Vascular Endothelial Growth Factor
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Topics |
- Angiogenesis Inhibitors
(pharmacology, therapeutic use)
- Animals
- Antineoplastic Combined Chemotherapy Protocols
(pharmacology, therapeutic use)
- Blood Vessels
(pathology, physiology)
- Carcinoma, Islet Cell
(blood supply, drug therapy, metabolism, pathology)
- Endothelium, Vascular
(cytology, drug effects, metabolism)
- Female
- Indoles
(pharmacology, therapeutic use)
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Neovascularization, Pathologic
- Oxindoles
- Pericytes
(drug effects, physiology)
- Platelet-Derived Growth Factor
(metabolism)
- Propionates
- Protein-Tyrosine Kinases
(antagonists & inhibitors)
- Pyrroles
(pharmacology, therapeutic use)
- Receptors, Platelet-Derived Growth Factor
(antagonists & inhibitors, genetics, metabolism)
- Receptors, Vascular Endothelial Growth Factor
(antagonists & inhibitors, metabolism)
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