Vandetanib inhibits both VEGFR-2 and EGFR signalling at clinically relevant drug levels in preclinical models of human cancer.
Vandetanib is a multi-targeted receptor tyrosine kinase inhibitor that is in clinical development for the treatment of solid tumours. This preclinical study examined the inhibition of two key signalling pathways (VEGFR-2, EGFR) at drug concentrations similar to those achieved in the clinic, and thei...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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2011
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| _version_ | 1797077024716619776 |
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| author | Brave, SR Odedra, R James, N Smith, N Marshall, G Acheson, K Baker, D Howard, Z Jackson, L Ratcliffe, K Wainwright, A Lovick, S Hickinson, D Wilkinson, R Barry, S Speake, G Ryan, A |
| author_facet | Brave, SR Odedra, R James, N Smith, N Marshall, G Acheson, K Baker, D Howard, Z Jackson, L Ratcliffe, K Wainwright, A Lovick, S Hickinson, D Wilkinson, R Barry, S Speake, G Ryan, A |
| author_sort | Brave, SR |
| collection | OXFORD |
| description | Vandetanib is a multi-targeted receptor tyrosine kinase inhibitor that is in clinical development for the treatment of solid tumours. This preclinical study examined the inhibition of two key signalling pathways (VEGFR-2, EGFR) at drug concentrations similar to those achieved in the clinic, and their contribution to direct and indirect antitumour effects of vandetanib. For in vitro studies, receptor phosphorylation was assessed by Western blotting and ELISA, cell proliferation was assessed using a cell viability endpoint, and effects on cell cycle determined using flow cytometry. For in vivo studies, Western blotting, ELISA and immunohistochemistry (IHC) were used to assess receptor phosphorylation. Cell culture experiments demonstrated that anti-proliferative effects of vandetanib resulted from inhibition of either EGFR or VEGFR-2 signalling in endothelial cells, but were associated with inhibition of EGFR signalling in tumour cells. Vandetanib inhibited both EGFR and VEGFR-2 signalling in normal lung tissue and in tumour xenografts. In a lung cancer model expressing an activating EGFR mutation, the activity of vandetanib was similar to that of a highly selective EGFR inhibitor (gefitinib), and markedly greater than that of a highly selective VEGFR inhibitor (vatalanib). These data suggest that at the plasma exposures achieved in the clinic, vandetanib will significantly inhibit both VEGFR-2 and EGFR signalling, and that both inhibition of angiogenesis and direct inhibition of tumour cell growth can contribute to treatment response. |
| first_indexed | 2024-03-07T00:11:52Z |
| format | Journal article |
| id | oxford-uuid:7980ee12-d7a0-4488-bc45-185942180fb0 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T00:11:52Z |
| publishDate | 2011 |
| record_format | dspace |
| spelling | oxford-uuid:7980ee12-d7a0-4488-bc45-185942180fb02022-03-26T20:37:56ZVandetanib inhibits both VEGFR-2 and EGFR signalling at clinically relevant drug levels in preclinical models of human cancer.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:7980ee12-d7a0-4488-bc45-185942180fb0EnglishSymplectic Elements at Oxford2011Brave, SROdedra, RJames, NSmith, NMarshall, GAcheson, KBaker, DHoward, ZJackson, LRatcliffe, KWainwright, ALovick, SHickinson, DWilkinson, RBarry, SSpeake, GRyan, AVandetanib is a multi-targeted receptor tyrosine kinase inhibitor that is in clinical development for the treatment of solid tumours. This preclinical study examined the inhibition of two key signalling pathways (VEGFR-2, EGFR) at drug concentrations similar to those achieved in the clinic, and their contribution to direct and indirect antitumour effects of vandetanib. For in vitro studies, receptor phosphorylation was assessed by Western blotting and ELISA, cell proliferation was assessed using a cell viability endpoint, and effects on cell cycle determined using flow cytometry. For in vivo studies, Western blotting, ELISA and immunohistochemistry (IHC) were used to assess receptor phosphorylation. Cell culture experiments demonstrated that anti-proliferative effects of vandetanib resulted from inhibition of either EGFR or VEGFR-2 signalling in endothelial cells, but were associated with inhibition of EGFR signalling in tumour cells. Vandetanib inhibited both EGFR and VEGFR-2 signalling in normal lung tissue and in tumour xenografts. In a lung cancer model expressing an activating EGFR mutation, the activity of vandetanib was similar to that of a highly selective EGFR inhibitor (gefitinib), and markedly greater than that of a highly selective VEGFR inhibitor (vatalanib). These data suggest that at the plasma exposures achieved in the clinic, vandetanib will significantly inhibit both VEGFR-2 and EGFR signalling, and that both inhibition of angiogenesis and direct inhibition of tumour cell growth can contribute to treatment response. |
| spellingShingle | Brave, SR Odedra, R James, N Smith, N Marshall, G Acheson, K Baker, D Howard, Z Jackson, L Ratcliffe, K Wainwright, A Lovick, S Hickinson, D Wilkinson, R Barry, S Speake, G Ryan, A Vandetanib inhibits both VEGFR-2 and EGFR signalling at clinically relevant drug levels in preclinical models of human cancer. |
| title | Vandetanib inhibits both VEGFR-2 and EGFR signalling at clinically relevant drug levels in preclinical models of human cancer. |
| title_full | Vandetanib inhibits both VEGFR-2 and EGFR signalling at clinically relevant drug levels in preclinical models of human cancer. |
| title_fullStr | Vandetanib inhibits both VEGFR-2 and EGFR signalling at clinically relevant drug levels in preclinical models of human cancer. |
| title_full_unstemmed | Vandetanib inhibits both VEGFR-2 and EGFR signalling at clinically relevant drug levels in preclinical models of human cancer. |
| title_short | Vandetanib inhibits both VEGFR-2 and EGFR signalling at clinically relevant drug levels in preclinical models of human cancer. |
| title_sort | vandetanib inhibits both vegfr 2 and egfr signalling at clinically relevant drug levels in preclinical models of human cancer |
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