Monitoring response to anti-angiogenic mTOR inhibitor therapy in vivo using (111)In-bevacizumab.
<p>BACKGROUND: The ability to image vascular endothelial growth factor (VEGF) could enable prospective, non-invasive monitoring of patients receiving anti-angiogenic therapy. This study investigates the specificity and pharmacokinetics of (111)In-bevacizumab binding to VEGF and its use for ass...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
BioMed Central
2017
|
| _version_ | 1797084135771078656 |
|---|---|
| author | Patel, N Able, S Allen, D Fokas, E Cornelissen, B Gleeson, F Harris, A Vallis, K |
| author_facet | Patel, N Able, S Allen, D Fokas, E Cornelissen, B Gleeson, F Harris, A Vallis, K |
| author_sort | Patel, N |
| collection | OXFORD |
| description | <p>BACKGROUND: The ability to image vascular endothelial growth factor (VEGF) could enable prospective, non-invasive monitoring of patients receiving anti-angiogenic therapy. This study investigates the specificity and pharmacokinetics of (111)In-bevacizumab binding to VEGF and its use for assessing response to anti-angiogenic therapy with rapamycin. Specificity of (111)In-bevacizumab binding to VEGF was tested in vitro with unmodified radiolabelled bevacizumab in competitive inhibition assays. Uptake of (111)In-bevacizumab in BALB/c nude mice bearing tumours with different amounts of VEGF expression was compared to that of isotype-matched control antibody ((111)In-IgG1κ) with an excess of unlabelled bevacizumab. Intratumoural VEGF was evaluated using ELISA and Western blot analysis. The effect of anti-angiogenesis therapy was tested by measuring tumour uptake of (111)In-bevacizumab in comparison to (111)In-IgG1κ following administration of rapamycin to mice bearing FaDu xenografts. Uptake was measured using gamma counting of ex vivo tumours and effect on vasculature by using anti-CD31 microscopy.</p><p> RESULTS: Specific uptake of (111)In-bevacizumab in VEGF-expressing tumours was observed. Rapamycin led to tumour growth delay associated with increased relative vessel size (8.5 to 10.3, P = 0.045) and decreased mean relative vessel density (0.27 to 0.22, P = 0.0015). Rapamycin treatment increased tumour uptake of (111)In-bevacizumab (68%) but not (111)In-IgGκ and corresponded with increased intratumoural VEGF165.</p><p> CONCLUSIONS: (111)In-bevacizumab accumulates specifically in VEGF-expressing tumours, and changes after rapamycin therapy reflect changes in VEGF expression. Antagonism of mTOR may increase VEGF in vivo, and this new finding provides the basis to consider combination studies blocking both pathways and a way to monitor effects.</p> |
| first_indexed | 2024-03-07T01:51:07Z |
| format | Journal article |
| id | oxford-uuid:9a1e6204-da92-4032-8d61-7b8679c09637 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:51:07Z |
| publishDate | 2017 |
| publisher | BioMed Central |
| record_format | dspace |
| spelling | oxford-uuid:9a1e6204-da92-4032-8d61-7b8679c096372022-03-27T00:19:11ZMonitoring response to anti-angiogenic mTOR inhibitor therapy in vivo using (111)In-bevacizumab.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:9a1e6204-da92-4032-8d61-7b8679c09637EnglishSymplectic Elements at OxfordBioMed Central2017Patel, NAble, SAllen, DFokas, ECornelissen, BGleeson, FHarris, AVallis, K<p>BACKGROUND: The ability to image vascular endothelial growth factor (VEGF) could enable prospective, non-invasive monitoring of patients receiving anti-angiogenic therapy. This study investigates the specificity and pharmacokinetics of (111)In-bevacizumab binding to VEGF and its use for assessing response to anti-angiogenic therapy with rapamycin. Specificity of (111)In-bevacizumab binding to VEGF was tested in vitro with unmodified radiolabelled bevacizumab in competitive inhibition assays. Uptake of (111)In-bevacizumab in BALB/c nude mice bearing tumours with different amounts of VEGF expression was compared to that of isotype-matched control antibody ((111)In-IgG1κ) with an excess of unlabelled bevacizumab. Intratumoural VEGF was evaluated using ELISA and Western blot analysis. The effect of anti-angiogenesis therapy was tested by measuring tumour uptake of (111)In-bevacizumab in comparison to (111)In-IgG1κ following administration of rapamycin to mice bearing FaDu xenografts. Uptake was measured using gamma counting of ex vivo tumours and effect on vasculature by using anti-CD31 microscopy.</p><p> RESULTS: Specific uptake of (111)In-bevacizumab in VEGF-expressing tumours was observed. Rapamycin led to tumour growth delay associated with increased relative vessel size (8.5 to 10.3, P = 0.045) and decreased mean relative vessel density (0.27 to 0.22, P = 0.0015). Rapamycin treatment increased tumour uptake of (111)In-bevacizumab (68%) but not (111)In-IgGκ and corresponded with increased intratumoural VEGF165.</p><p> CONCLUSIONS: (111)In-bevacizumab accumulates specifically in VEGF-expressing tumours, and changes after rapamycin therapy reflect changes in VEGF expression. Antagonism of mTOR may increase VEGF in vivo, and this new finding provides the basis to consider combination studies blocking both pathways and a way to monitor effects.</p> |
| spellingShingle | Patel, N Able, S Allen, D Fokas, E Cornelissen, B Gleeson, F Harris, A Vallis, K Monitoring response to anti-angiogenic mTOR inhibitor therapy in vivo using (111)In-bevacizumab. |
| title | Monitoring response to anti-angiogenic mTOR inhibitor therapy in vivo using (111)In-bevacizumab. |
| title_full | Monitoring response to anti-angiogenic mTOR inhibitor therapy in vivo using (111)In-bevacizumab. |
| title_fullStr | Monitoring response to anti-angiogenic mTOR inhibitor therapy in vivo using (111)In-bevacizumab. |
| title_full_unstemmed | Monitoring response to anti-angiogenic mTOR inhibitor therapy in vivo using (111)In-bevacizumab. |
| title_short | Monitoring response to anti-angiogenic mTOR inhibitor therapy in vivo using (111)In-bevacizumab. |
| title_sort | monitoring response to anti angiogenic mtor inhibitor therapy in vivo using 111 in bevacizumab |
| work_keys_str_mv | AT pateln monitoringresponsetoantiangiogenicmtorinhibitortherapyinvivousing111inbevacizumab AT ables monitoringresponsetoantiangiogenicmtorinhibitortherapyinvivousing111inbevacizumab AT allend monitoringresponsetoantiangiogenicmtorinhibitortherapyinvivousing111inbevacizumab AT fokase monitoringresponsetoantiangiogenicmtorinhibitortherapyinvivousing111inbevacizumab AT cornelissenb monitoringresponsetoantiangiogenicmtorinhibitortherapyinvivousing111inbevacizumab AT gleesonf monitoringresponsetoantiangiogenicmtorinhibitortherapyinvivousing111inbevacizumab AT harrisa monitoringresponsetoantiangiogenicmtorinhibitortherapyinvivousing111inbevacizumab AT vallisk monitoringresponsetoantiangiogenicmtorinhibitortherapyinvivousing111inbevacizumab |