Cox-2 inhibition enhances the activity of sunitinib in human renal cell carcinoma xenografts View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2013-01-15

AUTHORS

X Wang, L Zhang, A O'Neill, B Bahamon, D C Alsop, J W Mier, S N Goldberg, S Signoretti, M B Atkins, C G Wood, R S Bhatt

ABSTRACT

Background:Sunitinib (Su), a tyrosine kinase inhibitor of VEGFR, is effective at producing tumour response in clear cell renal cell carcinoma (cRCC), but resistance to therapy is inevitable. As COX-2 is a known mediator of tumour growth, we explored the potential benefit of COX-2 inhibition in combination with VEGFR inhibition in attempts at delaying tumour progression on Su.Methods:COX-2 expression was compared with areas of hypoxia in tumours that progressed on Su vs untreated tumours. Mice bearing human cRCC xenografts were treated with Su and the COX-2 inhibitor, celecoxib, and the effects on tumour growth were assessed. Sequential vs concurrent regimens were compared.Results:COX-2 expression was increased in cRCC xenografts in areas of tumour hypoxia. The combination of Su and celecoxib achieved longer times to tumour progression compared to treatment with either agent alone or to untreated control animals in four models. This effect was seen with concurrent but not with sequential therapy.Conclusion:COX-2 inhibition can extend the effectiveness of VEGFR inhibition. This effect is dependent on the timing of therapy. Clinical trials combining Su and COX-2 inhibitors should be considered as a means delaying time to progression on sunitinib in patients with metastatic cRCC. More... »

PAGES

319-326

Journal

TITLE

British Journal of Cancer

ISSUE

2

VOLUME

108

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/bjc.2012.591

DOI

http://dx.doi.org/10.1038/bjc.2012.591

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1045309529

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/23322198


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34 schema:description Background:Sunitinib (Su), a tyrosine kinase inhibitor of VEGFR, is effective at producing tumour response in clear cell renal cell carcinoma (cRCC), but resistance to therapy is inevitable. As COX-2 is a known mediator of tumour growth, we explored the potential benefit of COX-2 inhibition in combination with VEGFR inhibition in attempts at delaying tumour progression on Su.Methods:COX-2 expression was compared with areas of hypoxia in tumours that progressed on Su vs untreated tumours. Mice bearing human cRCC xenografts were treated with Su and the COX-2 inhibitor, celecoxib, and the effects on tumour growth were assessed. Sequential vs concurrent regimens were compared.Results:COX-2 expression was increased in cRCC xenografts in areas of tumour hypoxia. The combination of Su and celecoxib achieved longer times to tumour progression compared to treatment with either agent alone or to untreated control animals in four models. This effect was seen with concurrent but not with sequential therapy.Conclusion:COX-2 inhibition can extend the effectiveness of VEGFR inhibition. This effect is dependent on the timing of therapy. Clinical trials combining Su and COX-2 inhibitors should be considered as a means delaying time to progression on sunitinib in patients with metastatic cRCC.
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