Journal Article

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

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

2013

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 692/699/67/1059 / 692/699/67/589/1588/1351 / Angiogenesis / Angiogenesis Inhibitors - administration & dosage / Angiogenesis Inhibitors - pharmacology / Angiogenesis Inhibitors - therapeutic use / Animals / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cancer therapies / Carcinoma, Renal Cell - drug therapy / Celecoxib / Cell Line, Tumor / Cell Proliferation - drug effects / Cyclooxygenase 2 - metabolism / Cyclooxygenase 2 Inhibitors - pharmacology / Cyclooxygenase 2 Inhibitors - therapeutic use / Drug Resistance / Epidemiology / Female / Humans / Hypoxia / Indoles - administration & dosage / Indoles - pharmacology / Indoles - therapeutic use / Interferon / Kidney cancer / Kidney Neoplasms - drug therapy / Kidneys / Kinases / Medical sciences / Metastasis / Mice / Molecular Medicine / Nephrology. Urinary tract diseases / Oncology / Patients / Pyrazoles - pharmacology / Pyrazoles - therapeutic use / Pyrroles - administration & dosage / Pyrroles - pharmacology / Pyrroles - therapeutic use / Receptors, Vascular Endothelial Growth Factor - antagonists & inhibitors / Response rates / Sulfonamides - pharmacology / Sulfonamides - therapeutic use / Sunitinib / Translational Therapeutics / Tumors / Tumors of the urinary system / Xenograft Model Antitumor Assays