Abstract
BackgroundCOX-2 inhibitors, such as celecoxib, and ubiquitin-proteasome pathway inhibitors, such as bortezomib, can down-regulate NF-κB, a transcription factor implicated in tumor growth. The objective of this study was to determine the maximum tolerated dose and dose-limiting toxicities of bortezomib in combination with celecoxib in patients with advanced solid tumors.MethodsPatients received escalating doses of bortezomib either on a weekly schedule (days 1, 8, 15, 22, and 29 repeated every 42 days) or on a twice-weekly administration schedule (days 1, 4, 8, and 11 repeated every 21 days), in combination with escalating doses of celecoxib twice daily throughout the study period from 200 mg to 400 mg twice daily.ResultsNo dose-limiting toxicity was observed during the study period. Two patients had stable disease lasting for four and five months each, and sixteen patients developed progressive disease.ConclusionThe combination of bortezomib and celecoxib was well tolerated, without dose limiting toxicities observed throughout the dosing ranges tested, and will be studied further at the highest dose levels investigated.Trial registration numberNCT00290680.
Highlights
COX-2 inhibitors, such as celecoxib, and ubiquitin-proteasome pathway inhibitors, such as bortezomib, can down-regulate Nuclear factor-κB (NF-κB), a transcription factor implicated in tumor growth
The ubiquitin-proteasome pathway is responsible for the ordered degradation of several regulatory proteins necessary for cells to progress through the cell cycle
The combination of bortezomib and celecoxib was well tolerated across the dose levels investigated
Summary
COX-2 inhibitors, such as celecoxib, and ubiquitin-proteasome pathway inhibitors, such as bortezomib, can down-regulate NF-κB, a transcription factor implicated in tumor growth. The ubiquitin-proteasome pathway plays an important role in cell cycle regulation, neoplastic growth, and metastasis [1,2]. Proteolytic removal of damaged or misfolded ubiquitinated proteins is an important part of the homeostatic function of the 26S proteasome. The 26S proteasome is vital in degrading regulatory proteins that govern cell cycle, transcription factor activation, cell trafficking, and apoptosis. The ubiquitin-proteasome pathway is responsible for the ordered degradation of several regulatory proteins necessary for cells to progress through the cell cycle. The tumor suppressor p53, which acts as a negative regulator of cell growth, is one example of targeted ubiquitin-proteasome (page number not for citation purposes)
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