%0 Journal Article
%T Bortezomib in combination with celecoxib in patients with advanced solid tumors: a phase I trial
%A John Hayslip
%A Uzair Chaudhary
%A Mark Green
%A Mario Meyer
%A Steven Dunder
%A Carol Sherman
%A Shanta Salzer
%A Andrew Kraft
%A Alberto J Montero
%J BMC Cancer
%D 2007
%I BioMed Central
%R 10.1186/1471-2407-7-221
%X Patients 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.No 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.The 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.NCT00290680.The ubiquitin-proteasome pathway plays an important role in cell cycle regulation, neoplastic growth, and metastasis [1,2]. At the heart of this degradative pathway is the 26S proteasome, an adenosine triphosphate-dependent protease. The 26S proteasome consists of a core 20S particle, which contains the catalytic proteinase functions, symmetrically bound to two copies of the regulatory 19S particle. Proteolytic removal of damaged or misfolded ubiquitinated proteins is an important part of the homeostatic function of the 26S proteasome. Additionally, 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 mediated degradation. p53 is required for the transcription of a number of genes involved in cell cycle control and DNA synthesis. p53 also plays an important role in apoptosis induced by cellular damage [3]. Cyclins and the cyclin-dependent kinase inhi
%U http://www.biomedcentral.com/1471-2407/7/221