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Abstract
The multicatalytic proteinase complex, or proteasome, is responsible for the majority of regulated eukaryotic protein turnover through the ubiquitin–proteasome pathway. Bortezomib (Velcade®, Millennium Pharmaceuticals, Inc.), the first drug specifically designed to target the proteasome, has recently entered the clinical arena. Previous preclinical studies showed that bortezomib had a unique cytotoxicity profile and that proteasome inhibition in vivo could be achieved safely with concomitant antitumor efficacy. In clinical studies, bortezomib has shown remarkable single-agent activity against relapsed and refractory multiple myeloma in both Phase I and II trials. Based on the latter, bortezomib has been approved by the US Food and Drug Administration for patients who have received two prior regimens and progressed on the second of these. Early results with bortezomib as a front-line therapy for multiple myeloma have shown a high response rate and further studies are ongoing. Preclinical studies support the possibility that modulation of proteasome function has great potential as a strategy for chemosensitization. Preliminary clinical trial results suggest that combinations using standard chemotherapeutics with bortezomib may have higher response rates in multiple myeloma than bortezomib as a single agent. Furthermore, these combinations may be able to recapture a response in patients whose disease was previously resistant to the standard agent, or bortezomib, or both. If borne out by additional studies, these results suggest that older treatment paradigms, in which drugs were used once but then discarded from the armamentarium upon disease progression, may need to be reassessed. Bortezomib may provide significant benefits to patients both alone and in combination with other agents and at several time points during the natural history of multiple myeloma.