Bortezomib (PS-341): a novel, first-in-class proteasome inhibitor for the treatment of multiple myeloma and other cancers.

BACKGROUND Multiple myeloma (MM) is an incurable malignancy that is diagnosed in approximately 15,000 people in the United States each year. The novel proteasome inhibitor bortezomib has shown antitumor activity in preclinical studies and has entered clinical trials, with encouraging results to date. METHODS We review and summarize preclinical work demonstrating the tumoricidal effects of proteasome inhibition, focusing on the potent and selective proteasome inhibitor bortezomib, the first such agent to progress to clinical trials. We also address the potential for bortezomib as a therapy for MM. RESULTS In preclinical studies bortezomib appears not only to have activity against MM cells, but also to downregulate protective interactions with bone marrow stromal cells and to inhibit blood vessel development. Proteasome inhibition also has been shown to interfere with protective interactions between MM cells and the bone marrow, and to restrict tumor-associated angiogenesis in preclinical models. CONCLUSIONS Proteasome inhibition is a promising new investigational avenue for cancer therapy. Bortezomib is currently available for the treatment of relapsed and refractory MM. Further trials are underway to assess the safety and efficacy of this agent in MM and a range of other cancers.