Discovery, Development, and clinical applications of bortezomib.

Proteasome inhibition is a novel, targeted approach in cancer therapy. Both natural and synthetic proteasome inhibitors selectively penetrate cancer cells, disrupting the orderly destruction of key regulatory proteins involved in tumorigenesis and metastasis. Disrupting the orderly destruction of regulatory proteins causes an imbalance of these proteins within the cell, which interferes with the systematic activation of signaling pathways required to maintain tumor cell growth and survival; therefore, cellular replication is inhibited and apoptosis ensues. Bortezomib (PS-341, Velcade), the first proteasome inhibitor evaluated in human clinical trials, has been approved by the US Food and Drug Administration for use in patients with refractory or relapsed multiple myeloma. Preclinical study results show that bortezomib suppresses tumor cell growth, induces apoptosis, overcomes resistance to standard chemotherapy agents and radiation therapy, and inhibits angiogenesis. Phase I study results established the antitumor activity of bortezomib, administered alone or in combination with standard chemotherapy agents, in patients with advanced hematologic malignancies or solid tumors, usually without additive toxicities. The results of phase II studies further supported the antitumor activity of bortezomib in patients with refractory or relapsed multiple myeloma and non-Hodgkin's lymphoma; less impressive results were observed in patients with stage IV renal cell cancer. Studies evaluating bortezomib in earlier stages of multiple myeloma, including first-line therapy, are under way. Evidence suggests that certain prognostic factors, such as older age and bone marrow containing more than 50% plasma cells, may be useful in predicting response and survival time in multiple myeloma patients receiving bortezomib. Further studies of bortezomib are needed to establish its full spectrum of activity, the ideal regimens for various tumor types, and clinically useful prognostic indicators that predict successful outcomes.