Bortezomib (PS-341)
Bortezomib (PS-341)
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.
The maintenance of cellular homeostasis and the ability of cells to respond to their environment depend on the orderly degradation of key regulatory proteins and their inhibitors. The 26S proteasome plays an essential role in the targeted degradation of such proteins and is therefore involved in the activation and inactivation of many cellular processes. Indeed, studies using proteasome inhibitors have shown that the proteasome is responsible for the elimination of more than 80% of all cellular proteins. Specific targets of the proteasome include cell-cycle proteins, tumor suppressors, and transcription factors, as well as mutant and damaged proteins.
The proteasome has been identified as an excellent target for cancer therapy because of its critical metabolic function. Importantly, preclinical research has shown that cancer cells seem to be more sensitive to the proapoptotic effects of proteasome inhibition than are normal cells. It has also been shown that protea-some inhibition enhances the sensitivity of cancer cells to traditional anticancer agents in both in vitro and in vivo preclinical studies.
This review summarizes preclinical work demonstrating the tumoricidal effects of proteasome inhibition, focusing on the potent and selective proteasome inhibitor bortezomib (formerly PS-341, LDP-341, MLN341), the first such agent to progress to clinical trials. In particular, we address the potential for bortezomib as a therapy for multiple myeloma (MM), an incurable malignancy that is diagnosed in approximately 15,000 people in the United States each year. A phase I study of bortezomib in hematologic malignancies established a dose schedule for additional clinical studies with a number of responses (including one complete remission) in patients with MM. This, combined with preclinical data of bortezomib activity in MM cell lines, drug-resistant cell lines, and patient-derived tumor lines, prompted the initiation of two phase II trials of bortezomib in patients with MM, both of which are now complete. Results from one of these trials are promising and show that heavily treated relapsed and refractory patients from the first cohort in this trial experienced manageable toxicities with encouraging response rates. A phase III trial is now underway in patients with relapsed MM, and bortezomib is also currently in single-agent and combination phase I studies in advanced solid tumors.
Abstract and Introduction
Abstract
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.
Introduction
The maintenance of cellular homeostasis and the ability of cells to respond to their environment depend on the orderly degradation of key regulatory proteins and their inhibitors. The 26S proteasome plays an essential role in the targeted degradation of such proteins and is therefore involved in the activation and inactivation of many cellular processes. Indeed, studies using proteasome inhibitors have shown that the proteasome is responsible for the elimination of more than 80% of all cellular proteins. Specific targets of the proteasome include cell-cycle proteins, tumor suppressors, and transcription factors, as well as mutant and damaged proteins.
The proteasome has been identified as an excellent target for cancer therapy because of its critical metabolic function. Importantly, preclinical research has shown that cancer cells seem to be more sensitive to the proapoptotic effects of proteasome inhibition than are normal cells. It has also been shown that protea-some inhibition enhances the sensitivity of cancer cells to traditional anticancer agents in both in vitro and in vivo preclinical studies.
This review summarizes preclinical work demonstrating the tumoricidal effects of proteasome inhibition, focusing on the potent and selective proteasome inhibitor bortezomib (formerly PS-341, LDP-341, MLN341), the first such agent to progress to clinical trials. In particular, we address the potential for bortezomib as a therapy for multiple myeloma (MM), an incurable malignancy that is diagnosed in approximately 15,000 people in the United States each year. A phase I study of bortezomib in hematologic malignancies established a dose schedule for additional clinical studies with a number of responses (including one complete remission) in patients with MM. This, combined with preclinical data of bortezomib activity in MM cell lines, drug-resistant cell lines, and patient-derived tumor lines, prompted the initiation of two phase II trials of bortezomib in patients with MM, both of which are now complete. Results from one of these trials are promising and show that heavily treated relapsed and refractory patients from the first cohort in this trial experienced manageable toxicities with encouraging response rates. A phase III trial is now underway in patients with relapsed MM, and bortezomib is also currently in single-agent and combination phase I studies in advanced solid tumors.
