Bortezomib, a proteasome inhibitor, in cancer therapy: from concept to clinic

The proteasome is a multiprotease complex that degrades the majority of cellular proteins in a highly regulated manner. The elimination of many key proteins by the proteasome is required for essential cellular processes, including cell-cycle progression, cell survival and cellular homeostasis. Conversely, inhibition of the proteasome results in cell-cycle arrest or programmed cell death. The observation that malignant cells were more susceptible to the effects of proteasome inhibition than normal cells raised the notion of proteasome inhibition as a novel approach in cancer therapy. The present review will focus on the potential for proteasome inhibitor therapy in cancer with bortezomib (Velcade(TM); formerly known as PS-341; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA). Bortezomib is an extremely potent and selective proteasome inhibitor. In cell culture and animal models of cancer, it has :potent tumoricidal effects and sensitizes cancer cells to conventional anticancer agents. Bortezomib is the only proteasome inhibitor that has entered clinical trials in patients with cancer. With approximately 200 patients treated in phase I trials to date, bortezonnib has been generally well tolerated at doses that achieve a desired degree of proteasome inhibition. Encouraging antitumor activity has been observed. These data served as the basis for phase 11 clinical trials of bortezomib in patients with a broad range of tumors and also for clinical studies of bortezomib plus chemotherapy. The early results of combination trials show that bortezomib was generally well tolerated at doses that resulted in a good level of proteasome inhibition when combined with chemotherapy in patients. in these trials. No major overlapping toxicities have been observed to date and there was evidence of antitumor activity by many of the combinations tested in chemorefractory patients. Phase 11 or definitive phase III studies of bortezomib and chemotherapy will be considered after the completion of these initial trials and should serve to contribute to a further understanding of the potential role of bortezomib in the treatment of human malignancies in the near future.