Proteasome inhibitors in the treatment of B-cell malignancies.
The proteasome, which plays a pivotal role in the control of many cell cycle-regulatory processes, has become the focus of new approaches to the treatment of cancer, including B-cell malignancies, and the first proteasome inhibitor, bortezomib (VELCADE; formerly PS-341), has entered clinical trials. The proteasome controls the stability of numerous proteins that regulate progression through the cell cycle and apoptosis, such as cyclins, cyclin-dependent kinases, tumor suppressors, and the nuclear factor-kB. By altering the stability or activity of these proteins, proteasome inhibitors sensitize malignant cells to apoptosis. Bortezomib is a dipeptidyl boronic acid proteasome inhibitor that effectively and specifically inhibits proteasome activity. In preclinical studies, bortezomib and other proteasome inhibitors have shown activity against a variety of B-cell malignancies, including multiple myeloma, diffuse large B-cell lymphoma, mantle cell lymphoma, and Hodgkin's lymphoma. These agents can induce apoptosis and sensitize tumor cells to radiation or chemotherapy. Based on these findings, phase I clinical trials were conducted with bortezomib in various solid and hematologic malignancies. In these studies, bortezomib was generally well tolerated with manageable toxicities. Phase II trials have been initiated for relapsed and refractory multiple myeloma, refractory chronic lymphocytic leukemia, and non-Hodgkin's lymphoma. Preliminary data from the multiple myeloma phase II study indicate that a significant number of patients responded to therapy or exhibited stable disease and that the drug had manageable toxicities. These findings, along with extensive preclinical data, suggest that bortezomib and other proteasome inhibitors may have far-reaching potential in the treatment of various cancers, including B-cell malignancies.
Schenkein
David
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Millennium Pharmaceuticals, Inc, Cambridge, MA 02139, USA. schenkein@mpi.com
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D001897:Boronic Acids / Q000627:therapeutic use; D000069286:Bortezomib; D018797:Cell Cycle Proteins / Q000378:metabolism; D002986:Clinical Trials as Topic; D004354:Drug Screening Assays, Antitumor; D004798:Enzymes / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D006689:Hodgkin Disease / Q000188:drug therapy / Q000201:enzymology; D006801:Humans; D015448:Leukemia, B-Cell / Q000188:drug therapy* / Q000201:enzymology; D007976:Leupeptins / Q000627:therapeutic use; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000201:enzymology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000201:enzymology; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy / Q000201:enzymology; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy / Q000201:enzymology; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D015513:Oncogene Proteins / Q000378:metabolism; D010447:Peptide Hydrolases / Q000502:physiology* / Q000648:ultrastructure; D011480:Protease Inhibitors / Q000627:therapeutic use*; D046988:Proteasome Endopeptidase Complex; D011719:Pyrazines / Q000627:therapeutic use; D013379:Substrate Specificity; D014157:Transcription Factors / Q000378:metabolism; D016896:Treatment Outcome
D001897:Boronic Acids; D018797:Cell Cycle Proteins; D004798:Enzymes; D007976:Leupeptins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D015513:Oncogene Proteins; D011480:Protease Inhibitors; D011719:Pyrazines; D014157:Transcription Factors; C067713:lactacystin; D000069286:Bortezomib; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D000111:Acetylcysteine