Update on the proteasome inhibitor bortezomib in hematologic malignancies.
The ubiquitin-proteasome system plays a crucial role in eukaryotic cells in maintaining protein homeostasis. Through the disruption of a variety of pathways and cell cycle checkpoints, proteasome inhibition leads to apoptosis and in experimental models can overcome chemoresistance. Bortezomib is the first of its class of proteasome inhibitors tested in humans that showed promising activity in several tumor types, and especially in hematologic malignancies, in phase I studies. The remarkable results obtained in phase II studies in multiple myeloma (MM) led to its fast-track approval by the US Food and Drug Administration in May 2003 for relapsed MM. More recent observation also revealed promising activity in non-Hodgkin's lymphoma. This review will explore the rationale for the use of bortezomib in hematologic malignancies as well as provide an update on the results of ongoing studies and future directions for the use of this new agent in hematologic malignancies. The mechanism of action of bortezomib and its nonoverlapping toxicity profile make it a very appealing drug for combination with other chemotherapeutic or biologic agents. Bortezomib represents an excellent example of how progress in understanding the biology of cancer cells can impact clinical practice and lead toward a new era of rational therapeutics.
Goy
Andre
A
Department of Lymphoma/Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. ahgoy@mdanderson.org
Gilles
Frederic
F
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death; D002986:Clinical Trials as Topic; D003546:Cysteine Endopeptidases / Q000502:physiology; D019337:Hematologic Neoplasms / Q000188:drug therapy*; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000502:physiology; D009101:Multiple Myeloma / Q000188:drug therapy; D046988:Proteasome Endopeptidase Complex; D011719:Pyrazines / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D001897:Boronic Acids; D009097:Multienzyme Complexes; D011719:Pyrazines; D000069286:Bortezomib; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex