Proteasome inhibition in hematologic malignancies.
Hematologic malignancies, including multiple myeloma (MM), will account for more than 100,000 new cases of cancer and over 57,000 deaths in the United States in 2003. Treatment of MM is a serious challenge, because despite a variety of available therapies, median survival is short. A new therapeutic area focuses on inhibiting the activity of the proteasome, a 26S protease complex involved in cell cycle regulation, cell adhesion, inflammation, and protein turnover. The novel proteasome inhibitor, bortezomib (Velcade), was recently approved for use in patients with refractory and relapsed MM and to date is the only proteasome inhibitor to have entered clinical trials. Bortezomib has demonstrated activity with manageable toxicity in a variety of hematologic malignancies in addition to MM, including leukemia and non-Hodgkin's lymphoma. This article reviews clinical information on bortezomib in hematologic malignancies both as monotherapy and in combination with dexamethasone. Preliminary reports of bortezomib in combination with Doxil (pegylated liposomal doxorubicin), melphalan, and thalidomide are discussed, and current trials are described. Available data suggest that bortezomib will be useful in the treatment of a variety of hematologic malignancies.
Richardson
Paul G
PG
Dana-Farber Cancer, Institute, Harvard Medical School, Boston, Massachusetts, USA. Paul_Richardson@dfci.harvard.edu
Hideshima
Teru
T
Mitsiades
Constantine
C
Anderson
Kenneth
K
D001247:Asthenia / Q000139:chemically induced; D001897:Boronic Acids / Q000009:adverse effects / Q000627:therapeutic use; D000069286:Bortezomib; D003546:Cysteine Endopeptidases; D003967:Diarrhea / Q000139:chemically induced; D019337:Hematologic Neoplasms / Q000188:drug therapy*; D006801:Humans; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D009325:Nausea / Q000139:chemically induced; D011480:Protease Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D046988:Proteasome Endopeptidase Complex; D011719:Pyrazines / Q000009:adverse effects / Q000627:therapeutic use; D016019:Survival Analysis; D016896:Treatment Outcome
D001897:Boronic Acids; D009097:Multienzyme Complexes; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex