Bortezomib for multiple myeloma.
The ubquitin-proteasome pathway is a key regulator of homeostasis within cells, degrading misfolded or redundant proteins, and also those involved in mediating transcription, cell-cycle progression and apoptosis. Inhibition of the 26S proteasome results in accumulation of such proteins and ultimately leads to cell death. Malignant cells are more susceptible to proteasome inhibition due to their higher proliferation rates, protein production and their dependence on anti-apoptotic molecules for cell survival. Bortezomib has recently gained European Commission approval for the treatment of relapsed multiple myeloma on the basis of clinical trials demonstrating its efficacy, tolerability and superiority to high-dose dexamethasone. Preclinical data demonstrates the ability to synergise with other chemotherapeutic agents and overcome drug resistance, and hence combination studies are underway. This review describes the pharmacology, toxicity, preclinical and clinical activity of bortezomib, predominantly in the setting of multiple myeloma.
Popat
Rakesh
R
Department of Haematology, St. Bartholomew's Hospital, West Smithfield, London, EC1A 7BE, UK. r.popat@qmul.ac.uk
Joel
Simon
S
Oakervee
Heather
H
Cavenagh
Jamie
J
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000069286:Bortezomib; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology; D011358:Product Surveillance, Postmarketing; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic
D000970:Antineoplastic Agents; D001897:Boronic Acids; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex