Clinical update: proteasome inhibitors in hematologic malignancies.
The proteasome inhibitor bortezomib (VELCADE; formerly PS-341, LDP-341, MLN341) is a novel dipeptide boronic acid. In cell culture and xenograft models, bortezomib showed potent activity, enhanced the sensitivity of cancer cells to traditional chemotherapeutics, and appeared to overcome drug resistance. In vitro, bortzomib downregulated the NF-kappaB pathway. NF-kappaB is a transcription factor that enhances the production of growth factors (e.g., IL-6), cell-adhesion molecules, and anti-apoptotic factors, all of which contribute to the growth of the tumor cell and/or protection from apoptosis. Phase II trials have been conducted in patients with relapsed and refractory multiple myeloma (SUMMIT trial, 202 patients) or relapsed myeloma (CREST trial, n=54) using a 1.3mg/m(2) dose given twice weekly for 2 weeks (days 1, 4, 8, 11; rest days 12-21). Both trials showed responses (including complete responses) with manageable toxicities, forming the basis for an ongoing phase III trial comparing response to bortezomib versus high-dose dexamethasone.
Richardson
Paul
P
Jerome Lipper Multiple Myeloma Center, Division of Hematologic Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. paul_richardson@dfci.harvard.edu
D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D003546:Cysteine Endopeptidases / Q000494:pharmacology; D015536:Down-Regulation; D004334:Drug Administration Schedule; D019337:Hematologic Neoplasms / Q000188:drug therapy*; D006801:Humans; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D009101:Multiple Myeloma / Q000188:drug therapy*; D016328:NF-kappa B / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex; D011719:Pyrazines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D001897:Boronic Acids; D009097:Multienzyme Complexes; D016328:NF-kappa B; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex