The proteasome: a novel target for anticancer therapy.
The proteasome is an ubiquituous enzyme complex that plays a critical role in the degradation of many proteins involved in cell cycle regulation, apoptosis and angiogenesis. Since these pathways are fundamental for cell survival and proliferation, particularly in cancer cells, the inhibition of proteasome is an attractive potential anticancer therapy. Bortezomib (Velcade, formerly PS-341) is an extremely potent and selective proteasome inhibitor that shows strong activity in in vitro and in vivo laboratory studies against many solid and hematologic tumor types. Moreover, bortezomib, mainly by inhibition of the NF-kappaB pathway, has a chemosensitizing effect when administered together with other antitumoral drugs. Clinical phase I trials, showed good tolerance of bortezomib at doses that achieved a desired degree of proteasome inhibition. Phase II studies showed high response rates in refractory multiple myeloma patients, which led to the accelerated approval of bortezomib by the Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) for this indication. A phase III trial comparing bortezomib to dexamethasone in refractory/relapsed multiple myeloma patients had to be halted due to a survival advantage in the bortezomib arm. Additional studies are focusing in the potential benefit of bortezomib in newly diagnosed multiple myeloma patients. In other solid and hematological malignancies, phase II studies with bortezomib alone or in combination are ongoing with encouraging results, particularly in lung cancer and lymphoma.
Montagut
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Medical Oncology Department & Experimental Cancer Therapeutics Unit, URTEC, Hospital del Mar, Barcelona, Spain.
Rovira
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Albanell
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D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001897:Boronic Acids / Q000494:pharmacology / Q000627:therapeutic use; D000069286:Bortezomib; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002986:Clinical Trials as Topic; D003907:Dexamethasone / Q000627:therapeutic use; D015195:Drug Design; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy / Q000201:enzymology; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011480:Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D061988:Proteasome Inhibitors; D011499:Protein Processing, Post-Translational; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D025801:Ubiquitin / Q000502:physiology
D000970:Antineoplastic Agents; D001897:Boronic Acids; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D025801:Ubiquitin; D000069286:Bortezomib; D003907:Dexamethasone; D046988:Proteasome Endopeptidase Complex