Bortezomib (Velcade)--a new therapeutic strategy for patients with refractory multiple myeloma.
Proteasome inhibitors are emerging as a promising class of anti-cancer therapeutic agents. The first of this new class of drugs with a clinical significance, bortezomib (PS 341, Velcade), is a modified dipeptidyl boronic acid. Bortezomib reduces the NF-kappaB translocation / transcription and blocks the drug-related signalling pathways critical to basic vital functions of myeloma cells. Bortezomib induces apoptosis by releasing cytochrome C from mitochondria and by activating caspase-9 and Jun-kinases (JNK) and the Fas-caspase-8-dependent apoptotic pathway. Bortezomib has been reported to down-regulate cytokine-induced expression of VCAM-1, a major ligand on bone marrow stromal cells for VLA-4; it inhibits the heterotypic adherence between the myeloma cells and stromal cells and blocks the signalling pathways of resistance to apoptosis. The drug has been shown experimentally to inhibit the IL-6-induced proliferation of myeloma cells; it demonstrates synergy with dexamethasone and inhibits angiogenesis. Phase II/ III clinical studies with Velcade have shown an overall therapeutic response rate of 35% in refractory, relapsed myeloma patients (Bladé criteria). These surprisingly good results, the drug's good tolerance and controllable side effects provide a solid base for further studies on bortezomib, including studies on the drug used as front line therapy.
Goranov
Stefcho E
SE
Clinic of Hematology, University hospital "St George", Plovdiv, 15A Vassil Aprilov St., 4002 Plovdiv, Bulgaria.
Goranova-Marinova
Veselina S
VS
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002986:Clinical Trials as Topic; D006801:Humans; D015394:Molecular Structure; D009101:Multiple Myeloma / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D011480:Protease Inhibitors / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001897:Boronic Acids; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib