Proteasome inhibition in multiple myeloma.
The ubiquitin-proteasome pathway is the major cellular degradative system for various proteins critical for proliferation, survival and homing of myeloma cells. Bortezomib is the first specific and reversible proteasome inhibitor for clinical application in humans. Phase I studies have defined the maximum tolerated dose and suggested activity against multiple myeloma. From single agent phase II studies, a rate of at least partial responses ranging from 27% for relapsed and refractory to 38% for second-line patients was derived. In comparison with pulsed dexamethasone, bortezomib enabled a higher response rate, a longer time to myeloma progression and a longer survival for patients after one to three prior lines of therapy. Preclinical and clinical phase I studies as well as initial phase II studies combining bortezomib with conventional chemotherapy or thalidomide support the assumption that bortezomib sensitizes myeloma cells to these drugs resulting in additive or synergistic activity.
Kropff
Martin
M
Department of Medicine/Haematology and Oncology, University of Münster, Albert-Schweitzer-Str. 33, 48149 Münster, Germany.
Bisping
Guido
G
Wenning
Doris
D
Berdel
Wolfgang E
WE
Kienast
Joachim
J
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D002986:Clinical Trials as Topic; D003907:Dexamethasone / Q000627:therapeutic use; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy*; D011480:Protease Inhibitors / Q000627:therapeutic use*; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000627:therapeutic use*; D012008:Recurrence; D025801:Ubiquitin / Q000378:metabolism
D000970:Antineoplastic Agents; D001897:Boronic Acids; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D025801:Ubiquitin; D000069286:Bortezomib; D003907:Dexamethasone