The
proteasome is the main extralysosomal system involved in intracellular proteolysis. A number of
proteasome substrates, including
cyclins, IkappaB, and p53, are critical to cell cycle progression and apoptosis. Interruption of the degradation of these substrates through
proteasome inhibition is a novel and unique approach to the treatment of
malignancies. First-generation
proteasome inhibitors lacked usefulness because of broad specificity and irreversible binding to the
proteasome. However, the later synthesis of the
peptide boronic acid proteasome inhibitor bortezomib allowed for selective, reversible binding. Basic investigations have reported the antitumor activity of
bortezomib in a variety of hematologic and solid
tumor models and have demonstrated the ability of
bortezomib to enhance chemosensitivity and overcome cellular mechanisms of drug resistance attributable, in part, to abrogation of
NF-kappaB induction. In patients with relapsed, refractory
multiple myeloma who had received a median of six prior regimens, treatment with
bortezomib resulted in a 35% response rate (complete plus partial plus minimal response) using criteria of the European Group for Blood and Marrow
Transplantation. Encouraging activity has been demonstrated with
bortezomib in the first-line treatment of myeloma and in patients with
mantle cell lymphoma. Investigations of its utility in the treatment of patients with solid
tumors are ongoing.