Proteasome inhibitor, bortezomib, for myeloma and lymphoma

Abstract

Bortezomib, a boronic acid, is a potent and selective proteasome inhibitor. The 20S proteasome is an enzyme complex present in cells, and it degrades many cell-cycle control factors, signal transduction factors, transcription factors, and oncogene and anti-oncogene products, thus controlling cell proliferation, differentiation, and apoptosis. Bortezomib is a novel molecular targeting agent which was designed to exhibit an antitumor effect by selectively inhibiting the 20S proteasome. Multiple myeloma is one of the incurable B-cell malignancies that continues to relapse with current treatment modalities, and the duration to progression becomes shorter in patients who repeatedly receive chemotherapy. There are no available treatment options in which durable efficacy can be expected after relapse; therefore, an effective therapy with a novel mechanism of action has been desired. In this review article, the results of clinical trials of bortezomib for multiple myeloma, including a Japanese phase I/II and pharmacokinetic/pharmacodynamic study, and those for non-Hodgkin lymphoma, especially for mantle cell lymphoma, are summarized. In the Japanese phase I/II study of bortezomib for relapsed multiple myeloma, this agent showed remarkable efficacy, with acceptable toxicities and unique pharmacokinetic/pharmacodynamic profiles, warranting further investigations, including more relevant administration schedules.

Macroautophagy and ERK phosphorylation counteract the anti-proliferative effect of proteasome inhibitor in gastric cancer cells

“…22 Recent studies also confirm the tolerability and activity of protesome inhibitor in the treatment of solid tumors, such as prostate and lung cancers. 23,24 There are also a number of studies demonstrating the anti-cancer effects of proteasome inhibitor in gastric cancer.…”

“…[18][19][20][21] Clinically, the use of proteasome inhibitor has been approved for the treatment of multiple myeloma and mantle cell lymphoma. 22 At present, clinical trials verifying the efficacy of proteasome inhibitor for the treatment of solid tumors are in progress. 23,24 Gastric cancer is one of the leading causes of cancer-related death in the world.…”

Quick detection of overexpressed genes caused by myeloma-specific chromosomal translocations using multiplex RT-PCR

“…After introduction into the clinic of newer molecular targeting drugs such as bortezomib (10,11), thalidomide (4-6) and its relative, lenalidomide (7-9) for MM treatment, the prognosis for these patients has improved dramatically. However, the mechanisms of carcinogenesis involved in myeloma and the roles of myeloma-specific chromosomal translocation and overexpression of genes due to the translocation remain unclear (12)(13)(14)(15)(16).…”

“…Patients with MM suffer from anemia, immunodeficiency, renal insufficiency (known as myeloma kidney), hyperviscosity syndrome, hypercalcemia and bone lesions due to the presence of space-occupying malignant myeloma cells in the bone marrow, reduced production of normal immunoglobulins (Ig), deposition of malignant paraprotein, hyper-paraproteinemia produced by myeloma cells and osteolytic cytokines secreted from myeloma cells (1)(2)(3). Although prognosis of MM was relatively poor until a few years ago (average survival span was estimated at approximately three years), the introduction of newer therapeutic agents such as thalidomide (4)(5)(6), lenalidomide (7)(8)(9) and bortezomib (10,11) has improved the prognosis for MM patients.…”

Toxicological Evaluation of Occidiofungin against Mice and Human Cancer Cell Lines

“…Bortezomib was used as a comparator for toxicity against human fibroblast and was serially diluted two-fold starting at a concentration of 5 µM and ending at 2.5 nM. Bortezomib is used clinically against myeloma and lymphoma cancers in patients' refractory against other chemotherapeutics [18] [19]. The plates were then incubated at 37˚C in 5% CO 2 for 48 hours.…”