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Proteasome inhibition and its therapeutic potential in multiple myeloma.

Chari A, Mazumder A, Jagannath S - Biologics (2010)

Bottom Line: Due to an unmet clinical need for treatment, the first in class proteasome inhibitor, bortezomib, moved from drug discovery to FDA approval in multiple myeloma in an unprecedented eight years.In the wake of this rapid approval arose a large number of questions about its mechanism of action and toxicity as well as its ultimate role in the treatment of this disease.We conclude with our current understanding of the mechanism of action of this agent and a discussion of the novel proteasome inhibitors under development, as it will be progress in these areas that will ultimately determine the true potential of proteasome inhibition in myeloma.

View Article: PubMed Central - PubMed

Affiliation: Mount Sinai School of Medicine, New York, NY, USA.

ABSTRACT
Due to an unmet clinical need for treatment, the first in class proteasome inhibitor, bortezomib, moved from drug discovery to FDA approval in multiple myeloma in an unprecedented eight years. In the wake of this rapid approval arose a large number of questions about its mechanism of action and toxicity as well as its ultimate role in the treatment of this disease. In this article, we briefly review the preclinical and clinical development of the drug as the underpinning for a systematic review of the large number of clinical trials that are beginning to shed some light on the full therapeutic potential of bortezomib in myeloma. We conclude with our current understanding of the mechanism of action of this agent and a discussion of the novel proteasome inhibitors under development, as it will be progress in these areas that will ultimately determine the true potential of proteasome inhibition in myeloma.

No MeSH data available.


Related in: MedlinePlus

Kinetics of thrombocytopenia associated with bortezomib therapy. Reproduced with permission from Lonial S, Waller EK, Richardson PG, et al. Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma. Blood. 2005;106(12):3777–3784.80 Copyright © 2005 American Society of Hematololgy.
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f10-btt-4-273: Kinetics of thrombocytopenia associated with bortezomib therapy. Reproduced with permission from Lonial S, Waller EK, Richardson PG, et al. Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma. Blood. 2005;106(12):3777–3784.80 Copyright © 2005 American Society of Hematololgy.

Mentions: The thrombocytopenia associated with bortezomib therapy has been well characterized. The platelet count drops during Days 1 to 14 and then rapidly recovers to baseline level during Days 15 to 21 (Figure 10). The mean reduction in relapsed/refractory patients is 60% and appears to be independent of the baseline platelet count, the concentration of the monoclonal protein, and bone marrow plasmacytosis. Murine studies demonstrated no cytotoxic effects on megakaryocytes, thus suggesting a mechanism distinct from traditional myelosuppressive chemotherapeutic agents.80


Proteasome inhibition and its therapeutic potential in multiple myeloma.

Chari A, Mazumder A, Jagannath S - Biologics (2010)

Kinetics of thrombocytopenia associated with bortezomib therapy. Reproduced with permission from Lonial S, Waller EK, Richardson PG, et al. Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma. Blood. 2005;106(12):3777–3784.80 Copyright © 2005 American Society of Hematololgy.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2990320&req=5

f10-btt-4-273: Kinetics of thrombocytopenia associated with bortezomib therapy. Reproduced with permission from Lonial S, Waller EK, Richardson PG, et al. Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma. Blood. 2005;106(12):3777–3784.80 Copyright © 2005 American Society of Hematololgy.
Mentions: The thrombocytopenia associated with bortezomib therapy has been well characterized. The platelet count drops during Days 1 to 14 and then rapidly recovers to baseline level during Days 15 to 21 (Figure 10). The mean reduction in relapsed/refractory patients is 60% and appears to be independent of the baseline platelet count, the concentration of the monoclonal protein, and bone marrow plasmacytosis. Murine studies demonstrated no cytotoxic effects on megakaryocytes, thus suggesting a mechanism distinct from traditional myelosuppressive chemotherapeutic agents.80

Bottom Line: Due to an unmet clinical need for treatment, the first in class proteasome inhibitor, bortezomib, moved from drug discovery to FDA approval in multiple myeloma in an unprecedented eight years.In the wake of this rapid approval arose a large number of questions about its mechanism of action and toxicity as well as its ultimate role in the treatment of this disease.We conclude with our current understanding of the mechanism of action of this agent and a discussion of the novel proteasome inhibitors under development, as it will be progress in these areas that will ultimately determine the true potential of proteasome inhibition in myeloma.

View Article: PubMed Central - PubMed

Affiliation: Mount Sinai School of Medicine, New York, NY, USA.

ABSTRACT
Due to an unmet clinical need for treatment, the first in class proteasome inhibitor, bortezomib, moved from drug discovery to FDA approval in multiple myeloma in an unprecedented eight years. In the wake of this rapid approval arose a large number of questions about its mechanism of action and toxicity as well as its ultimate role in the treatment of this disease. In this article, we briefly review the preclinical and clinical development of the drug as the underpinning for a systematic review of the large number of clinical trials that are beginning to shed some light on the full therapeutic potential of bortezomib in myeloma. We conclude with our current understanding of the mechanism of action of this agent and a discussion of the novel proteasome inhibitors under development, as it will be progress in these areas that will ultimately determine the true potential of proteasome inhibition in myeloma.

No MeSH data available.


Related in: MedlinePlus