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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

The addition of bortezomib to chemotherapeutic agents results in synergistic cytotoxicity in multiple myeloma cells: A) Melphalan-resistant cell line (RPMI8228/LR) treated for 24 hours with varying concentrations of melphalan alone or in combination with a noncytotoxic dose of bortezomib; B) Doxorubicin-resistant cell line (U266/dox4) treated for 24 hours with varying concentrations of doxorubicin alone or in combination with a noncytotoxic dose of bortezomib. C) Fresh myeloma cells treated with varying concentrations of melphalan alone or in combination with a noncytotoxic dose of bortezomib. Reproduced with permission from Ma MH, Yang HH, Parker K, et al. The proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemotherapeutic agents. Clin Cancer Res. 2003;9(3):1136–1144.18 Copyright © 2003 American Association for Cancer Research.
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f5B-btt-4-273: The addition of bortezomib to chemotherapeutic agents results in synergistic cytotoxicity in multiple myeloma cells: A) Melphalan-resistant cell line (RPMI8228/LR) treated for 24 hours with varying concentrations of melphalan alone or in combination with a noncytotoxic dose of bortezomib; B) Doxorubicin-resistant cell line (U266/dox4) treated for 24 hours with varying concentrations of doxorubicin alone or in combination with a noncytotoxic dose of bortezomib. C) Fresh myeloma cells treated with varying concentrations of melphalan alone or in combination with a noncytotoxic dose of bortezomib. Reproduced with permission from Ma MH, Yang HH, Parker K, et al. The proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemotherapeutic agents. Clin Cancer Res. 2003;9(3):1136–1144.18 Copyright © 2003 American Association for Cancer Research.

Mentions: As the safety and efficacy results for bortezomib monotherapy were accumulating, combination therapy was being explored in the preclinical setting. Hideshima et al found that the growth inhibitory effects of bortezomib and dexamethasone on a myeloma cell line were additive (Figure 5A).6 Ma et al found that the addition of a noncytotoxic dose of bortezomib to chemotherapeutic agents could increase the sensitivity of chemoresistant myeloma cells by 100,000 to 1,000,000-fold without affecting normal hematopoietic cells (Figure 5B).18


Proteasome inhibition and its therapeutic potential in multiple myeloma.

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

The addition of bortezomib to chemotherapeutic agents results in synergistic cytotoxicity in multiple myeloma cells: A) Melphalan-resistant cell line (RPMI8228/LR) treated for 24 hours with varying concentrations of melphalan alone or in combination with a noncytotoxic dose of bortezomib; B) Doxorubicin-resistant cell line (U266/dox4) treated for 24 hours with varying concentrations of doxorubicin alone or in combination with a noncytotoxic dose of bortezomib. C) Fresh myeloma cells treated with varying concentrations of melphalan alone or in combination with a noncytotoxic dose of bortezomib. Reproduced with permission from Ma MH, Yang HH, Parker K, et al. The proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemotherapeutic agents. Clin Cancer Res. 2003;9(3):1136–1144.18 Copyright © 2003 American Association for Cancer Research.
© Copyright Policy
Related In: Results  -  Collection

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

f5B-btt-4-273: The addition of bortezomib to chemotherapeutic agents results in synergistic cytotoxicity in multiple myeloma cells: A) Melphalan-resistant cell line (RPMI8228/LR) treated for 24 hours with varying concentrations of melphalan alone or in combination with a noncytotoxic dose of bortezomib; B) Doxorubicin-resistant cell line (U266/dox4) treated for 24 hours with varying concentrations of doxorubicin alone or in combination with a noncytotoxic dose of bortezomib. C) Fresh myeloma cells treated with varying concentrations of melphalan alone or in combination with a noncytotoxic dose of bortezomib. Reproduced with permission from Ma MH, Yang HH, Parker K, et al. The proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemotherapeutic agents. Clin Cancer Res. 2003;9(3):1136–1144.18 Copyright © 2003 American Association for Cancer Research.
Mentions: As the safety and efficacy results for bortezomib monotherapy were accumulating, combination therapy was being explored in the preclinical setting. Hideshima et al found that the growth inhibitory effects of bortezomib and dexamethasone on a myeloma cell line were additive (Figure 5A).6 Ma et al found that the addition of a noncytotoxic dose of bortezomib to chemotherapeutic agents could increase the sensitivity of chemoresistant myeloma cells by 100,000 to 1,000,000-fold without affecting normal hematopoietic cells (Figure 5B).18

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