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      Bortezomib (Velcade™) in the Treatment of Multiple Myeloma

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          Abstract

          The introduction of bortezomib, a novel first-in-class proteasome inhibitor, has been a major break through in the treatment of multiple myeloma. It is currently approved for the treatment of myeloma in the relapsed setting post transplant or as a second line treatment in patients unsuitable for transplantation. In pre-clinical studies bortezomib showed a number of different anti-myeloma effects including disruption of the cell cycle and induction of apoptosis, alteration of the bone marrow microenvironment and inhibition of nuclear factor kappa B (NFκB). Due to its novel mechanism of action, bortezomib has been shown to induce responses in previously refractory patients (including those with poor risk cytogenetics), and results in an increased progression free and overall survival in relapsed patients when compared with dexamethasone treatment alone. It is well tolerated and can be administered in the outpatient setting with manageable toxicities. Peripheral neuropathy is the most common dose limiting toxicity and thrombocytopenia can generally be managed with platelet transfusions without reducing or omitting doses. Bortezomib shows a synergistic effect in combination with dexamethasone and also sensitises myeloma cells to the effects of other chemotherapeutic agents with major response rates of over 50% being shown in the relapsed setting. Initial data from ongoing trials in front line therapy are encouraging with response rates of 80%–90% when bortezomib is given in combination with other agents and importantly, the ability to mobilize peripheral blood stem cells is not impaired.

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          Most cited references 61

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          NF-kappaB in cancer: from innocent bystander to major culprit.

          Nuclear factor of kappaB (NF-kappaB) is a sequence-specific transcription factor that is known to be involved in the inflammatory and innate immune responses. Although the importance of NF-KB in immunity is undisputed, recent evidence indicates that NF-kappaB and the signalling pathways that are involved in its activation are also important for tumour development. NF-kappaB should therefore receive as much attention from cancer researchers as it has already from immunologists.
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            The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells.

            Human multiple myeloma (MM) is a presently incurable hematological malignancy, and novel biologically based therapies are urgently needed. Proteasome inhibitors represent a novel potential anticancer therapy. In this study, we demonstrate that the proteasome inhibitor PS-341 directly inhibits proliferation and induces apoptosis of human MM cell lines and freshly isolated patient MM cells; inhibits mitogen-activated protein kinase growth signaling in MM cells; induces apoptosis despite induction of p21 and p27 in both p53 wild-type and p53 mutant MM cells; overcomes drug resistance; adds to the anti-MM activity of dexamethasone; and overcomes the resistance to apoptosis in MM cells conferred by interleukin-6. PS-341 also inhibits the paracrine growth of human MM cells by decreasing their adherence to bone marrow stromal cells (BMSCs) and related nuclear factor kappaB-dependent induction of interleukin-6 secretion in BMSCs, as well as inhibiting proliferation and growth signaling of residual adherent MM cells. These data, therefore, demonstrate that PS-341 both acts directly on MM cells and alters cellular interactions and cytokine secretion in the BM millieu to inhibit tumor cell growth, induce apoptosis, and overcome drug resistance. Given the acceptable animal and human toxicity profile of PS-341, these studies provide the framework for clinical evaluation of PS-341 to improve outcome for patients with this universally fatal hematological malignancy.
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              Proteasome inhibitors: a novel class of potent and effective antitumor agents.

              The ubiquitin-proteasome pathway plays a critical role in the regulated degradation of proteins involved in cell cycle control and tumor growth. Dysregulating the degradation of such proteins should have profound effects on tumor growth and cause cells to undergo apoptosis. To test this hypothesis, we developed a novel series of proteasome inhibitors, exemplified by PS-341, which we describe here. As determined by the National Cancer Institute in vitro screen, PS-341 has substantial cytotoxicity against a broad range of human tumor cells, including prostate cancer cell lines. The PC-3 prostate cell line was, therefore, chosen to further examine the antitumor activity of PS-341. In vitro, PS-341 elicits proteasome inhibition, leading to an increase in the intracellular levels of specific proteins, including the cyclin-dependent kinase inhibitor, p21. Moreover, exposure of such cells to PS-341 caused them to accumulate in the G2-M phase of the cell cycle and subsequently undergo apoptosis, as indicated by nuclear condensation and poly(ADP-ribose) polymerase cleavage. Following weekly i.v. treatment of PS-341 to mice bearing the PC-3 tumor, a significant decrease (60%) in tumor burden was observed in vivo. Direct injection of PS-341 into the tumor also caused a substantial (70%) decrease in tumor volume with 40% of the drug-treated mice having no detectable tumors at the end of the study. Studies also revealed that i.v. administration of PS-341 resulted in a rapid and widespread distribution of PS-341, with highest levels identified in the liver and gastrointestinal tract and lowest levels in the skin and muscle. Modest levels were found in the prostate, whereas there was no apparent penetration of the central nervous system. An assay to follow the biological activity of the PS-341 was established and used to determine temporal drug activity as well as its ability to penetrate tissues. As such, PS-341 was shown to penetrate PC-3 tumors and inhibit intracellular proteasome activity 1.0 h after i.v. dosing. These data illustrate that PS-341 not only reaches its biological target but has a direct effect on its biochemical target, the proteasome. Importantly, the data show that inhibition of this target site by PS-341 results in reduced tumor growth in murine tumor models. Together, the results highlight that the proteasome is a novel biochemical target and that inhibitors such as PS-341 represent a unique class of antitumor agents. PS-341 is currently under clinical evaluation for advanced cancers.
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                September 2006
                September 2006
                : 2
                : 3
                : 271-279
                Affiliations
                Haemato-oncology Unit, Royal Marsden Hospital Downs Road, Sutton, Surrey, UK
                Author notes
                Correspondence: Faith E Davies, Haemato-oncology Unit, Royal Marsden Hospital, Downs Road, Sutton, Surrey, UK Tel +44 20 8661 3672 Fax +44 20 8642 9634 Email Faith.Davies@ 123456icr.ac.uk
                Article
                1936263
                18360602
                © 2006 Dove Medical Press Limited. All rights reserved
                Categories
                Review

                Medicine

                bortezomib, myeloma, proteasome inhibition, treatment

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